Biomedicines

11 pages, 2140 KiB

Open AccessArticle

The Hydroxypyridinone Iron Chelator DIBI Reduces Bacterial Load and Inflammation in Experimental Lung Infection

by Xiyang Zhang, Rhea Nickerson, Lauren Burton, Ashley Stueck, Bruce Holbein, Zhenyu Cheng, Juan Zhou and Christian Lehmann

Biomedicines 2024, 12(7), 1452; https://doi.org/10.3390/biomedicines12071452 (registering DOI) - 29 Jun 2024

Abstract

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. [...] Read more.

Iron plays a critical role in lung infections due to its function in the inflammatory immune response but also as an important factor for bacterial growth. Iron chelation represents a potential therapeutic approach to inhibit bacterial growth and pathologically increased pro-inflammatory mediator production. The present study was designed to investigate the impact of the iron chelator DIBI in murine lung infection induced by intratracheal Pseudomonas aeruginosa (strain PA14) administration. DIBI is a polymer with a polyvinylpyrrolidone backbone containing nine 3-hydroxy-1-(methacrylamidoethyl)-2-methyl-4(1H) pyridinone (MAHMP) residues per molecule and was given by intraperitoneal injection either as a single dose (80 mg/kg) immediately after PA14 administration or a double dose (second dose 4 h after PA14 administration). The results showed that lung NF-κBp65 levels, as well as levels of various inflammatory cytokines (TNFα, IL-1β, IL-6) both in lung tissue and bronchoalveolar lavage fluid (BALF), were significantly increased 24 h after PA14 administration. Single-dose DIBI did not affect the bacterial load or inflammatory response in the lungs or BALF. However, two doses of DIBI significantly decreased bacterial load, attenuated NF-κBp65 upregulation, reduced inflammatory cytokines production, and relieved lung tissue damage. Our findings support the conclusion that the iron chelator, DIBI, can reduce lung injury induced by P. aeruginosa, via its anti-bacterial and anti-inflammatory effects. Full article

(This article belongs to the Special Issue Leukocyte-Endothelial Interactions within the Microcirculation)

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1 pages, 134 KiB

Open AccessCorrection

Correction: De La Franier et al. Long-Term Reduction of Bacterial Adhesion on Polyurethane by an Ultra-Thin Surface Modifier. Biomedicines 2022, 10, 979

by Brian De La Franier, Dalal Asker, Benjamin Hatton and Michael Thompson

Biomedicines 2024, 12(7), 1451; https://doi.org/10.3390/biomedicines12071451 (registering DOI) - 28 Jun 2024

Abstract

In the published publication [...] Full article

(This article belongs to the Special Issue New Techniques and Materials for Biomedical Applications)

17 pages, 992 KiB

Open AccessArticle

Resistant Starch-Encapsulated Probiotics Attenuate Colorectal Cancer Cachexia and 5-Fluorouracil-Induced Microbial Dysbiosis

by Jui-Ling Wang, Yu-Siang Chen, Kuo-Chin Huang, Chin-Hsing Yeh, Miles Chih-Ming Chen, Lawrence Shih-Hsin Wu and Yi-Han Chiu

Biomedicines 2024, 12(7), 1450; https://doi.org/10.3390/biomedicines12071450 (registering DOI) - 28 Jun 2024

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Abstract

5-Fluorouracil (5-FU) is commonly used as the primary chemotherapy for colorectal cancer (CRC). However, it can lead to unwanted chemoresistance. Resistant starch (RS), which functions similarly to fermentable dietary fiber, has the potential to reduce the risk of CRC. The effects of RS [...] Read more.

5-Fluorouracil (5-FU) is commonly used as the primary chemotherapy for colorectal cancer (CRC). However, it can lead to unwanted chemoresistance. Resistant starch (RS), which functions similarly to fermentable dietary fiber, has the potential to reduce the risk of CRC. The effects of RS on improving CRC-associated cachectic symptoms and 5-FU chemotherapy-induced microbial dysbiosis remain unknown. Female BALB/cByJNarl mice were randomly divided into four groups: one tumor group (with CT26 colonic carcinoma but no treatment) and three CT26 colonic carcinoma-bearing groups that were administered 20 mg/kg 5-FU (T+5-FU group), a probiotic cocktail (4 × 10⁸ CFUs) plus chemotherapy (T+5-FU+Pro), or resistant-starch-encapsulated probiotics plus chemotherapy (T+5-FU+RS-Pro). T+5-FU and T+5-FU+RS-Pro administration significantly suppressed tumor growth and activated apoptotic cell death in CT26-bearing mice. 5-FU-induced increases in inflammatory cytokines and NF-κB signaling were mitigated by the Pro or RS-Pro supplementation. A gut microbial composition comparison indicated that the abundance of intestinal bacteria in the T and T+5-FU groups decreased significantly, while the groups receiving Pro or RS-Pro maintained a greater abundance and healthy gut microbiota composition, suggesting that RS can reduce the microbial dysbiosis that occurs during 5-FU chemotherapy. The use of RS-Pro before chemotherapy should be considered for the regulation of chemotherapy-associated cachectic symptoms, inflammation, and chemotherapy-induced microbial dysbiosis. Full article

(This article belongs to the Special Issue Disease Biomarkers in the Precision Medicine Era: A Comprehensive Multi-omics Analysis)

17 pages, 6364 KiB

Open AccessArticle

The Strong Activation of p53 Tumor Suppressor Drives the Synthesis of the Enigmatic Isoform of DUSP13 Protein

by Małgorzata Krześniak, Barbara Łasut-Szyszka, Agnieszka Będzińska, Agnieszka Gdowicz-Kłosok and Marek Rusin

Biomedicines 2024, 12(7), 1449; https://doi.org/10.3390/biomedicines12071449 (registering DOI) - 28 Jun 2024

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Abstract

The p53 tumor suppressor protein activates various sets of genes depending on its covalent modifications, which are controlled by the nature and intensity of cellular stress. We observed that actinomycin D and nutlin-3a (A + N) collaborate in inducing activating phosphorylation of p53. [...] Read more.

The p53 tumor suppressor protein activates various sets of genes depending on its covalent modifications, which are controlled by the nature and intensity of cellular stress. We observed that actinomycin D and nutlin-3a (A + N) collaborate in inducing activating phosphorylation of p53. Our recent transcriptomic data demonstrated that these substances strongly synergize in the upregulation of DUSP13, a gene with an unusual pattern of expression, coding for obscure phosphatase having two isoforms, one expressed in the testes and the other in skeletal muscles. In cancer cells exposed to A + N, DUSP13 is expressed from an alternative promoter in the intron, resulting in the expression of an isoform named TMDP-L1. Luciferase reporter tests demonstrated that this promoter is activated by both endogenous and ectopically expressed p53. We demonstrated for the first time that mRNA expressed from this promoter actually produces the protein, which can be detected with Western blotting, in all examined cancer cell lines with wild-type p53 exposed to A + N. In some cell lines, it is also induced by clinically relevant camptothecin, by nutlin-3a acting alone, or by a combination of actinomycin D and other antagonists of p53-MDM2 interaction—idasanutlin or RG7112. This isoform, fused with green fluorescent protein, localizes in the perinuclear region of cells. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular and Translational Medicine in Poland, 3rd Edition)

17 pages, 579 KiB

Open AccessReview

Advanced and Metastatic Non-Melanoma Skin Cancer: Epidemiology, Risk Factors, Clinical Features, and Treatment Options

by Zoe Gabrielle Attal, Walid Shalata, Arina Soklakova, Lena Tourkey, Sondos Shalata, Omar Abu Saleh, Fahed Abu Salamah, Ibrahim Alatawneh and Alexander Yakobson

Biomedicines 2024, 12(7), 1448; https://doi.org/10.3390/biomedicines12071448 (registering DOI) - 28 Jun 2024

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Abstract

Non-melanoma skin cancers (NMSC) form the majority of skin cancers, with basal cell carcinoma (BCC) being the most common and cutaneous squamous cell carcinoma (cSCC) being second. Prolonged ultraviolet (UV) exposure, aging, male gender, and immunosuppression represent most of the causes of this [...] Read more.

Non-melanoma skin cancers (NMSC) form the majority of skin cancers, with basal cell carcinoma (BCC) being the most common and cutaneous squamous cell carcinoma (cSCC) being second. Prolonged ultraviolet (UV) exposure, aging, male gender, and immunosuppression represent most of the causes of this category of diseases. BCCs and cSCCs both include different types of skin cancers, such as nodular or morpheaform BCC or flat cSCC. Locally advanced and metastatic NMSCs cannot be treated surgically; thus, systemic therapy (TKI and Immunotherapy) is needed. Interestingly, NMSCs are frequently linked to abnormal Hedgehog (HH) signaling which most systemic immunotherapies for these cancers are based upon. Of note, the first line therapies of BCC, sonidegib and vismodegib, are HH inhibitors. Programmed death receptor 1 antibody (PD-1) inhibitors such as cemiplimab, pembrolizumab, and nivolumab have been approved for the treatment of cSCC. Thus, this paper reviews the epidemiology, risk factors, clinical features, and treatment options for both BCC and cSCC. Full article

(This article belongs to the Special Issue Mechanisms of Cell Death in Cancer Cells: A New Therapeutic Opportunity—2nd Edition)

21 pages, 1941 KiB

Open AccessArticle

Surface-Enhanced Raman Spectroscopy Combined with Multivariate Analysis for Fingerprinting Clinically Similar Fibromyalgia and Long COVID Syndromes

by Shreya Madhav Nuguri, Kevin V. Hackshaw, Silvia de Lamo Castellvi, Yalan Wu, Celeste Matos Gonzalez, Chelsea M. Goetzman, Zachary D. Schultz, Lianbo Yu, Rija Aziz, Michelle M. Osuna-Diaz, Katherine R. Sebastian, W. Michael Brode, Monica M. Giusti and Luis Rodriguez-Saona

Biomedicines 2024, 12(7), 1447; https://doi.org/10.3390/biomedicines12071447 (registering DOI) - 28 Jun 2024

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Abstract

Fibromyalgia (FM) is a chronic central sensitivity syndrome characterized by augmented pain processing at diffuse body sites and presents as a multimorbid clinical condition. Long COVID (LC) is a heterogenous clinical syndrome that affects 10–20% of individuals following COVID-19 infection. FM and LC [...] Read more.

Fibromyalgia (FM) is a chronic central sensitivity syndrome characterized by augmented pain processing at diffuse body sites and presents as a multimorbid clinical condition. Long COVID (LC) is a heterogenous clinical syndrome that affects 10–20% of individuals following COVID-19 infection. FM and LC share similarities with regard to the pain and other clinical symptoms experienced, thereby posing a challenge for accurate diagnosis. This research explores the feasibility of using surface-enhanced Raman spectroscopy (SERS) combined with soft independent modelling of class analogies (SIMCAs) to develop classification models differentiating LC and FM. Venous blood samples were collected using two supports, dried bloodspot cards (DBS, n = 48 FM and n = 46 LC) and volumetric absorptive micro-sampling tips (VAMS, n = 39 FM and n = 39 LC). A semi-permeable membrane (10 kDa) was used to extract low molecular fraction (LMF) from the blood samples, and Raman spectra were acquired using SERS with gold nanoparticles (AuNPs). Soft independent modelling of class analogy (SIMCA) models developed with spectral data of blood samples collected in VAMS tips showed superior performance with a validation performance of 100% accuracy, sensitivity, and specificity, achieving an excellent classification accuracy of 0.86 area under the curve (AUC). Amide groups, aromatic and acidic amino acids were responsible for the discrimination patterns among FM and LC syndromes, emphasizing the findings from our previous studies. Overall, our results demonstrate the ability of AuNP SERS to identify unique metabolites that can be potentially used as spectral biomarkers to differentiate FM and LC. Full article

(This article belongs to the Special Issue Advanced Research on Fibromyalgia (2nd Edition))

18 pages, 887 KiB

Open AccessReview

Glycosylation and Its Role in Immune Checkpoint Proteins: From Molecular Mechanisms to Clinical Implications

by Jingyi Liu, Ximo Xu, Hao Zhong, Mengqin Yu, Naijipu Abuduaini, Sen Zhang, Xiao Yang and Bo Feng

Biomedicines 2024, 12(7), 1446; https://doi.org/10.3390/biomedicines12071446 (registering DOI) - 28 Jun 2024

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Abstract

Immune checkpoint proteins have become recent research hotspots for their vital role in maintaining peripheral immune tolerance and suppressing immune response function in a wide range of tumors. Therefore, investigating the immunomodulatory functions of immune checkpoints and their therapeutic potential for clinical use [...] Read more.

Immune checkpoint proteins have become recent research hotspots for their vital role in maintaining peripheral immune tolerance and suppressing immune response function in a wide range of tumors. Therefore, investigating the immunomodulatory functions of immune checkpoints and their therapeutic potential for clinical use is of paramount importance. The immune checkpoint blockade (ICB) is an important component of cancer immunotherapy, as it targets inhibitory immune signaling transduction with antagonistic antibodies to restore the host immune response. Anti-programmed cell death-1 (PD-1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) monoclonal antibodies are two main types of widely used ICBs that drastically improve the survival and prognosis of many patients with cancer. Nevertheless, the response rate of most cancer types remains relatively low due to the drug resistance of ICBs, which calls for an in-depth exploration to improve their efficacy. Accumulating evidence suggests that immune checkpoint proteins are glycosylated in forms of N-glycosylation, core fucosylation, or sialylation, which affect multiple biological functions of proteins such as protein biosynthesis, stability, and interaction. In this review, we give a brief introduction to several immune checkpoints and summarize primary molecular mechanisms that modulate protein stability and immunosuppressive function. In addition, newly developed methods targeting glycosylation on immune checkpoints for detection used to stratify patients, as well as small-molecule agents disrupting receptor–ligand interactions to circumvent drug resistance of traditional ICBs, in order to increase the clinical efficacy of immunotherapy strategies of patients with cancer, are also included to provide new insights into scientific research and clinical treatments. Full article

(This article belongs to the Section Immunology and Immunotherapy)

12 pages, 584 KiB

Open AccessArticle

Study of Periodontal Bacteria in Diabetic Wistar Rats: Assessing the Anti-Inflammatory Effects of Carvacrol and Magnolol Hydrogels

by Georgiana Ioana Potra Cicalău, Olivia Andreea Marcu, Timea Claudia Ghitea, Gabriela Ciavoi, Raluca Cristina Iurcov, Corina Beiusanu, Daniela Florina Trifan, Laura Grațiela Vicaș and Mariana Ganea

Biomedicines 2024, 12(7), 1445; https://doi.org/10.3390/biomedicines12071445 (registering DOI) - 28 Jun 2024

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Abstract

Periodontal disease and diabetes often co-occur; both are characterized by chronic inflammation. This study aimed to investigate the anti-inflammatory effects of carvacrol and magnolol when incorporated into a periodontal hydrogel and topically applied to Wistar rats with diabetes-associated periodontal disease. Forty male albino [...] Read more.

Periodontal disease and diabetes often co-occur; both are characterized by chronic inflammation. This study aimed to investigate the anti-inflammatory effects of carvacrol and magnolol when incorporated into a periodontal hydrogel and topically applied to Wistar rats with diabetes-associated periodontal disease. Forty male albino Wistar rats were divided into four groups: PD (induced diabetes and periodontitis), PDC (induced diabetes and periodontitis treated with carvacrol), PDM (induced diabetes and periodontitis treated with magnolol), and PDCM (induced diabetes and periodontitis treated with both carvacrol and magnolol). Post treatment, gingival tissue samples were collected to measure levels of the pro-inflammatory cytokines IL-6 and TNF-α. The PDCM group exhibited significantly lower levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) compared to the PD group. The combined application of a periodontal hydrogel containing carvacrol and magnolol may significantly reduce gingival inflammation in rats with diabetes-associated periodontal disease. Full article

(This article belongs to the Section Microbiology in Human Health and Disease)

15 pages, 7587 KiB

Open AccessArticle

Hydrogen-Rich Water (HRW) Reduces Fatty Acid-Induced Lipid Accumulation and Oxidative Stress Damage through Activating AMP-Activated Protein Kinase in HepG2 Cells

by Sing-Hua Tsou, Sheng-Chieh Lin, Wei-Jen Chen, Hui-Chih Hung, Chun-Cheng Liao, Edy Kornelius, Chien-Ning Huang, Chih-Li Lin and Yi-Sun Yang

Biomedicines 2024, 12(7), 1444; https://doi.org/10.3390/biomedicines12071444 (registering DOI) - 28 Jun 2024

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Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive fat accumulation in the liver. Intracellular oxidative stress induced by lipid accumulation leads to various hepatocellular injuries including fibrosis. However, no effective method for mitigating MASLD without substantial side effects currently exists. Molecular [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by excessive fat accumulation in the liver. Intracellular oxidative stress induced by lipid accumulation leads to various hepatocellular injuries including fibrosis. However, no effective method for mitigating MASLD without substantial side effects currently exists. Molecular hydrogen (H₂) has garnered attention due to its efficiency in neutralizing harmful reactive oxygen species (ROS) and its ability to penetrate cell membranes. Some clinical evidence suggests that H₂ may alleviate fatty liver disease, but the precise molecular mechanisms, particularly the regulation of lipid droplet (LD) metabolism, remain unclear. This study utilized an in vitro model of hepatocyte lipid accumulation induced by free fatty acids (FFAs) to replicate MASLD in HepG2 cells. The results demonstrated a significant increase in LD accumulation due to elevated FFA levels. However, the addition of hydrogen-rich water (HRW) effectively reduced LD accumulation. HRW decreased the diameter of LDs and reduced lipid peroxidation and FFA-induced oxidative stress by activating the AMPK/Nrf2/HO-1 pathway. Overall, our findings suggest that HRW has potential as an adjunctive supplement in managing fatty liver disease by reducing LD accumulation and enhancing antioxidant pathways, presenting a novel strategy for impeding MASLD progression. Full article

(This article belongs to the Special Issue Metabolic Diseases Regulators)

24 pages, 4889 KiB

Open AccessArticle

Respiratory SARS-CoV-2 Infection Causes Skeletal Muscle Atrophy and Long-Lasting Energy Metabolism Suppression

by Sachiko T. Homma, Xingyu Wang, Justin J. Frere, Adam C. Gower, Jingsong Zhou, Jean K. Lim, Benjamin R. tenOever and Lan Zhou

Biomedicines 2024, 12(7), 1443; https://doi.org/10.3390/biomedicines12071443 (registering DOI) - 28 Jun 2024

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Abstract

Muscle fatigue represents the most prevalent symptom of long-term COVID, with elusive pathogenic mechanisms. We performed a longitudinal study to characterize histopathological and transcriptional changes in skeletal muscle in a hamster model of respiratory SARS-CoV-2 infection and compared them with influenza A virus [...] Read more.

Muscle fatigue represents the most prevalent symptom of long-term COVID, with elusive pathogenic mechanisms. We performed a longitudinal study to characterize histopathological and transcriptional changes in skeletal muscle in a hamster model of respiratory SARS-CoV-2 infection and compared them with influenza A virus (IAV) and mock infections. Histopathological and bulk RNA sequencing analyses of leg muscles derived from infected animals at days 3, 30, and 60 post-infection showed no direct viral invasion but myofiber atrophy in the SARS-CoV-2 group, which was accompanied by persistent downregulation of the genes related to myofibers, ribosomal proteins, fatty acid β-oxidation, tricarboxylic acid cycle, and mitochondrial oxidative phosphorylation complexes. While both SARS-CoV-2 and IAV infections induced acute and transient type I and II interferon responses in muscle, only the SARS-CoV-2 infection upregulated TNF-α/NF-κB but not IL-6 signaling in muscle. Treatment of C2C12 myotubes, a skeletal muscle cell line, with combined IFN-γ and TNF-α but not with IFN-γ or TNF-α alone markedly impaired mitochondrial function. We conclude that a respiratory SARS-CoV-2 infection can cause myofiber atrophy and persistent energy metabolism suppression without direct viral invasion. The effects may be induced by the combined systemic interferon and TNF-α responses at the acute phase and may contribute to post-COVID-19 persistent muscle fatigue. Full article

(This article belongs to the Special Issue Latest Research in Post-COVID (Long COVID): Pathological and Treatment Studies of Sequelae and Complications—2nd Edition)

26 pages, 5983 KiB

Open AccessArticle

Cannabidiol and Beta-Caryophyllene Combination Attenuates Diabetic Neuropathy by Inhibiting NLRP3 Inflammasome/NFκB through the AMPK/sirT3/Nrf2 Axis

by Islauddin Khan, Sukhmandeep Kaur, Arun K. Rishi, Breana Boire, Mounika Aare and Mandip Singh

Biomedicines 2024, 12(7), 1442; https://doi.org/10.3390/biomedicines12071442 (registering DOI) - 28 Jun 2024

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Abstract

Background: In this study, we investigated in detail the role of cannabidiol (CBD), beta-caryophyllene (BC), or their combinations in diabetic peripheral neuropathy (DN). The key factors that contribute to DN include mitochondrial dysfunction, inflammation, and oxidative stress. Methods: Briefly, streptozotocin (STZ) (55 mg/kg) [...] Read more.

Background: In this study, we investigated in detail the role of cannabidiol (CBD), beta-caryophyllene (BC), or their combinations in diabetic peripheral neuropathy (DN). The key factors that contribute to DN include mitochondrial dysfunction, inflammation, and oxidative stress. Methods: Briefly, streptozotocin (STZ) (55 mg/kg) was injected intraperitoneally to induce DN in Sprague–Dawley rats, and we performed procedures involving Randall Sellito calipers, a Von Frey aesthesiometer, a hot plate, and cold plate methods to determine mechanical and thermal hyperalgesia in vivo. The blood flow to the nerves was assessed using a laser Doppler device. Schwann cells were exposed to high glucose (HG) at a dose of 30 mM to induce hyperglycemia and DCFDA, and JC1 and Mitosox staining were performed to determine mitochondrial membrane potential, reactive oxygen species, and mitochondrial superoxides in vitro. The rats were administered BC (30 mg/kg), CBD (15 mg/kg), or combination via i.p. injections, while Schwann cells were treated with 3.65 µM CBD, 75 µM BC, or combination to assess their role in DN amelioration. Results: Our results revealed that exposure to BC and CBD diminished HG-induced hyperglycemia in Schwann cells, in part by reducing mitochondrial membrane potential, reactive oxygen species, and mitochondrial superoxides. Furthermore, the BC and CBD combination treatment in vivo could prevent the deterioration of the mitochondrial quality control system by promoting autophagy and mitochondrial biogenesis while improving blood flow. CBD and BC treatments also reduced pain hypersensitivity to hyperalgesia and allodynia, with increased antioxidant and anti-inflammatory action in diabetic rats. These in vivo effects were attributed to significant upregulation of AMPK, sirT3, Nrf2, PINK1, PARKIN, LC3B, Beclin1, and TFAM functions, while downregulation of NLRP3 inflammasome, NFκB, COX2, and p62 activity was noted using Western blotting. Conclusions: the present study demonstrated that STZ and HG-induced oxidative and nitrosative stress play a crucial role in the pathogenesis of diabetic neuropathy. We find, for the first time, that a CBD and BC combination ameliorates DN by modulating the mitochondrial quality control system. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids 2.0)

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18 pages, 3018 KiB

Open AccessArticle

Expression of hsa-miRNA-15b, -99b, -181a and Their Relationship to Angiogenesis in Renal Cell Carcinoma

by József Király, Erzsébet Szabó, Petra Fodor, Anna Vass, Mahua Choudhury, Rudolf Gesztelyi, Csaba Szász, Tibor Flaskó, Nikoletta Dobos, Barbara Zsebik, Ákos József Steli, Gábor Halmos and Zsuzsanna Szabó

Biomedicines 2024, 12(7), 1441; https://doi.org/10.3390/biomedicines12071441 - 27 Jun 2024

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Abstract

Background: MicroRNAs (miRNAs) play a regulatory role in various human cancers. The roles of hsa-miR-15a-5p, hsa-miR-99b-5p, and hsa-miR-181a-5p have not been fully explored in the angiogenesis of renal cell carcinoma (RCC). Aims: The present study aimed to evaluate the expression of these miRNAs [...] Read more.

Background: MicroRNAs (miRNAs) play a regulatory role in various human cancers. The roles of hsa-miR-15a-5p, hsa-miR-99b-5p, and hsa-miR-181a-5p have not been fully explored in the angiogenesis of renal cell carcinoma (RCC). Aims: The present study aimed to evaluate the expression of these miRNAs in tumorous and adjacent healthy tissues of RCC. Methods: Paired tumorous and adjacent normal kidney tissues from 20 patients were studied. The expression levels of hsa-miR-15b-5p, hsa-miR-99b-5p, and hsa-miR-181a-5p were quantified by TaqMan miRNA Assays. Putative targets were analyzed by qRT-PCR. Results: Significant downregulation of all three miRNAs investigated was observed in tumorous samples compared to adjacent normal kidney tissues. Spearman analysis showed a negative correlation between the expression levels of miRNAs and the pathological grades of the patients. Increased expression of vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α), a tissue inhibitor of metalloproteinases-1 (TIMP-1), was observed in tumorous samples compared to adjacent normal tissues. Depletion of tissue inhibitors of metalloproteinase-2 (TIMP-2) and metalloproteinase-2 (MMP-2) was detected compared to normal adjacent tissues. The examined miRNAs might function as contributing factors to renal carcinogenesis. However, more prospective studies are warranted to evaluate the potential role of miRNAs in RCC angiogenesis. Full article

(This article belongs to the Special Issue Renal Cell Carcinoma: From Pathophysiology to Novel Therapeutic Approaches (3rd Edition))

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14 pages, 411 KiB

Open AccessArticle

The Analysis of ECE1 and PPARG Variants in the Development of Osteopenia and Osteoporosis in Postmenopausal Women

by Izabela Uzar, Anna Bogacz, Małgorzata Łuszczyńska, Marlena Wolek, Katarzyna Kotrych, Andrzej Modrzejewski, Bogusław Czerny, Paweł Ziętek and Adam Kamiński

Biomedicines 2024, 12(7), 1440; https://doi.org/10.3390/biomedicines12071440 - 27 Jun 2024

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Abstract

Osteoporosis is a multifactorial systemic skeletal disease that is characterized by a low bone mineral density (BMD) and the microarchitectural deterioration of bone tissue, leading to bone fragility. The search for new genes that may play an important role in the regulation of [...] Read more.

Osteoporosis is a multifactorial systemic skeletal disease that is characterized by a low bone mineral density (BMD) and the microarchitectural deterioration of bone tissue, leading to bone fragility. The search for new genes that may play an important role in the regulation of bone mass and the development of osteoporosis is ongoing. Recently, it was found that altering the activity of the endothelin-1-converting enzyme encoded by the ECE1 gene may affect bone mineral density (BMD). Another gene involved in the process of osteoblast differentiation and maturation is believed to be PPARG (peroxisome proliferator-activated receptor gamma). This participates in regulating the transformation of stem cells and affects the process of bone formation and resorption. Therefore, we analyzed the association of the ECE1 and PPARG variants with osteopenia and osteoporosis risk in the Polish population. This study included a group (n = 608) of unrelated Polish women (245 individuals with osteoporosis (aged: 57 ± 9), 109 individuals with osteopenia (aged: 53 ± 8) and 254 healthy controls (aged: 54 ± 8)). The real-time PCR technique was used to determine the genetic variants for rs213045 (-338G>T) and rs213046 (-839A>C) of the ECE1 gene and rs1801282 (Pro12Ala, C>G) of the PPARG gene. Analysis of the PPARG rs1801282 variants did not show any association with the risk of osteoporosis and osteopenia. However, in the densitometric results, lower median Z-score values were observed for the T allele compared to the G allele for the rs213045 variant of the ECE1 gene (−1.11 ± 1.07 vs. −0.78 ± 1.21, p = 0.021). Moreover, the TT genotype for the rs213045 variant was more common in women with osteopenia (13.8%, OR = 2.82, p < 0.05) and osteoporosis (7.8%, OR = 1.38, p > 0.05) compared to the control group (5.5%). Additionally, our results suggested that the T allele of rs213045 was more common in women with osteopenia compared to the controls. We further observed that the haplotype containing two major GA alleles of ECE1 (rs213045, rs213046) could reduce the risk of osteopenia in our population. Finally, we found that women with osteoporosis had statistically significantly lower body mass and BMI values compared to the control group. Our results suggest that the ECE1 rs213045 variant may increase the risk of osteopenia. However, the data obtained require confirmation in further studies. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Bone and Cartilage Diseases 2.0)

21 pages, 2574 KiB

Open AccessArticle

Suppressing Pro-Apoptotic Proteins by siRNA in Corneal Endothelial Cells Protects against Cell Death

by Susanne Staehlke, Siddharth Mahajan, Daniel Thieme, Peter Trosan and Thomas A. Fuchsluger

Biomedicines 2024, 12(7), 1439; https://doi.org/10.3390/biomedicines12071439 - 27 Jun 2024

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Abstract

Corneal endothelial cells (CE) are critical for the cornea’s transparency. For severe corneal damage, corneal tissue transplantation is the most promising option for restoring vision. However, CE apoptotic cell death occurs during the storage of donor corneas for transplantation. This study used small [...] Read more.

Corneal endothelial cells (CE) are critical for the cornea’s transparency. For severe corneal damage, corneal tissue transplantation is the most promising option for restoring vision. However, CE apoptotic cell death occurs during the storage of donor corneas for transplantation. This study used small interfering (si)RNA-mediated silencing of pro-apoptotic proteins as a novel strategy to protect CE against apoptosis. Therefore, the pro-apoptotic proteins Bax and Bak were silenced in the human corneal endothelial cell line (HCEC-12) by transfection with Accell™siRNA without any adverse effects on cell viability. When apoptosis was induced, e.g., etoposide, the caspase-3 activity and Annexin V-FITC/PI assay indicated a significantly reduced apoptosis rate in Bax+Bak-siRNA transfected HCECs compared to control (w/o siRNA). TUNEL assay in HCECs exposed also significantly lower cell death in Bax+Bak-siRNA (7.5%) compared to control (w/o siRNA: 32.8%). In ex vivo donor corneas, a significant reduction of TUNEL-positive CEs in Bax+Bak-siRNA corneas (8.1%) was detectable compared to control-treated corneas (w/o siRNA: 27.9%). In this study, we demonstrated that suppressing pro-apoptotic siRNA leads to inhibiting CE apoptosis. Gene therapy with siRNA may open a new translational approach for corneal tissue treatment in the eye bank before transplantation, leading to graft protection and prolonged graft survival. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomedicines—Ophthalmology Disorders)

11 pages, 594 KiB

Open AccessArticle

Spontaneous Reduction in the Intermetatarsal Angle in Distal First Metatarsal Osteotomies with No Lateral Head Displacement in Hallux Valgus

by Jean-Yves Coillard, Romain Rey, Alessandro Civinini, Fabien Billuart, Eli Schmidt, Cesar de Cesar Netto, Riccardo Sacco and Matthieu Lalevée

Biomedicines 2024, 12(7), 1438; https://doi.org/10.3390/biomedicines12071438 - 27 Jun 2024

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Abstract

Background: The outcomes of first metatarsal (M1) distal osteotomies in hallux valgus (HV) can be improved, especially for intermetatarsal angle (IMA) correction, which is mainly based on lateral displacement of the M1 head (i.e., translation) through the osteotomy. Conversely, there is a spontaneous [...] Read more.

Background: The outcomes of first metatarsal (M1) distal osteotomies in hallux valgus (HV) can be improved, especially for intermetatarsal angle (IMA) correction, which is mainly based on lateral displacement of the M1 head (i.e., translation) through the osteotomy. Conversely, there is a spontaneous reduction in the IMA in first metatarsophalangeal joint (MTP1) arthrodesis. But we do not know whether this can be applied to distal osteotomies. We propose a distal osteotomy, called 3D chevron, which combines supination and varization of the M1 head. This might realign soft tissues around the MTP1, potentially leading to a spontaneous reduction in the IMA by an analogous mechanism to MTP1 fusion. Therefore, our study aimed to assess whether spontaneous reductions in IMAs exist in distal M1 osteotomies in the absence of lateral translations of M1 heads. Methods: A prospective continuous series of 25 3D chevrons was performed. Two groups were formed during surgery. Patients requiring no M1 head lateral displacement were included in the “successful correction without translation” group, and patients requiring M1 head lateral displacement were included in the “failed correction without translation” group. Radiographic analysis was performed preoperatively and at 1 year postoperatively. Results: Twenty-two women and three men, with a mean age of 44.8 ± 14.2 years and a mean body mass index of 22.6 ± 4.1 kg/m², underwent follow-up at one year after surgery. The “successful correction without translation” group was composed of HV with milder deformities (13/25 HVs, median preoperative IMA = 13 (IQR 2)) compared to the “failed correction without translation” group (median IMA = 16 (IQR 2.25) p < 0.001). Spontaneous reductions in IMAs were observed in the “successful correction without translation” group, with a median decrease in the IMA of 6 degrees (CI95%[5.5; 8.0]; p < 0.001) between preoperative and 1-year radiographs. Conclusion: Distal osteotomies allow for spontaneous reduction in the IMA in HV. First metatarsal head translation through an osteotomy should not be considered as the only procedure to correct IMAs in distal osteotomies. Full article

(This article belongs to the Special Issue Advanced Research on Muscle and Bone Diseases)

16 pages, 3331 KiB

Open AccessArticle

Utility of Radiological Follow Up of Main-Duct Intraductal Papillary Mucinous Neoplasms and Mixed-Type Intraductal Papillary Mucinous Neoplasms

by Roie Tzadok, Rivka Kessner, Einat Ritter, Asaf Aizic, Hila Yashar, Sapir Lazar, Yuval Katz, Zur Ronen-Amsalem, Arthur Chernomorets, Oren Shibolet and Dana Ben-Ami Shor

Biomedicines 2024, 12(7), 1437; https://doi.org/10.3390/biomedicines12071437 - 27 Jun 2024

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Abstract

Background: Intraductal papillary mucinous neoplasms (IPMNs) have the potential to evolve into pancreatic adenocarcinoma (PDAC). While main-duct IPMNs (MD-IPMNs), involving the main pancreatic duct (MPD), are less common than side-branch IPMNs (SB-IPMNs) or mixed-type IPMNs (mixed-IPMNs), their malignant transformation potential is far greater. [...] Read more.

Background: Intraductal papillary mucinous neoplasms (IPMNs) have the potential to evolve into pancreatic adenocarcinoma (PDAC). While main-duct IPMNs (MD-IPMNs), involving the main pancreatic duct (MPD), are less common than side-branch IPMNs (SB-IPMNs) or mixed-type IPMNs (mixed-IPMNs), their malignant transformation potential is far greater. Controversy exists between different guidelines in terms of recommended management strategies. This study was aimed at assessing the utility of the radiological follow up of MD-IPMNs and mixed-type IPMNs, including prevalence of worrisome radiological findings as well as clinical and laboratory parameters, and their correlation with the development of progression or pancreatic adenocarcinoma. Methods: Eighty-four patients with MD-IPMNs or mixed-type IPMNs who underwent at least one magnetic resonance cholangiopancreatography (MRCP) were included. Clinical and laboratory data were obtained retrospectively. A cross-sectional analysis was carried out to establish clinical and laboratory parameters associated with development of PDAC. A retrospective cohort analysis was performed on 44 patients who had at least six months of follow up, trying to identify factors correlating with worrisome radiological features. Results: Nine cases (10.7%) of PDAC were recorded in this cohort. The laboratory and imaging factors associated with cyst size progression greater than 5 mm during follow up were elevated alanine transaminase (ALT) levels, the maximal cyst size, and the MPD diameter. Cross-sectional analysis indicated that PDAC was associated with nausea (p = 0.01), as well as increased levels of aspartate aminotransferase (AST) (p = 0.05), gamma glutamyl transpeptidase (GGT) (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01). Conclusions: Elevated levels of liver enzymes were associated with IPMN progression and, subsequently, the development of PDAC. ALT levels, maximal cyst size, and MPD diameter are associated with the progression of cyst size. These data may aid in risk-stratifying patients when determining the follow up approach for IPMNs. Full article

(This article belongs to the Special Issue New Insights in Gastric, Colorectal, and Pancreatic Cancer)

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15 pages, 7110 KiB

Open AccessArticle

PGC1-Alpha/Sirt3 Signaling Pathway Mediates the Anti-Pulmonary Fibrosis Effect of Hirudin by Inhibiting Fibroblast Senescence

by Bin He, Qian Zeng, Yumei Tian, Yuyang Luo, Minlin Liao, Wenjie Huang, Bin Wu, Ziqiang Luo, Xiaoting Huang, Wei Liu and Siyuan Tang

Biomedicines 2024, 12(7), 1436; https://doi.org/10.3390/biomedicines12071436 - 27 Jun 2024

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease for which there is a lack of effective pharmacological treatments. Hirudin, a natural peptide extracted from leeches, has been used for broad pharmacological purposes. In this study, we investigated the therapeutic effects [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease for which there is a lack of effective pharmacological treatments. Hirudin, a natural peptide extracted from leeches, has been used for broad pharmacological purposes. In this study, we investigated the therapeutic effects of hirudin on IPF and its related mechanism of action. By constructing a mouse model of pulmonary fibrosis and treating it with hirudin in vivo, we found that hirudin exerted anti-fibrotic, anti-oxidative, and anti-fibroblast senescence effects. Moreover, using an in vitro model of stress-induced premature senescence in primary mouse lung fibroblasts and treating with hirudin, we observed inhibition of fibroblast senescence and upregulation of PGC1-alpha and Sirt3 expression. However, specific silencing of PGC1-alpha or Sirt3 suppressed the anti-fibroblast senescence effect of hirudin. Thus, the PGC1-alpha/Sirt3 pathway mediates the anti-fibroblast senescence effect of hirudin, potentially serving as a molecular mechanism underlying its anti-fibrosis and anti-oxidative stress effects exerted on the lungs. Full article

(This article belongs to the Special Issue Pathogenesis, Diagnosis, and Treatment of Respiratory Diseases)

12 pages, 3034 KiB

Open AccessArticle

The Sublingual Microcirculation in Critically Ill Children with Septic Shock Undergoing Hemoadsorption: A Pilot Study

by Gabriella Bottari, Valerio Confalone, Jacques Creteur, Corrado Cecchetti and Fabio Silvio Taccone

Biomedicines 2024, 12(7), 1435; https://doi.org/10.3390/biomedicines12071435 - 27 Jun 2024

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Abstract

Background: The importance of perfusion-guided resuscitation in septic shock has recently emerged. We explored whether the use of hemoadsorption led to a potential beneficial role in microvascular alterations in this clinical setting. Methods: A pre-planned secondary analysis of a Phase-II interventional single-arm [...] Read more.

Background: The importance of perfusion-guided resuscitation in septic shock has recently emerged. We explored whether the use of hemoadsorption led to a potential beneficial role in microvascular alterations in this clinical setting. Methods: A pre-planned secondary analysis of a Phase-II interventional single-arm pilot study (NCT05658588) was carried out, where 17 consecutive septic shock children admitted into PICU were treated with continuous renal replacement therapy (CRRT) and CytoSorb. Thirteen patients were eligible to be investigated with sublingual microcirculation at baseline, 24, 48, 72 and 96 h from the onset of blood purification. Patients achieving a microvascular flow index (MFI) ≥ 2.5 and/or proportion of perfused vessels (PPV) exceeding 90% by 96 h were defined as responders. Results: In 10/13 (77%), there was a significant improvement in MFIs (p = 0.01) and PPVs% (p = 0.04) between baseline and 24 h from the end of treatment. Eight patients displayed a high heterogenicity index (HI > 0.5) during blood purification and among these, five showed an improvement by the end of treatment (HI < 0.5). Conclusions: In this pilot study, we have found a potential association between CytoSorb hemoadsorption and a microcirculation improvement in pediatric patients with septic shock, particularly when this observation has been associated with hemodynamic improvement. Full article

(This article belongs to the Section Molecular and Translational Medicine)

16 pages, 734 KiB

Open AccessArticle

S-Nitroso Human Serum Albumin Enhances Left Ventricle Hemodynamic Performance and Reduces Myocardial Damage after Local Ischemia–Reperfusion Injury

by Daniele Linardi, Seth Hallström, Giovanni Battista Luciani and Alessio Rungatscher

Biomedicines 2024, 12(7), 1434; https://doi.org/10.3390/biomedicines12071434 - 27 Jun 2024

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Abstract

Endothelial nitric oxide (NO) production is crucial in maintaining vascular homeostasis. However, in the context of ischemia–reperfusion (I/R) injury, uncoupled endothelial nitric oxide synthase (eNOS) can exacerbate reactive oxygen species (ROS) generation. Supplementation with S-nitroso human serum albumin (S-NO-HSA) offers a potential solution [...] Read more.

Endothelial nitric oxide (NO) production is crucial in maintaining vascular homeostasis. However, in the context of ischemia–reperfusion (I/R) injury, uncoupled endothelial nitric oxide synthase (eNOS) can exacerbate reactive oxygen species (ROS) generation. Supplementation with S-nitroso human serum albumin (S-NO-HSA) offers a potential solution by mitigating eNOS uncoupling, thereby enhancing NO bioavailability. In a study conducted at the University of Verona, male rats underwent thoracotomy followed by 30 min left anterior descendant coronary (LAD) occlusion and subsequent reperfusion. Hemodynamic parameters were meticulously assessed using a conductance catheter inserted via the carotid artery. The rats were stratified into two main groups based on reperfusion duration and the timing of drug infusion, with the effects of S-NO-HSA evaluated after 2 or 24 h. Remarkably, intravenous administration of S-NO-HSA, initiated before or during ischemia, exhibited notable benefits. It significantly improved left ventricular function, safeguarded energetic substrates such as phosphocreatine and ATP, and sustained glutathione levels akin to basal conditions, indicative of diminished oxidative stress. The data from this study strongly suggest a protective role for S-NO-HSA in mitigating I/R injury induced by LAD artery occlusion, a phenomenon observed at both 2 and 24 h post-reperfusion. These findings underscore the promising therapeutic potential of NO supplementation in alleviating myocardial damage subsequent to ischemic insult. Full article

(This article belongs to the Special Issue Molecular Insights into Myocardial Infarction)

14 pages, 763 KiB

Open AccessArticle

Relationship between Serum Sirtuin 1 and Growth Hormone/Insulin-like Growth Factor 1 Concentrations in Children with Growth Hormone Deficiency and Idiopathic Short Stature

by Anna Fedorczak, Dorota Kowalik, Justyna Kopciuch, Ewa Głowacka, Katarzyna Mikołajczyk, Marcin Tkaczyk, Andrzej Lewiński and Renata Stawerska

Biomedicines 2024, 12(7), 1433; https://doi.org/10.3390/biomedicines12071433 - 27 Jun 2024

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Abstract

Sirtuin 1 (SIRT1) inhibits growth hormone (GH) intracellular signaling for the insulin-like growth factor 1 (IGF-1) synthesis via the janus kinase (JAK)/signal transducer and activator of transcription proteins (STATs) pathway. The aim of this study was to compare SIRT1 concentrations in children with [...] Read more.

Sirtuin 1 (SIRT1) inhibits growth hormone (GH) intracellular signaling for the insulin-like growth factor 1 (IGF-1) synthesis via the janus kinase (JAK)/signal transducer and activator of transcription proteins (STATs) pathway. The aim of this study was to compare SIRT1 concentrations in children with GH deficiency (GHD) and so-called idiopathic short stature (ISS, non-GH deficient), in order to determine the possible impact of changes in serum SIRT1 concentrations on the GH-IGF-1 axis. The study group included 100 short-stature children: 38 with GHD and 62 with ISS (maxGH in two stimulation tests <10 and ≥10 ng/mL, respectively). The control group consisted of 47 healthy, normal-height children. For each child, the concentrations of SIRT1, IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3) were determined and the IGF-1/IGFBP-3 molar ratio was calculated. The level of SIRT1 was significantly higher in both groups of short children than in the controls (p < 0.0001), but there were no differences between GHD and ISS (mean ± SD: 0.89 ± 0.45 for ISS; 1.24 ± 0, 86 for GHD; and 0.29 ± 0.21 for controls). A significant negative correlation was found between SIRT1 and height standard deviation score (SDS), IGF-1 and IGF-1/IGFBP-3, but not between SIRT1 and maxGH. Elevated SIRT1 levels may serve as one of the mechanisms through which the secretion of IGF-1 is reduced in children with short stature; however, further research is required to confirm this issue. Full article

(This article belongs to the Special Issue State-of-the-Art Endocrinology and Metabolism Research in Poland (Volume II))

30 pages, 919 KiB

Open AccessReview

Examining the Efficacy and Safety of Combined Locoregional Therapy and Immunotherapy in Treating Hepatocellular Carcinoma

by Nojan Bajestani, Gavin Wu, Ahmed Hussein and Mina S. Makary

Biomedicines 2024, 12(7), 1432; https://doi.org/10.3390/biomedicines12071432 - 27 Jun 2024

Viewed by 188

Abstract

More than 800,000 people worldwide are diagnosed with HCC (hepatocellular carcinoma) each year, with approximately 700,000 deaths alone occurring in that same year. Treatment of HCC presents complex therapeutic challenges, particularly in intermediate and advanced stages. LRTs such as transarterial chemoembolization (TACE) and [...] Read more.

More than 800,000 people worldwide are diagnosed with HCC (hepatocellular carcinoma) each year, with approximately 700,000 deaths alone occurring in that same year. Treatment of HCC presents complex therapeutic challenges, particularly in intermediate and advanced stages. LRTs such as transarterial chemoembolization (TACE) and ablations have been the mainstay treatment for early to intermediate-stage HCC, and systemic therapies are used to treat intermediate-late-stage HCC. However, novel literature describing combining LRT with systemic therapies has shown promising results. This review explores recent advances in both liver-directed techniques for hepatocellular carcinoma, including bland transarterial embolization, chemoembolization, radioembolization, and ablative therapies in conjunction as well as with systemic therapies, with a focus on combination therapies, patient selection, procedural technique, periprocedural management, and outcomes. Our findings suggest that LRT combined with systemic therapies is a viable strategy for improving progression-free survival and time to progression for patients with intermediate-to-late-stage HCC. However, further investigation is required to refine treatment protocols and define patient cohorts that would benefit the most. Full article

(This article belongs to the Special Issue New Insights into the Diagnosis and Treatment of Hepatocellular Carcinoma)

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31 pages, 1762 KiB

Open AccessArticle

Phytochemical Characterization and Antioxidant Activity Evaluation for Some Plant Extracts in Conjunction with Pharmacological Mechanism Prediction: Insights into Potential Therapeutic Applications in Dyslipidemia and Obesity

by Elena Iuliana Ilie, Liliana Popescu, Emanuela-Alice Luță, Andrei Biță, Alexandru Radu Corbu, Dragoș Paul Mihai, Ana Corina Pogan, Teodora Dalila Balaci, Alexandru Mincă, Ligia Elena Duțu, Octavian Tudorel Olaru, Rica Boscencu and Cerasela Elena Gîrd

Biomedicines 2024, 12(7), 1431; https://doi.org/10.3390/biomedicines12071431 - 27 Jun 2024

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Abstract

Lipid metabolism dysregulation can lead to dyslipidemia and obesity, which are major causes of cardiovascular disease and associated mortality worldwide. The purpose of the study was to obtain and characterize six plant extracts (ACE—Allii cepae extractum; RSE—Rosmarini extractum; CHE— [...] Read more.

Lipid metabolism dysregulation can lead to dyslipidemia and obesity, which are major causes of cardiovascular disease and associated mortality worldwide. The purpose of the study was to obtain and characterize six plant extracts (ACE—Allii cepae extractum; RSE—Rosmarini extractum; CHE—Cichorii extractum; CE—Cynarae extractum; AGE—Apii graveolentis extractum; CGE—Crataegi extractum) as promising adjuvant therapies for the prevention and treatment of dyslipidemia and its related metabolic diseases. Phytochemical screening revealed that RSE was the richest extract in total polyphenols (39.62 ± 13.16 g tannic acid/100 g dry extract) and phenolcarboxylic acids (22.05 ± 1.31 g chlorogenic acid/100 g dry extract). Moreover, the spectrophotometric chemical profile highlighted a significant concentration of flavones for CGE (5.32 ± 0.26 g rutoside/100 g dry extract), in contrast to the other extracts. UHPLC-MS quantification detected considerable amounts of phenolic constituents, especially chlorogenic acid in CGE (187.435 ± 1.96 mg/g extract) and rosmarinic acid in RSE (317.100 ± 2.70 mg/g extract). Rosemary and hawthorn extracts showed significantly stronger free radical scavenging activity compared to the other plant extracts (p < 0.05). Pearson correlation analysis and the heatmap correlation matrix indicated significant correlations between phytochemical contents and in vitro antioxidant activities. Computational studies were performed to investigate the potential anti-obesity mechanism of the studied extracts using target prediction, homology modeling, molecular docking, and molecular dynamics approaches. Our study revealed that rosmarinic acid (RA) and chlorogenic acid (CGA) can form stable complexes with the active site of carbonic anhydrase 5A by either interacting with the zinc-bound catalytic water molecule or by directly binding Zn²⁺. Further studies are warranted to experimentally validate the predicted CA5A inhibitory activities of RA and CGA and to investigate the hypolipidemic and antioxidant activities of the proposed plant extracts in animal models of dyslipidemia and obesity. Full article

(This article belongs to the Special Issue Phytochemicals: Current Status and Future Prospects)

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19 pages, 5700 KiB

Open AccessArticle

Safety, Tolerability, and EEG-Based Target Engagement of STP1 (PDE3,4 Inhibitor and NKCC1 Antagonist) in a Randomized Clinical Trial in a Subgroup of Patients with ASD

by Craig A. Erickson, Laura Perez-Cano, Ernest V. Pedapati, Eric Painbeni, Gregory Bonfils, Lauren M. Schmitt, Hannah Sachs, Meredith Nelson, Lisa De Stefano, Grace Westerkamp, Adriano L. S. de Souza, Oliver Pohl, Offir Laufer, Gil Issachar, Thomas Blaettler, Jean-Marc Hyvelin and Lynn A. Durham

Biomedicines 2024, 12(7), 1430; https://doi.org/10.3390/biomedicines12071430 - 27 Jun 2024

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Abstract

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a [...] Read more.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1’s mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest. Full article

(This article belongs to the Special Issue Diagnostic Biomarkers and Novel Therapeutics Targets for Fragile X Syndrome, Autism Spectrum Disorders and Genetic Neurodevelopmental Diseases: Advances and Challenges)

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9 pages, 1828 KiB

Open AccessArticle

Limited Clinical Impact of Genetic Associations between Celiac Disease and Type 2 Inflammatory Diseases: Insights from Mendelian Randomization

by Mahmud Omar, Mohammad Omar, Salih Nassar, Adi Lahat and Kassem Sharif

Biomedicines 2024, 12(7), 1429; https://doi.org/10.3390/biomedicines12071429 - 27 Jun 2024

Viewed by 185

Abstract

Background: Celiac disease, a gluten-triggered autoimmune disorder, is known for its systemic inflammatory effects. Its genetic associations with type 2 inflammatory diseases like asthma, allergic rhinitis, and atopic dermatitis remain unclear, prompting this study to explore their potential genetic interplay. Methods: Utilizing two-sample [...] Read more.

Background: Celiac disease, a gluten-triggered autoimmune disorder, is known for its systemic inflammatory effects. Its genetic associations with type 2 inflammatory diseases like asthma, allergic rhinitis, and atopic dermatitis remain unclear, prompting this study to explore their potential genetic interplay. Methods: Utilizing two-sample Mendelian randomization (TSMR), we examined the genetic associations using 15 genetic instruments from GWAS datasets. Our analysis focused on celiac disease and its relation to asthma, allergic rhinitis, atopic dermatitis, and IgE-mediated food allergies. A power analysis was conducted to determine the study’s detection capabilities, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using various MR methods. Results: Our Mendelian randomization analysis identified statistically significant genetic associations between celiac disease and several type 2 inflammatory diseases, although these were practically insignificant. Specifically, celiac disease was associated with a slight increase in the risk of atopic dermatitis (OR = 1.037) and a minor protective effect against asthma (OR = 0.97). The link with allergic rhinitis was statistically detectable (OR = 1.002) but practically negligible. Despite robust statistical confirmation through various sensitivity analyses, all observed effects remained within the range of practical equivalence (ROPE). Conclusions: Our study identifies potential genetic associations between celiac disease and certain type 2 inflammatory diseases. However, these associations, predominantly within the ROPE range, suggest only limited clinical implications. These findings highlight the need for cautious interpretation and indicate that further exploration for clinical applications may not be warranted at this stage. Full article

(This article belongs to the Special Issue Allergic Diseases and Asthma: Molecular Diagnosis and Precision Medicine)

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15 pages, 6366 KiB

Open AccessArticle

Adaptive and Compensatory Neural Signatures in Fibromyalgia: An Analysis of Resting-State and Stimulus-Evoked EEG Oscillations

by Lucas Camargo, Kevin Pacheco-Barrios, Lucas M. Marques, Wolnei Caumo and Felipe Fregni

Biomedicines 2024, 12(7), 1428; https://doi.org/10.3390/biomedicines12071428 - 27 Jun 2024

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Abstract

This study aimed to investigate clinical and physiological predictors of brain oscillatory activity in patients with fibromyalgia (FM), assessing resting-state power, event-related desynchronization (ERD), and event-related synchronization (ERS) during tasks. We performed a cross-sectional analysis, including clinical and neurophysiological data from 78 subjects [...] Read more.

This study aimed to investigate clinical and physiological predictors of brain oscillatory activity in patients with fibromyalgia (FM), assessing resting-state power, event-related desynchronization (ERD), and event-related synchronization (ERS) during tasks. We performed a cross-sectional analysis, including clinical and neurophysiological data from 78 subjects with FM. Multivariate regression models were built to explore predictors of electroencephalography bands. Our findings show a negative correlation between beta oscillations and pain intensity; fibromyalgia duration is positively associated with increased oscillatory power at low frequencies and in the beta band; ERS oscillations in the theta and alpha bands seem to be correlated with better symptoms of FM; fatigue has a signature in the alpha band—a positive relationship in resting-state and a negative relationship in ERS oscillations. Specific neural signatures lead to potential clusters of neural adaptation, in which beta oscillatory activity in the resting state represents a more adaptive activity when pain levels are low and stimulus-evoked oscillations at lower frequencies are likely brain compensatory mechanisms. These neurophysiological changes may help to understand the impact of long-term chronic pain in the central nervous system and the descending inhibitory system in fibromyalgia subjects. Full article

(This article belongs to the Special Issue Advancements in Neuroscience: A Special Issue in Honour of Ramón Y Cajal)

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15 pages, 924 KiB

Open AccessArticle

Clinical Genetic Testing for Hearing Loss: Implications for Genetic Counseling and Gene-Based Therapies

by Nam K. Lee, Kristin M. Uhler, Patricia J. Yoon and Regie Lyn P. Santos-Cortez

Biomedicines 2024, 12(7), 1427; https://doi.org/10.3390/biomedicines12071427 - 27 Jun 2024

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Abstract

Genetic factors contribute significantly to congenital hearing loss, with non-syndromic cases being more prevalent and genetically heterogeneous. Currently, 150 genes have been associated with non-syndromic hearing loss, and their identification has improved our understanding of auditory physiology and potential therapeutic targets. Hearing loss [...] Read more.

Genetic factors contribute significantly to congenital hearing loss, with non-syndromic cases being more prevalent and genetically heterogeneous. Currently, 150 genes have been associated with non-syndromic hearing loss, and their identification has improved our understanding of auditory physiology and potential therapeutic targets. Hearing loss gene panels offer comprehensive genetic testing for hereditary hearing loss, and advancements in sequencing technology have made genetic testing more accessible and affordable. Currently, genetic panel tests available at a relatively lower cost are offered to patients who face financial barriers. In this study, clinical and audiometric data were collected from six pediatric patients who underwent genetic panel testing. Known pathogenic variants in MYO15A, GJB2, and USH2A were most likely to be causal of hearing loss. Novel pathogenic variants in the MYO7A and TECTA genes were also identified. Variable hearing phenotypes and inheritance patterns were observed amongst individuals with different pathogenic variants. The identification of these variants contributes to the continually expanding knowledge base on genetic hearing loss and lays the groundwork for personalized treatment options in the future. Full article

(This article belongs to the Special Issue Genetic Research on Hearing Loss 2.0)

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11 pages, 2166 KiB

Open AccessArticle

The Role of Semaphorin 6D (Sema6D) in Non-Muscle-Invasive Bladder Cancer—A Preliminary Study on Human Plasma and Urine

by Piotr Purpurowicz, Tomasz W. Kaminski, Władysław Kordan, Anna J. Korzekwa, Zbigniew Purpurowicz and Zbigniew Jabłonowski

Biomedicines 2024, 12(7), 1426; https://doi.org/10.3390/biomedicines12071426 - 27 Jun 2024

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Abstract

The incidence of bladder cancer worldwide in the last three decades has been increasing in both men and women. So far, there is no established non-invasive bladder cancer biomarker in daily clinical practice. Semaphorin 6D (sema6D) is a transmembrane protein that belongs to [...] Read more.

The incidence of bladder cancer worldwide in the last three decades has been increasing in both men and women. So far, there is no established non-invasive bladder cancer biomarker in daily clinical practice. Semaphorin 6D (sema6D) is a transmembrane protein that belongs to the class VI semaphorins. The aim of this study was to evaluate for the first time the potential role of sema6D in bladder cancer. The study group consisted of 40 patients with non-muscle-invasive bladder cancer (NMIBC) and the control group of 20 patients without malignancies. There was a statistically significantly higher urinary sema6D concentration in patients than controls (p < 0.05) but no significant difference in plasma 6D. There were no statistically significant differences in urinary or plasma concentration of sema6D between low- or high-grade cancer and according to the tumor stage in TNM classification. There was a statistically significant negative correlation between plasma sema6D and age of patients (R = −0.6; p = 0.019). Plasma sema6D does not seem to be useful in the clinical practice at this point. However, the urinary sema6D concentration could potentially serve as a marker of NMIBC used for diagnostic purposes, monitoring, and early relapse detection or the assessment of the treatment efficacy. Urinary sema6D is probably not associated with the grading or staging of NMIBC, so it cannot be used for the prediction of disease prognosis. Full article

(This article belongs to the Special Issue Bladder Cancer: From Pathophysiology to Novel Therapeutic Approaches)

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18 pages, 1686 KiB

Open AccessArticle

Relationship between Carotid Intima-Media Thickness, Periodontal Disease, and Systemic Inflammation Biomarkers in an Adult Population

by Catalina Latorre Uriza, Nelly S. Roa, Juliana Velosa-Porras, Jean Carlos Villamil Poveda, Liliana Otero, Alvaro J. Ruiz and Francina María Escobar Arregoces

Biomedicines 2024, 12(7), 1425; https://doi.org/10.3390/biomedicines12071425 - 27 Jun 2024

Viewed by 213

Abstract

A positive relationship has been reported between advanced periodontitis and carotid intima-media thickness (cIMT) measurement. The aim of this study was to investigate this relationship with parameters for periodontitis, such as PISA and systemic inflammation biomarkers. An observational descriptive cross-sectional study was conducted. [...] Read more.

A positive relationship has been reported between advanced periodontitis and carotid intima-media thickness (cIMT) measurement. The aim of this study was to investigate this relationship with parameters for periodontitis, such as PISA and systemic inflammation biomarkers. An observational descriptive cross-sectional study was conducted. A blood sample was collected from 75 subjects to analyze glucose, total cholesterol, HDL, LDL, and cytokine values. Increased cIMT was found in 32% of the patients with fewer teeth. Patients with periodontitis had a larger periodontal inflamed surface area (PISA) (p = 0.000) and had a 1.42-times-higher risk of having increased cIMT values compared to periodontally healthy individuals, though without a statistically significant association. Higher values in the left cIMT, IL-8, and TNF-α were found in men than in women with significant differences. In the multivariate analysis involving cytokines, age continues to be linked to increased cIMT values. INF-γ showed a trend towards a protective effect; as the IMT-M decreases, there is an increase in the expression of INF-γ, and a higher proportion of subjects with elevated INF-γ concentrations demonstrated normal IMT-C. This study did not find a statistically significant association between cIMT and periodontal disease, but the risk of having increased cIMT is 1.42-times higher for individuals with periodontitis. Full article

(This article belongs to the Special Issue Relationship between Periodontal Disease and Systemic Disease)

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11 pages, 1036 KiB

Open AccessArticle

Differential Impact of Tumor Endothelial Angiopoietin-2 and Podoplanin in Lymphatic Endothelial Cells on HCC Outcomes with Tyrosine Kinase Inhibitor Treatment According to Sex

by Simone Lasagni, Rosina Maria Critelli, Fabiola Milosa, Dario Saltini, Filippo Schepis, Adriana Romanzi, Francesco Dituri, Grazia Serino, Lorenza Di Marco, Alessandra Pivetti, Filippo Scianò, Gianluigi Giannelli and Erica Villa

Biomedicines 2024, 12(7), 1424; https://doi.org/10.3390/biomedicines12071424 - 26 Jun 2024

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Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are [...] Read more.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are the only potential treatment option. Despite extensive research, predictors of response to these therapies remain elusive. This study aimed to analyze the biological and histopathological characteristics of HCC patients treated with TKIs, focusing on angiogenesis and lymphangiogenesis. Immunohistochemistry quantified the expression of angiopoietin-2 (Ang2), lymphatic endothelial cells (LEC) podoplanin, and C-type Lectin Domain Family 2 (CLEC-2), key factors in neoangiogenesis and lymphangiogenesis. An increased expression of endothelial Ang2 and LEC podoplanin predicted a lower risk of metastasis. Female patients had significantly longer overall survival and survival on TKIs, associated with higher tumor expression of endothelial Ang2 and LEC podoplanin. Moreover, LEC podoplanin expression and a longer time on TKIs were independently correlated with improved survival on TKI therapy at Cox regression analysis. These findings suggest that endothelial Ang2 and LEC podoplanin could be potential biomarkers for predicting treatment outcomes and guiding therapeutic strategies in HCC patients treated with TKIs. Full article

(This article belongs to the Special Issue Recent Advances of Receptor Tyrosine Kinases in Solid Tumors)

20 pages, 12134 KiB

Open AccessArticle

Identification and Validation of JAM-A as a Novel Prognostic and Immune Factor in Human Tumors

by Tianyi Ren, You Zheng, Feichang Liu, Chenyu Liu, Bo Zhang, He Ren, Xinyue Gao, Yuexian Wei, Qiang Sun and Hongyan Huang

Biomedicines 2024, 12(7), 1423; https://doi.org/10.3390/biomedicines12071423 - 26 Jun 2024

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Abstract

Junctional adhesion molecule-A (JAM-A), also known as F11 receptor (F11R), is a transmembrane glycoprotein that is involved in various biological processes, including cancer initiation and progression. However, the functional characteristics and significance of JAM-A in pan-cancer remain unexplored. In this study, we used [...] Read more.

Junctional adhesion molecule-A (JAM-A), also known as F11 receptor (F11R), is a transmembrane glycoprotein that is involved in various biological processes, including cancer initiation and progression. However, the functional characteristics and significance of JAM-A in pan-cancer remain unexplored. In this study, we used multiple databases to gain a comprehensive understanding of JAM-A in human cancers. JAM-A was widely expressed in various tissues, mainly located on the microtubules and cell junctions. Aberrant expression of JAM-A was detected in multiple cancers at both mRNA and protein levels, which can be correlated with poorer prognosis and may be attributed to genetic alterations and down-regulated DNA methylation. JAM-A expression was also associated with immune infiltration and may affect immunotherapy responses in several cancers. Functional enrichment analysis indicated that JAM-A participated in tight junction and cancer-related pathways. In vitro experiments verified that JAM-A knockdown suppressed the proliferation and migration abilities of breast cancer cells and liver cancer cells. Overall, our study suggests that JAM-A is a pan-cancer regulator and a potential biomarker for predicting prognosis and immune-therapeutic responses for different tumors. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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Biomedicines, Volume 12, Issue 7 (July 2024) – 75 articles

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