Search Results (1,335)

Background: Aging is associated with the development of various disorders, including postural imbalance, which increases the risk of falls and related health complications. This study examines changes in static postural balance after a 4-week intervention involving appropriate exercise and an optimized daily regimen. Additionally, it explores the relationship between these changes and the steroidome. Methods: The study was conducted on a clinically homogeneous group of 41 females around their sixth decade, diagnosed with anxiety-depressive syndrome and treated with selective serotonin reuptake inhibitors (SSRIs). Postural balance was assessed using the dual-scales method (DLLL-DSM), which estimates postural imbalance by evaluating differences in the lower limb load in the standing position. Correlations between initial DLLL-DSM values, age, BMI, and the baseline levels of nine serum steroids, as well as post-intervention changes in five steroids, were analyzed using multivariate regression (OPLS model). Results: A significant reduction in lower limb load differences (-ΔDLLL-DSM), indicating improved postural balance, was observed. The -ΔDLLL-DSM strongly correlated with initial DLLL-DSM values, age, BMI, initial levels of nine serum steroids, and post-intervention changes in five steroids (R = 0.892, p < 0.001). Furthermore, initial DLLL-DSM values negatively correlated with adrenal androgen androstenediol sulfate and various sulfated 5α/β-reduced androgen metabolites (R = 0.323, p < 0.05), suggesting that the activity of steroid sulfotransferase (SULT2A1) and C17-hydroxylase-C17,20-lyase (CYP17A1) at the lyase step is negatively associated with postural imbalance in elderly females. Conclusions: The findings suggest that even severe postural imbalance can be effectively and relatively rapidly improved through an appropriate exercise-based intervention and an optimized daily regimen, provided that initial adrenal activity is not significantly impaired. Additionally, the identified associations between steroid levels and postural balance provide new insights into the hormonal mechanisms regulating balance control in older individuals. Full article

Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth. Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers. Full article

Background: Increased expression of MET and hepatocyte growth factor (HGF)-related molecules has been positively correlated with poor prognosis in renal cell carcinoma (RCC). In the current study, the expression and phosphorylation of MET in metastatic RCC (mRCC) are determined by immunohistochemistry, and the therapeutic effect of MET and HGF activation-targeting agents for RCC cell lines is analyzed. Methods: Immunohistochemistry was performed for 76 formalin-fixed paraffin-embedded specimens (primary tumor: 32, metastatic site: 44). The therapeutic effect of capmatinib (MET-I) and SRI-31215 (inhibitor of HGF-activating proteases: HGFA-I) was determined based on the inhibition of MET phosphorylation, cell proliferation, and cell migration in 786-O and caki-1 cell lines. Results: Increased expression and phosphorylation of MET were observed in both primary tumor and metastatic sites; however, phosphorylation was significantly upregulated in metastatic sites (p = 0.0001). In an assay of RCC cell lines, the strongest inhibition of MET phosphorylation, cell proliferation, and migration was confirmed with the combined used of MET-I and HGFA-I. Conclusions: Phosphorylation of MET was significantly upregulated in metastasis, which suggested the importance of downregulation in the treatment of mRCC. Our findings suggest that dual inhibition of MET and HGF activation may offer a promising strategy for mRCC treatment, warranting further clinical validation. Full article

Janus kinase inhibitors (JAKis) represent a relatively new class of immunomodulatory drugs with potent effects on various cytokine signalling pathways. They have revolutionized the treatment landscape for autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. However, their ability to modulate immune responses presents a dual-edged nature, influencing both protective immunity and pathological inflammation. This review explores the complex role of JAKis in infectious settings, highlighting both beneficial and detrimental effects. On the one hand, experimental models suggest that JAK inhibition can impair host defence mechanisms, increasing susceptibility to certain bacterial and viral infections. For example, tofacitinib-treated mice exhibited more severe joint erosions in Staphylococcus aureus (S. aureus) septic arthritis and showed impaired viral clearance in herpes simplex encephalitis. Additionally, clinical data confirm an increased risk of herpes zoster in patients receiving JAKis, underscoring the need for rigorous monitoring. On the other hand, JAK inhibition has demonstrated protective effects in certain infectious and hyperinflammatory conditions. In sepsis models, including cecal ligation and puncture (CLP) and S. aureus bacteraemia, tofacitinib improved survival by attenuating excessive inflammation. Furthermore, JAKis, particularly baricitinib, have shown substantial efficacy in mitigating cytokine storms during severe COVID-19 infections, leading to improved clinical outcomes and reduced mortality. These observations suggest that JAKis have a role in modulating hyperinflammatory responses in select infectious contexts. In conclusion, JAKis present a complex interplay between immunosuppression and immunomodulation. While they increase the risk of certain infections, they also show potential in managing hyperinflammatory conditions such as cytokine storms. The key challenge is determining which patients and situations benefit most from JAKis while minimizing risks, requiring a careful and personalized treatment approach. Full article

Objective: Cutaneous immune-related adverse events (cirAEs) represent a prevalent manifestation of adverse reactions linked to immune checkpoint inhibitors (ICIs) therapy, substantially affecting patients’ quality of life. This systematic review and meta-analysis aimed to quantify the pooled incidence of cirAEs in this population and strengthen clinical awareness for early recognition and management. Methods: A comprehensive search of PubMed, Embase, CINAHL, Cochrane Library, CBM, CNKI, and Wanfang databases was conducted from inception to December 2022. Literature that reported the incidence of cirAEs in patients with lung cancer receiving ICIs therapy was included. A meta-analysis was conducted using R software, version 4.4.1 to estimate the pooled incidence of cirAEs, and a random-effects model was used for data synthesis. Begg’s rank correlation and funnel plots were used to assess publication bias. Results: A total of 99 articles involving 23,814 patients with lung cancer receiving ICIs therapy were included, with publication dates ranging from 2012 to 2022. The meta-analysis results reveal that the incidence of cirAEs in patients with lung cancer was 20.26% (95% confidence interval [CI (17.12–23.81)]. Significant differences were observed between all subgroups, including continent, study type, combination therapy, dual ICIs therapy, and diagnostic criteria for cirAEs for Grade 1–2 and Grade 3–4 incidences. Conclusions: The incidence of cirAEs in patients with lung cancer is relatively high, particularly undergoing combined or dual ICIs therapy. To comprehensively characterize cirAEs in patients with lung cancer, large-scale multicenter studies integrating real-world pharmacovigilance data are warranted to establish precise incidence estimates and identify clinically significant risk factors. Implications for clinical practice: This review’s insights aroused clinical staff’s attention and concern about cirAEs, potentially enhancing the quality of life of patients with cancer. Full article

Novel herbicide development is a challenge for weed control. Protoporphyrinogen oxidase (PPO) and p-hydroxyphenylpyruvate dioxygenase (HPPD) are two key enzymes involved in plant photosynthesis. The multi virtual screening protocol was adopted to design a common skeleton based on the two target enzymes, and fragment growth of the skeleton was performed. The constructed compounds were searched for structural similarity, and the accuracy of the selected compounds was further verified using the Bayesian model. Finally, eight compounds were obtained, and the binding mode with the target was studied deeply. The obtained compounds interact with the key residues of HPPD and PPO proteins similarly to commercial herbicides, and the stability of binding with proteins is also good. The activity of the screening results was determined by an enzyme activity test in vitro. The herbicidal effect of the compound was studied by phenotypic experiment. The final results showed that Z-4 and Z-7 have the potential to become new dual-target herbicides. Full article

Fuchs endothelial corneal dystrophy (FECD) is a progressive disorder characterized by endothelial cell loss and excessive extracellular matrix (ECM) accumulation leading to corneal dysfunction. Emricasan, a pan-caspase inhibitor, was investigated for its therapeutic potential in suppressing these pathological changes. Patient-derived FECD cells and stress-induced cell models were treated with emricasan to assess its effects on apoptosis and ECM production. Caspase-specific knockdown experiments were performed to identify key mediators. Col8a2^Q455K/Q455K mice, model mice of early-onset FECD, received twice-daily administration of 0.1% emricasan eye drops from 8 to 28 weeks of age. Endothelial cell density, hexagonality, cell size variation, and guttae area were evaluated by contact specular microscopy, while transcriptomic changes were analyzed via RNA sequencing. Emricasan effectively reduced apoptosis and ECM production in vitro by selectively inhibiting caspase-7 without affecting canonical TGF-β signaling. In vivo, emricasan-treated mice exhibited significantly higher endothelial cell density, improved hexagonality, and reduced variation in cell size compared with controls. Transcriptome analysis revealed distinct gene expression changes in the corneal endothelium following emricasan treatment. These findings suggest that emricasan exerts dual protective effects by inhibiting caspase-7-mediated ECM accumulation and broadly suppressing apoptosis, highlighting its potential as a pharmacological therapy for FECD. Full article

This study investigates the dual catalytic inhibition mechanisms of chlorobenzene (CBz) formation during combustion using N- and S-modified layered double hydroxides (LDHs). The metal hydroxide layers in these LDHs primarily suppress lower-chlorinated CBzs (e.g., trichlorobenzene-dichlorobenzene) under inert conditions by inhibiting direct chlorination, achieving inhibition rates above 80%. In contrast, N/S functional groups, particularly thioacetamide, enhance catalytic inhibition efficiency under air, increasing it from 17.8% to 77.3% in the solid phase by controlling catalytic chlorination and limiting highly chlorinated CBzs (e.g., pentachlorobenzene–hexachlorobenzene). These findings highlight the complementary roles of metal hydroxide layers and N/S functional groups in reducing CBz formation, offering insights for developing efficient, multifunctional inhibitors for waste incineration pollution control. While promising, the scaling up of the application of LDH-based inhibitors may face challenges related to synthesis complexity and cost, requiring further research to provide a theoretical foundation for their large-scale application. Full article

The assembly of amyloidogenic proteins and peptides into toxic oligomeric and fibrillar aggregates is closely connected to the onset and progression of more than 50 protein diseases, such as Alzheimer’s disease, Parkinson’s disease, prion disease, and type 2 diabetes, to name only a few. Considerable research efforts at identifying the therapeutic strategies against these maladies are currently focused on preventing and inhibiting pathogenic protein aggregation by various agents. Plant-based extracts and compounds have emerged as promising sources of potential inhibitors due to their dual role as nutraceuticals as part of healthy diets and as specific pharmaceuticals when administered at higher concentrations. In recent decades, several plant extracts and plant-extracted compounds have shown potential to modulate protein aggregation. An ever-growing body of research on plant-based amyloid inhibitors requires a detail analysis of existing data to identify potential knowledge gaps. This review summarizes the recent progress in amyloid inhibition using 17 flavonoids, 11 polyphenolic non-flavonoid compounds, 23 non-phenolic inhibitors, and 59 plant extracts, with the main emphasis on directly modulating the fibrillation of four amyloid proteins, namely amyloid-β peptide, microtubule-associated protein tau, α-synuclein, and human islet amyloid polypeptide. Full article

Breast cancer is the most common malignancy among women globally, with incidence rates continuing to rise. A comprehensive understanding of its risk factors and the underlying biological mechanisms that drive tumor initiation is essential for developing effective prevention strategies. This review examines key non-modifiable risk factors, such as genetic predisposition, demographic characteristics, family history, mammographic density, and reproductive milestones, as well as modifiable risk factors like exogenous hormone exposure, obesity, diet, and physical inactivity. Importantly, reproductive history plays a dual role, providing long-term protection while temporarily increasing breast cancer risk shortly after pregnancy. Current chemoprevention strategies primarily depend on selective estrogen receptor modulators (SERMs), including tamoxifen and raloxifene, which have demonstrated efficacy in reducing the incidence of estrogen receptor-positive breast cancer but remain underutilized due to adverse effects. Emerging approaches such as aromatase inhibitors, RANKL inhibitors, progesterone antagonists, PI3K inhibitors, and immunoprevention strategies show promise for expanding preventive options. Understanding the interactions between risk factors, hormonal influences, and tumorigenesis is critical for optimizing breast cancer prevention and advancing safer, more targeted chemopreventive interventions Full article

The skin is continuously exposed to environmental changes, rendering it vulnerable to damage from external stressors that contribute to premature skin aging. This study aims to explore skin longevity pathways stimulated by a rose extract (RE) derived from petals. Human keratinocytes treated with RE exhibited a significant increase in NRF2 (NF-E2-related factor 2; ≈2–4% of induction) and LAMP2A (Lysosome-Associated Membrane Protein 2A; ≈6–12% of induction) levels. The presence of RE significantly mitigated the increase in carbonylation levels (≈34–37% of protection) and the number of labeled P16^INK4A cells (≈60–72% of protection), associated with proliferation arrest, both induced by exposure to BAP (Benzo[a]pyrene) coupled with UV-A (Ultraviolet A) irradiation. The beneficial effects mediated by RE were inhibited by Compound C, a specific AMPK inhibitor (AMP-activated protein kinase). The involvement of the AMPK pathway in mediating the beneficial effects of RE has been confirmed by assessing its activation through the evaluation of its phosphorylation state which was significantly elevated in the presence of RE compared to the stress condition. In conclusion, the activation of the AMPK pathway enhances antioxidant defenses and promotes autophagy. This dual action, mediated by RE, helps protect skin cells from oxidative damage and senescence while maintaining proteostasis, skin integrity, and cellular proliferation under pollution-induced stress (BAP + UV-A). These findings highlight the potential in mitigating age-related skin changes through the modulation of longevity pathways. Full article

Immune checkpoint inhibitors have revolutionized cancer treatment but remain limited by on-target/off-tumor effects that narrow their therapeutic window. Although PD-L1 is mainly expressed by tumor cells, these effects could reduce bloodstream availability and tumor accumulation of PD-L1 inhibitors. Enhancing tumor specificity through bispecific proteins targeting two tumor-associated antigens offers a promising strategy. This study evaluated a bispecific Nanofitin, B10–B11, targeting PD-L1 and EGFR. In vitro, B10–B11 efficiently bound to human A431 and murine CT26 cell lines, validating these models for in vivo studies. Nanofitins’ accumulation in tumors and their anti-tumor efficacy were assessed, respectively, in A431 xenograft and CT26 immunocompetent mouse models. In both experiments, B10–B11 was compared with its albumin binding fused counterpart (B10–B11-ABNF). This study showed that the dual-targeting approach with the bispecific Nanofitin enhanced in vitro PD-L1 neutralization compared to the monomeric form and led to in vivo anti-tumor activity evidenced by reduced tumor growth and increased CD3+ T cells and F4/80+ macrophages in tumors. This activity was further correlated with Nanofitin’s tumor accumulation at 7 h post-injection, which was highest for the B10–B11-ABNF. This study highlights the potential of bispecific Nanofitins, particularly with albumin binding to enable rapid and uniform tumor accumulation of effective PD-L1 immunotherapy. Full article

Porcine epidemic diarrhea virus (PEDV) causes a highly contagious intestinal disease with severe economic impacts on the global swine industry. The non-structural protein 13 (nsp13), a viral helicase, is essential for viral replication, making it a promising target for antiviral drug development. In this study, through virtual screening and molecular dynamics simulations, Vancomycin, a small-molecule drug also clinically used as an antibacterial agent, was identified to exhibit a stable binding affinity for PEDV nsp13. The NTPase and ATP-dependent RNA helicase activities of PEDV nsp13 were confirmed in vitro, and the optimal biochemical reaction conditions for its dsRNA unwinding activity were established. Further experiments demonstrated that Vancomycin effectively inhibited the dual enzymatic activities of PEDV nsp13 and reduced PEDV infections in vitro. This research highlights Vancomycin as a novel inhibitor of PEDV nsp13, providing valuable mechanistic insights and serving as a model for antiviral drug discovery. While this study suggests its potential for repurposing as a therapeutic agent against PEDV, further investigations are required to evaluate its feasibility in vivo, particularly in terms of safety, efficacy, and practical applicability. Full article

Interferon Regulatory Factors (IRFs) are critical modulators of immune and inflammatory responses, yet their roles in Alzheimer’s disease (AD) and other neurodegenerative disorders remain incompletely understood. While IRFs are recognized for their regulatory functions in neuroinflammation, microglial activation, and neuronal survival, their dual roles as both drivers of pathological inflammation and mediators of neuroprotective pathways underscore a sophisticated regulatory paradox in neurodegenerative disorders. This review aims to synthesize current evidence on IRF-mediated neuroinflammation in AD and related diseases, focusing on the multifaceted functions of key IRF family members, including IRF1, IRF3, and IRF7. We critically evaluate their divergent roles: IRF1 and IRF3, for instance, exacerbate neuroinflammatory cascades and amyloid-beta (Aβ) pathology in AD, whereas IRF7 may paradoxically suppress inflammation under specific conditions. Additionally, we explore IRF dysregulation in Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington’s disease, emphasizing shared and distinct mechanisms across neurodegenerative disorders. Restoring IRF balance through genetic manipulation, small-molecule inhibitors, or microbiome-derived modulators could attenuate neuroinflammation, enhance Aβ clearance, and protect neuronal integrity. Ultimately, this work provides a framework for future research to harness IRF signaling pathways in the development of precision therapies for AD and other neurodegenerative diseases. Full article

Due to the increasing prevalence of antimicrobial resistance, the efficacy of standard triple therapy for Helicobacter pylori (H. pylori) infection has declined, with eradication rates now falling below 80% in most countries. Although bismuth quadruple therapy and concomitant therapy are advised in regions with high clarithromycin resistance, these treatments commonly cause frequent adverse events and require the use of two or three antibiotics. This review article evaluates the effectiveness of 14-day mono-antibiotic therapies for H. pylori infection through randomized controlled trials conducted from 1 October 2014 to 1 October 2024. The pooled eradication rates for 14-day high-dose amoxicillin/proton pump inhibitor (PPI) dual therapies were 86.1% (3335/3875; 95% confidence interval (CI): 85.1–87.2%) by intention-to-treat (ITT) analysis and 87.3% (3232/3702; 95% CI: 86.2–88.4%) by per-protocol (PP) analysis. For 14-day high-dose amoxicillin/vonoprazan dual therapies, the rates were 87.4% (1085/1241; 95% CI: 85.5–89.2%) by ITT and 93.0% (1044/1124; 95% CI: 91.5–94.5%) by PP. In the penicillin-allergic population, 14-day tetracycline/vonoprazan dual therapy showed eradication rates of 92.0% (138/150) by ITT and 95.1% (135/142) by PP. In conclusion, 14-day tetracycline/vonoprazan dual therapy presents an effective option for eradicating H. pylori in patients allergic to penicillin. For those without a penicillin allergy, first-line treatments can include 14-day mono-antibiotic regimens, such as high-dose amoxicillin/PPI dual, high-dose amoxicillin/vonoprazan dual, and tetracycline/vonoprazan dual therapies. Full article