Int. J. Mol. Sci., Volume 24, Issue 2 (January-2 2023) – 912 articles

Early identification of pre-diabetes provides an opportunity for intervention and treatment to delay its progression to type 2 diabetes mellitus (T2DM). We aimed to identify the biomarkers of impaired glucose tolerance (IGT) through bioinformatics analysis. The GSE76896 dataset, including non-diabetic (ND), IGT, and T2DM clinical samples, was deeply analyzed to identify 309 Co-DEGs for IGT and T2DM. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that inflammatory responses and the PI3K-AKT signaling pathway are important patho-physiological features of IGT and T2DM. Protein–protein interaction (PPI) network analysis and cytoHubba technolgy identified seven hub genes: namely, CCL2, CXCL1, CXCL8, EDN1, FGF13, MMP1, and NGF. The expression and ROC curves of these hub genes were validated using the GSE38642 dataset. Through an immunofluorescence assay, we found that the expression of FGF13 in islets of mice in the HFD and T2DM groups was significantly lower than in the control group. Similarly, the level of FGF13 in the sera of IGT and T2DM patients was lower than that in the healthy group. Together, these results suggest that FGF13 can be treated as a novel biomarker of IGT, which may provide new targets for the diagnosis and treatment of pre-diabetes and T2DM. Full article

The gut microbiota and its derived metabolites greatly impact the host immune system, both innate and adaptive responses. Gut dysbiosis and altered levels of microbiota-derived metabolites have been described in several immune-related and immune-mediated diseases such as intestinal bowel disease, multiple sclerosis, or colorectal cancer. Gut microbial-derived metabolites are synthesized from dietary compounds ingested by the host or host-produced metabolites, and additionally, some bacterial products can be synthesized de novo. In this review, we focus on the two first metabolites families including short-chain fatty acids, indole metabolites, polyamines, choline-derived compounds, and secondary bile acids. They all have been described as immunoregulatory molecules that specifically affect the adaptive immune system and T helper 17 and regulatory T cells. We discuss the mechanisms of action and the consequences in health and diseases related to these gut microbial-derived metabolites. Finally, we propose that the exogenous administration of these molecules or other compounds that bind to their immunoregulatory receptors in a homologous manner could be considered therapeutic approaches. Full article

KB-R7943, an isothiourea derivative, has been recognized as an inhibitor in the reverse mode of the Na⁺-Ca²⁺ exchanging process. This compound was demonstrated to prevent intracellular Na⁺-dependent Ca²⁺ uptake in intact cells; however, it is much less effective at preventing extracellular Na⁺-dependent Ca²⁺ efflux. Therefore, whether or how this compound may produce any perturbations on other types of ionic currents, particularly on voltage-gated Na⁺ current (I_Na), needs to be further studied. In this study, the whole-cell current recordings demonstrated that upon abrupt depolarization in pituitary GH₃ cells, the exposure to KB-R7943 concentration-dependently depressed the transient (I_Na(T)) or late component (I_Na(L)) of I_Na with an IC₅₀ value of 11 or 0.9 μM, respectively. Likewise, the dissociation constant for the KB-R7943-mediated block of I_Na on the basis of a minimum reaction scheme was estimated to be 0.97 μM. The presence of benzamil or amiloride could suppress the I_Na(L) magnitude. The instantaneous window Na⁺ current (I_Na(W)) activated by abrupt ascending ramp voltage (V_ramp) was suppressed by adding KB-R7943; however, subsequent addition of deltamethrin or tefluthrin (Tef) effectively reversed KB-R7943-inhibted I_Na(W). With prolonged duration of depolarizing pulses, the I_Na(L) amplitude became exponentially decreased; moreover, KB-R7943 diminished I_Na(L) magnitude. The resurgent Na⁺ current (I_Na(R)) evoked by a repolarizing V_ramp was also suppressed by adding this compound; moreover, subsequent addition of ranolazine or Tef further diminished or reversed, respectively, its reduction in I_Na(R) magnitude. The persistent Na⁺ current (I_Na(P)) activated by sinusoidal voltage waveform became enhanced by Tef; however, subsequent application of KB-R7943 counteracted Tef-stimulated I_Na(P). The docking prediction reflected that there seem to be molecular interactions of this molecule with the hNa_V1.2 or hNa_V1.7 channels. Collectively, this study highlights evidence showing that KB-R7943 has the propensity to perturb the magnitude and gating kinetics of I_Na (e.g., I_Na(T), I_Na(L), I_Na(W), I_Na(R), and I_Na(P)) and that the Na_V channels appear to be important targets for the in vivo actions of KB-R7943 or other relevant compounds. Full article

Next to cow’s milk and eggs, plant foods, i.e., legumes, tree nuts and cereal grains, most often sensitise atopic children. Storage proteins constitutes the most relevant protein fraction of plant foods, causing primary sensitisation. They exhibit strong allergenic properties and immunogenicity. Our goal was to analyse sensitisation to 26 plant storage proteins in a group of 76 children aged 0–5 years with chronic symptoms of atopic dermatitis using Allergy Explorer ALEX2 and to discover changes in serum protein–peptide patterns in allergic patients with the use of MALDI-TOF-MS. We reported that 25% of children were allergic to 2S albumins, 19.7% to 7S globulins, 13.2% to 11S globulins and 1.3% to cereal prolamins. The most common allergenic molecules were Ara h 1 (18.4%), Ara h 2 (17.1%), Ara h 6 (15.8%) and Ara h 3 (11.8%) from peanuts, and the mean serum sIgE concentrations in allergic patients were 10.93 kUA/L, 15.353 kUA/L, 15.359 kUA/L and 9.038 kUA/L, respectively. In children allergic to storage proteins compared to the other patients (both allergic and non-allergic), the cell cycle control protein 50A, testis-expressed sequence 13B, DENN domain-containing protein 5A and SKI family transcriptional corepressor 2 were altered. Our results indicate that the IgE-mediated allergy to storage proteins is a huge problem in a group of young, atopic children, and show the potential of proteomic analysis in the prediction of primary sensitisation to plant foods. It is the next crucial step for understanding the molecular consequences of allergy to storage proteins. Full article

Four-stranded folded structures, such as G-quadruplexes and i-motifs in the genome, have attracted a growing interest nowadays since they have been discovered in the telomere and in several oncogene promoter regions. Their biological relevance is undeniable since their existence in living cells has been observed. In vivo they take part in the regulation of gene expression, in vitro they are used in the analytical biochemistry. They are attractive and promising targets for cancer therapy. Pressure studies can reveal specific aspects of the molecular processes. Pressure tuning experiments allow the determination of the volumetric parameters of the folded structures and of the folding–unfolding processes. Here, we review the thermodynamic parameters with a special focus on the volumetric ones, which were determined using pressure tuning spectroscopic experiments on the G-quadruplex and i-motif nucleic acid forms. Full article

Myofibroblasts escape apoptosis and proliferate abnormally under pathological conditions, especially fibrosis; they synthesize and secrete a large amount of extracellular matrix (ECM), such as α-SMA and collagen, which leads to the distortion of organ parenchyma structure, an imbalance in collagen deposition and degradation, and the replacement of parenchymal cells by fibrous connective tissues. Fibroblast to myofibroblast transition (FMT) is considered to be the main source of myofibroblasts. Therefore, it is crucial to explore the influencing factors regulating the process of FMT for the prevention, treatment, and diagnosis of FMT-related diseases. In recent years, non-coding RNAs, including microRNA, long non-coding RNAs, and circular RNAs, have attracted extensive attention from scientists due to their powerful regulatory functions, and they have been found to play a vital role in regulating FMT. In this review, we summarized ncRNAs which regulate FMT during fibrosis and found that they mainly regulated signaling pathways, including TGF-β/Smad, MAPK/P38/ERK/JNK, PI3K/AKT, and WNT/β-catenin. Furthermore, the expression of downstream transcription factors can be promoted or inhibited, indicating that ncRNAs have the potential to be a new therapeutic target for FMT-related diseases. Full article

Eugenol, cinnamaldehyde and D-limonene, the main components of natural essential oils, are endowed with antioxidant and anti-inflammatory properties which allow them to induce beneficial effects on intestinal, cardiac and neuronal levels. In order to characterize their pharmacokinetic profiles and aptitude to permeate in the central nervous system after intravenous and oral administration to rats, new analytical procedures, easily achievable with HPLC-UV techniques, were developed. The terminal half-lives of these compounds range from 12.4 ± 0.9 (D-limonene) and 23.1 ± 1.6 min (cinnamaldehyde); their oral bioavailability appears relatively poor, ranging from 4.25 ± 0.11% (eugenol) to 7.33 ± 0.37% (cinnamaldehyde). Eugenol evidences a marked aptitude to permeate in the cerebrospinal fluid (CSF) of rats following both intravenous and oral administrations, whereas cinnamaldehyde appears able to reach the CSF only after intravenous administration; limonene is totally unable to permeate in the CSF. Eugenol was therefore recruited for in vitro studies of viability and time-/dose-dependent dopamine release in neuronal differentiated PC12 cells (a recognized cellular model mimicking dopaminergic neurons), evidencing its ability to increase cell viability and to induce dopamine release according to a U-shaped time-course curve. Moreover, concentration-response data suggest that eugenol may induce beneficial effects against Parkinson’s disease after oral administration. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer due to its molecular heterogeneity and poor clinical outcomes. Analysis of circulating cell-free tumor nucleic acids (ctNAs) can improve our understanding of TNBC and provide efficient and non-invasive clinical biomarkers that may be representative of tumor heterogeneity. In this review, we summarize the potential of ctNAs to aid TNBC diagnosis and prognosis. For example, tumor fraction of circulating cell-free DNA (TFx) may be useful for molecular prognosis of TNBC: high TFx levels after neoadjuvant chemotherapy have been associated with shorter progression-free survival and relapse-free survival. Mutations and copy number variations of TP53 and PIK3CA/AKT genes in plasma may be important markers of TNBC onset, progression, metastasis, and for clinical follow-up. In contrast, the expression profile of circulating cell-free tumor non-coding RNAs (ctncRNAs) can be predictive of molecular subtypes of breast cancer and thus aid in the identification of TBNC. Finally, dysregulation of some circulating cell-free tumor miRNAs (miR17, miR19a, miR19b, miR25, miR93, miR105, miR199a) may have a predictive value for chemotherapy resistance. In conclusion, a growing number of efforts are highlighting the potential of ctNAs for future clinical applications in the diagnosis, prognosis, and follow-up of TNBC. Full article

Brown planthopper (BPH), a monophagous phloem feeder, consumes a large amount of photoassimilates in rice and causes wilting. A near-isogenic line ‘TNG71-Bph45’ was developed from the Oryza sativa japonica variety ‘Tainung 71 (TNG71) carrying a dominant BPH-resistance locus derived from Oryza nivara (IRGC 102165) near the centromere of chromosome 4. We compared the NIL (TNG71-Bph45) and the recurrent parent to explore how the Bph45 gene confers BPH resistance. We found that TNG71-Bph45 is less attractive to BPH at least partially because it produces less limonene. Chiral analysis revealed that the major form of limonene in both rice lines was the L-form. However, both L- and D-limonene attracted BPH when applied exogenously to TNG71-Bph45 rice. The transcript amounts of limonene synthase were significantly higher in TNG71 than in TNG71-Bph45 and were induced by BPH infestation only in the former. Introgression of the Bph45 gene into another japonica variety, Tainan 11, also resulted in a low limonene content. Moreover, several dominantly acting BPH resistance genes introduced into the BPH-sensitive IR24 line compromised its limonene-producing ability and concurrently decreased its attractiveness to BPH. These observations suggest that reducing limonene production may be a common resistance strategy against BPH in rice. Full article

The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab. Full article

Fibrotic diseases, such as systemic sclerosis (SSc), idiopathic pulmonary fibrosis, renal fibrosis and liver cirrhosis are characterized by tissue overgrowth due to excessive extracellular matrix (ECM) deposition. Fibrosis progression is caused by ECM overproduction and the inhibition of ECM degradation due to several events, including inflammation, vascular endothelial dysfunction, and immune abnormalities. Recently, it has been reported that urokinase plasminogen activator (uPA) and its receptor (uPAR), known to be fibrinolytic factors, orchestrate the inflammatory response, vascular homeostasis, and immune homeostasis system. The uPA/uPAR system may show promise as a potential therapeutic target for fibrotic diseases. This review considers the role of the uPA/uPAR system in the progression of fibrotic diseases. Full article

Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm. Full article

Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium in the oral cavity, pharynx, sino-nasal region, and larynx. Laryngeal squamous cell carcinoma (LSCC) represents one-third of all head and neck cancers. Dysregulated RNA-related pathways define an important molecular signature in this aggressive carcinoma. The Survival Motor Neuron (SMN) protein regulates fundamental aspects of the RNA metabolism but, curiously, its role in cancer is virtually unknown. For the first time, here, we focus on the SMN in the cancer context. We conducted a pilot study in a total of 20 patients with LSCC where the SMN was found overexpressed at both the protein and transcript levels. By a cellular model of human laryngeal carcinoma, we demonstrated that the SMN impacts cancer-relevant behaviors and perturbs key players of cell migration, invasion, and adhesion. Furthermore, in LSCC we showed a physical interaction between the SMN and the epidermal growth factor receptor (EGFR), whose overexpression is an important feature in these tumors. This study proposes the SMN protein as a novel therapeutic target in LSSC and likely in the whole spectrum of HNSCC. Overall, we provide the first analysis of the SMN in human cancer. Full article

KRAS is one of the most commonly mutated genes, an event that leads to development of highly aggressive and resistant to any type of available therapy tumors. Mutated KRAS drives a complex network of lipid metabolic rearrangements to support the adaptation of cancer cells to harsh environmental conditions and ensure their survival. Because there has been only a little success in the continuous efforts of effectively targeting KRAS-driven tumors, it is of outmost importance to delineate the exact mechanisms of how they get rewired, leading to this distinctive phenotype. Therefore, the aim of this review is to summarize the available data acquired over the last years with regard to the lipid metabolic regulation of KRAS-driven tumors and elucidate their specific characteristics in an attempt to unravel novel therapeutic targets. Full article

The potential utility of microRNAs (miRNAs) as diagnostic or prognostic biomarkers, as well as therapeutic targets, for chronic kidney disease (CKD) has been advocated. However, studies evaluating the expression profile of the same miRNA signatures in CKD report contradictory findings. This review aimed to characterize miRNAs associated with CKD and/or measures of kidney function and kidney damage in the general population, and also in high-risk subgroups, including people with hypertension (HTN), diabetes mellitus (DM) and human immunodeficiency virus (HIV) infection. Medline via PubMed, Scopus, Web of Science, and EBSCOhost databases were searched to identify relevant studies published in English or French languages on or before 30 September 2022. A total of 75 studies fulfilled the eligibility criteria: CKD (n = 18), diabetic kidney disease (DKD) (n = 51) and HTN-associated CKD (n = 6), with no study reporting on miRNA profiles in people with HIV-associated nephropathy. In individuals with CKD, miR-126 and miR-223 were consistently downregulated, whilst in DKD, miR-21 and miR-29b were consistently upregulated and miR-30e and let-7a were consistently downregulated in at least three studies. These findings suggest that these miRNAs may be involved in the pathogenesis of CKD and therefore invites further research to explore their clinical utility for CKD prevention and control. Full article

Current molecular classification approaches for endometrial cancer (EC) often employ multiple testing platforms. Some subtypes still lack univocal prognostic significance, highlighting the need for risk sub-stratification. The tumor immune microenvironment (TIME) is associated with tumor progression and prognosis. We sought to investigate the feasibility of classifying EC via DNA sequencing and interrogate immunologic signatures and prognostic markers across and within subtypes, respectively. Formalin-fixed paraffin-embedding (FFPE) samples from 50 EC patients underwent targeted DNA and RNA sequencing, and multiplex immunofluorescence assay for TIME. DNA sequencing classified 10%, 20%, 52%, and 18% of patients into the subtype of POLE-mutant, microsatellite instability-high (MSI-H), TP53-wt, and TP53-mutant. POLE-mutant tumors expressed the highest T-effector and IFN-γ signature and the lowest innate anti-PD-1 resistance signature among subtypes. TP53-wt revealed a converse enrichment trend for these immunologic signatures. Survival analyses using the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA-UCEC) dataset identified associations of CCR5 (hazard ratio (HR) = 0.71, p = 0.035), TNFRSF14 (HR = 0.58, p = 0.028), and IL-10 (HR = 2.5, p = 0.012) with overall survival within MSI-H, TP53-mutant, and TP53-wt subtype, respectively. A TIME comparison between the sub-stratified subgroups of our cohort revealed upregulated tumor infiltration of immune cells in the low-risk subgroups. Our study demonstrates that targeted DNA sequencing is an effective one-stop strategy to classify EC. Immunomodulatory genes may serve as prognostic markers within subtypes. Full article

Mutual synergistic folding (MSF) proteins belong to a recently emerged subclass of disordered proteins, which are disordered in their monomeric forms but become ordered in their oligomeric forms. They can be identified by experimental methods following their unfolding, which happens in a single-step cooperative process, without the presence of stable monomeric intermediates. Only a limited number of experimentally validated MSF proteins are accessible. The amino acid composition of MSF proteins shows high similarity to globular ordered proteins, rather than to disordered ones. However, they have some special structural features, which makes it possible to distinguish them from globular proteins. Even in the possession of their oligomeric three-dimensional structure, classification can only be performed based on unfolding experiments, which are frequently absent. In this work, we demonstrate a simple protocol using molecular dynamics simulations, which is able to indicate that a protein structure belongs to the MSF subclass. The presumption of the known atomic resolution quaternary structure is an obvious limitation of the method, and because of its high computational time requirements, it is not suitable for screening large databases; still, it is a valuable in silico tool for identification of MSF proteins. Full article

Stroke, one of the leading causes of disability and death worldwide, is a severe neurological disease that threatens human life. Protopanaxatriol (PPT), panaxatriol-type saponin aglycone, is a rare saponin that exists in Panax ginseng and Panax Noto-ginseng. In this study, we established an oxygen-glucose deprivation (OGD)-PC12 cell model and middle cerebral artery occlusion/reperfusion (MCAO/R) model to evaluate the neuroprotective effects of PPT in vitro and in vivo. In addition, metabolomics analysis was performed on rat plasma and brain tissue samples to find relevant biomarkers and metabolic pathways. The results showed that PPT could significantly regulate the levels of LDH, MDA, SOD, TNF-α and IL-6 factors in OGD-PC12 cells in vitro. PPT can reduce the neurological deficit score and infarct volume of brain tissue in rats, restore the integrity of the blood-brain barrier, reduce pathological damage, and regulate TNF-α, IL-1β, IL-6, MDA, and SOD factors. In addition, the results of metabolomics found that PPT can regulate 19 biomarkers involving five metabolic pathways, including amino acid metabolism, arachidonic acid metabolism, sphingolipid metabolism, and glycerophospholipid metabolism. Thus, it could be inferred that PPT might serve as a novel natural agent for MCAO/R treatment. Full article

Dietary composition substantially determines human health and affects complex diseases, including obesity, inflammation and cancer. Thus, food supplements have been widely used to accommodate dietary composition to the needs of individuals. Among the promising supplements are dietary phospholipids (PLs) that are commonly found as natural food ingredients and as emulsifier additives. The aim of the present study was to evaluate the effect of major PLs found as food supplements on the morphology of intestinal epithelial cells upon short-term and long-term high-dose feeding in mice. In the present report, the effect of short-term and long-term high dietary PL content was studied in terms of intestinal health and leaky gut syndrome in male mice. We used transmission electron microscopy to evaluate endothelial morphology at the ultrastructural level. We found mitochondrial damage and lipid droplet accumulation in the intracristal space, which rendered mitochondria more sensitive to respiratory uncoupling as shown by a mitochondrial respiration assessment in the intestinal crypts. However, this mitochondrial damage was insufficient to induce intestinal permeability. We propose that high-dose PL treatment impairs mitochondrial morphology and acts through extensive membrane utilization via the mitochondria. The data suggest that PL supplementation should be used with precaution in individuals with mitochondrial disorders. Full article

Abnormal mutations in the microbial structure of early-weaning mammals are an important cause of enteritis. Based on the multiple known beneficial functions of butyrate, we hypothesized that butyrate would alleviate the imbalance of intestinal homeostasis induced by early weaning in animals. However, the mechanisms of action between butyrate and intestinal microbes are still poorly explored. In this study, we aimed to investigate whether butyrate exerts beneficial effects on the structure of the intestinal flora of weanling rabbits and their intestinal homeostasis, growth and development, and we attempted to elucidate the potential mechanisms of action through a combined omics analysis. We found that dietary butyrate upregulated the transcription of tight junction-related proteins in the epithelial barrier and improved the intestinal microbial structure by suppressing harmful bacteria and promoting beneficial ones. Intestinal and plasma metabolomes were also altered. The bile acid secretion, α-linolenic acid, apoptotic, and prostate cancer pathways responded to the positive dietary butyrate-induced metabolic changes in the weanling rabbits, resulting in the inhibition of inflammation, improved antioxidant capacity, increased rates of cell proliferation and survival, and decreased levels of apoptosis. Additionally, dietary butyrate suppressed the release of pro-inflammatory factors and enhanced positive appetite regulation, which increased the average daily gain of the rabbits. These results demonstrated that dietary butyrate can help maintain the integrity of the intestinal epithelial barrier, improve the structural composition of the intestinal microflora, enhance organismal metabolism, inhibit inflammation, reduce post-weaning anorexia, and promote growth and development in early-weaning rabbits. These positive effects of dietary butyrate were exerted via the modulation of the microbe–gut–brain axis. Full article

The emerging concept of cancer stem cells (CSCs) as the key driver behind carcinogenesis, progression, and diversity has displaced the prior model of a tumor composed of cells with similar subsequently acquired mutations and an equivalent capacity for renewal, invasion, and metastasis. This significant change has shifted the research focus toward targeting CSCs to eradicate cancer. CSCs may be characterized using cell surface markers. They are defined by their capacity to self-renew and differentiate, resist conventional therapies, and generate new tumors following repeated transplantation in xenografted mice. CSCs’ functional capabilities are governed by various intracellular and extracellular variables such as pluripotency-related transcription factors, internal signaling pathways, and external stimuli. Numerous natural compounds and synthetic chemicals have been investigated for their ability to disrupt these regulatory components and inhibit stemness and terminal differentiation in CSCs, hence achieving clinical implications. However, no cancer treatment focuses on the biological consequences of these drugs on CSCs, and their functions have been established. This article provides a biomedical discussion of cancer at the time along with an overview of CSCs and their origin, features, characterization, isolation techniques, signaling pathways, and novel targeted therapeutic approaches. Additionally, we highlighted the factors endorsed as controlling or helping to promote stemness in CSCs. Our objective was to encourage future studies on these prospective treatments to develop a framework for their application as single or combined therapeutics to eradicate various forms of cancer. Full article

Lithium chloride (LiCl) has been widely researched and utilized as a therapeutic option for bipolar disorder (BD). Several pathways, including cell signaling and signal transduction pathways in mammalian cells, are shown to be regulated by LiCl. LiCl can negatively control the expression and activity of PGM2, a phosphoglucomutase that influences sugar metabolism in yeast. In the presence of galactose, when yeast cells are challenged by LiCl, the phosphoglucomutase activity of PGM2p is decreased, causing an increase in the concentration of toxic galactose metabolism intermediates that result in cell sensitivity. Here, we report that the null yeast mutant strains DBP7∆ and YRF1-6∆ exhibit increased LiCl sensitivity on galactose-containing media. Additionally, we demonstrate that DBP7 and YRF1-6 modulate the translational level of PGM2 mRNA, and the observed alteration in translation seems to be associated with the 5′-untranslated region (UTR) of PGM2 mRNA. Furthermore, we observe that DBP7 and YRF1-6 influence, to varying degrees, the translation of other mRNAs that carry different 5′-UTR secondary structures. Full article

Cardiac fibrosis is a common pathological feature of different cardiovascular diseases, characterized by the aberrant deposition of extracellular matrix (ECM) proteins in the cardiac interstitium, myofibroblast differentiation and increased fibrillar collagen deposition stimulated by transforming growth factor (TGF)-β activation. Biglycan (BGN), a small leucine-rich proteoglycan (SLRPG) integrated within the ECM, plays a key role in matrix assembly and the phenotypic control of cardiac fibroblasts. Moreover, BGN is critically involved in pathological cardiac remodeling through TGF-β binding, thus causing myofibroblast differentiation and proliferation. Adenosine receptors (ARs), and in particular A_2AR, may play a key role in stimulating fibrotic damage through collagen production/deposition, as a consequence of cyclic AMP (cAMP) and AKT activation. For this reason, A_2AR modulation could be a useful tool to manage cardiac fibrosis in order to reduce fibrotic scar deposition in heart tissue. Therefore, the aim of the present study was to investigate the possible crosstalk between A_2AR and BGN modulation in an in vitro model of TGF-β-induced fibrosis. Immortalized human cardiac fibroblasts (IM-HCF) were stimulated with TGF-β at the concentration of 10 ng/mL for 24 h to induce a fibrotic phenotype. After applying the TGF-β stimulus, cells were treated with two different A_2AR antagonists, Istradefylline and ZM241385, for an additional 24 h, at the concentration of 10 µM and 1 µM, respectively. Both A_2AR antagonists were able to regulate the oxidative stress induced by TGF-β through intracellular reactive oxygen species (ROS) reduction in IM-HCFs. Moreover, collagen1a1, MMPs 3/9, BGN, caspase-1 and IL-1β gene expression was markedly decreased following A_2AR antagonist treatment in TGF-β-challenged human fibroblasts. The results obtained for collagen1a1, SMAD3, α-SMA and BGN were also confirmed when protein expression was evaluated; phospho-Akt protein levels were also reduced following Istradefylline and ZM241385 use, thus suggesting that collagen production involves AKT recruited by the A_2AR. These results suggest that A_2AR modulation might be an effective therapeutic option to reduce the fibrotic processes involved in heart pathological remodeling. Full article

It is well ascertained that airway inflammation has a key role in the genesis of numerous respiratory pathologies, including asthma, chronic obstructive pulmonary disease, and acute respiratory distress syndrome. Pulmonary tissue inflammation and anti-inflammatory responses implicate an intricate relationship between local and infiltrating immune cells and structural pulmonary cells. Alarmins are endogenic proteins discharged after cell injury in the extracellular microenvironment. The purpose of our review is to highlight the alterations in respiratory diseases involving some alarmins, such as high mobility group box 1 (HMGB1) and interleukin (IL)-33, and their inter-relationships and relationships with genetic non-coding material, such as microRNAs. The role played by these alarmins in some pathophysiological processes confirms the existence of an axis composed of HMGB1 and IL-33. These alarmins have been implicated in ferroptosis, the onset of type 2 inflammation and airway alterations. Moreover, both factors can act on non-coding genetic material capable of modifying respiratory function. Finally, we present an outline of alarmins and RNA-based therapeutics that have been proposed to treat respiratory pathologies. Full article

In cells, oxidative stress is an imbalance between the production/accumulation of oxidants and the ability of the antioxidant system to detoxify these reactive products. Reactive oxygen species (ROS), cause multiple cellular damages through their interaction with biomolecules such as lipids, proteins, and DNA. Genotoxic damage caused by oxidative stress has become relevant since it can lead to mutation and play a central role in malignant transformation. The evidence describes chronic oxidative stress as an important factor implicated in all stages of the multistep carcinogenic process: initiation, promotion, and progression. In recent years, ambient air pollution by particulate matter (PM) has been cataloged as a cancer risk factor, increasing the incidence of different types of tumors. Epidemiological and toxicological evidence shows how PM-induced oxidative stress could mediate multiple events oriented to carcinogenesis, such as proliferative signaling, evasion of growth suppressors, resistance to cell death, induction of angiogenesis, and activation of invasion/metastasis pathways. In this review, we summarize the findings regarding the involvement of oxidative and genotoxic mechanisms generated by PM in malignant cell transformation. We also discuss the importance of new approaches oriented to studying the development of tumors associated with PM with more accuracy, pursuing the goal of weighing the impact of oxidative stress and genotoxicity as one of the main mechanisms associated with its carcinogenic potential. Full article

S-layers are involved in the adaptation of bacteria to the outside environment and in pathogenesis, often representing special virulence factors. Vegetative cells of the entomopathogenic bacterium Brevibacillus laterosporus are characterized by an overproduction of extracellular surface layers that are released in the medium during growth. The purpose of this study was to characterize cell wall proteins of this bacterium and to investigate their involvement in pathogenesis. Electron microscopy observations documented the presence of multiple S-layers, including an outermost (OW) and a middle (MW) layer, in addition to the peptidoglycan layer covering the plasma membrane. After identifying these proteins (OWP and MWP) by mass spectrometry analyses, and determining their gene sequences, the cell wall multilayer-released fraction was successfully isolated and used in insect bioassays alone and in combination with bacterial spores. This study confirmed a central role of spores in bacterial pathogenicity to insects but also detected a significant virulence associated with fractions containing released cell wall multilayer proteins. Taken together, S-layer proteins appear to be part of the toxins and virulence factors complex of this microbial control agent of invertebrate pests. Full article

The utilization of cardiac progenitor cells (CPCs) has been shown to induce favorable regenerative effects. While there are various populations of endogenous CPCs in the heart, there is no consensus regarding which population is ideal for cell-based regenerative therapy. Early-stage progenitor cells can be differentiated into all cardiovascular lineages, including cardiomyocytes and endothelial cells. Identifying an Islet-1+ (Isl-1+) early-stage progenitor population with enhanced stemness, multipotency and differentiation potential would be beneficial for the development of novel regenerative therapies. Here, we investigated the transcriptome of human neonatal Isl-1+ CPCs. Isl-1+ human neonatal CPCs exhibit enhanced stemness properties and were found to express Spalt-like transcription factor 4 (SALL4). SALL4 plays a role in embryonic development as well as proliferation and expansion of hematopoietic progenitor cells. SALL4, SOX2, EpCAM and TBX5 are co-expressed in the majority of Isl-1+ clones isolated from neonatal patients. The pre-mesendodermal transcript TFAP2C was identified in select Isl-1, SALL4, SOX2, EpCAM and TBX5 expressing clones. The ability to isolate and expand pre-mesendodermal stage cells from human patients is a novel finding that holds potential value for applications in regenerative medicine. Full article

The formation of biofilms on the surface of dental implants and abutment materials may lead to peri-implantitis and subsequent implant failure. Recently, innovative materials such as polyether-ether-ketone (PEEK) and its modifications have been used as abutment materials. However, there is limited knowledge on microbial adhesion to PEEK materials. The aim of this in vivo study was to investigate biofilm formation on the surface of conventional (titanium and zirconia) and PEEK implant abutment materials. Split specimens of titanium, zirconia, PEEK, and modified PEEK (PEEK-BioHPP) were manufactured, mounted in individual removable acrylic upper jaw splints, and worn by 20 healthy volunteers for 24 h. The surface roughness was determined using widefield confocal microscopy. Biofilm accumulation was investigated by fluorescence microscopy and quantified by imaging software. The surface roughness of the investigated materials was <0.2 µm and showed no significant differences between the materials. Zirconia showed the lowest biofilm formation, followed by titanium, PEEK, and PEEK-BioHPP. Differences were significant (p < 0.001) between the investigated materials, except for the polyether-ether-ketones. Generally, biofilm formation was significantly higher (p < 0.05) in the posterior region of the oral cavity than in the anterior region. The results of the present study show a material-dependent susceptibility to biofilm formation. The risk of developing peri-implantitis may be reduced by a specific choice of abutment material. Full article

APX is a key antioxidant enzyme in higher plants, scavenging H₂O₂ with ascorbate in several cellular compartments. Here, we report the crystal structures of cytosolic ascorbate peroxidase from switchgrass (Panicum virgatum L., Pvi), a strategic feedstock plant with several end uses. The overall structure of PviAPX was similar to the structures of other APX family members, with a bound ascorbate molecule at the ɣ-heme edge pocket as in other APXs. Our results indicated that the H₂O₂-dependent oxidation of ascorbate displayed positive cooperativity. Significantly, our study suggested that PviAPX can oxidize a broad range of phenylpropanoids with δ-meso site in a rather similar efficiency, which reflects its role in the fortification of cell walls in response to insect feeding. Based on detailed structural and kinetic analyses and molecular docking, as well as that of closely related APX enzymes, the critical residues in each substrate-binding site of PviAPX are proposed. Taken together, these observations shed new light on the function and catalysis of PviAPX, and potentially benefit efforts improve plant health and biomass quality in bioenergy and forage crops. Full article