Helicobacter pylori infection remains one of the most common chronic bacterial infections worldwide and represents a major etiological factor in diseases of the upper gastrointestinal tract, including chronic gastritis, peptic ulcer disease, and gastric cancer. Despite continuous refinement of eradication regimens based on antibiotics and proton pump inhibitors, treatment efficacy has progressively declined, primarily due to increasing antimicrobial resistance and the ability of H. pylori to form biofilm structures. Accumulating evidence indicates that biofilm formation, bacterial virulence, and modulation of host immune responses constitute an interconnected network of mechanisms that collectively promote bacterial persistence and therapeutic failure. This review outlines an integrated pathogenic framework for H. pylori, focusing on the functional interplay between key virulence determinants - including CagA, VacA, neutrophil-activating protein (NAP), high-temperature requirement A (HtrA), IceA, DupA, urease, catalase, and adhesins - and their contribution to biofilm development, epithelial barrier disruption, and sustained gastric inflammation. Biofilm formation is highlighted as a central adaptive strategy that not only limits antibiotic penetration but also induces metabolic dormancy, enhances efflux pump activity, and increases tolerance to oxidative stress and immune-mediated clearance, thereby significantly reducing the effectiveness of standard eradication therapies. In addition, the review incorporates novel insights derived from recent high-throughput omics approaches, including genomics, transcriptomics, proteomics, and metabolomics, which have advanced the understanding of H. pylori pathogenicity, adaptive responses, and resistance mechanisms at a systems level. A major emphasis is placed on recent advances in therapeutic strategies that extend beyond conventional antibiotic-based regimens. The review summarizes current pharmacological approaches, including the use of more potent acid-suppressive agents such as vonoprazan, susceptibility-guided and personalized eradication therapies, and emerging anti-biofilm interventions, including antimicrobial peptides, phytochemicals, small-molecule inhibitors, and enzymatic degradation of the extracellular polymeric matrix. In addition, nanotechnology-based drug delivery systems are discussed as promising tools to improve antibiotic stability, bioavailability, and targeted release within the hostile gastric environment. In conclusion, effective management of H. pylori infection requires a mechanistically informed and multidisciplinary approach that integrates bacterial virulence, biofilm biology, host immune modulation, and regional antimicrobial resistance profiles. The combination of established pharmacological therapies with innovative anti-biofilm and nanomedicine-based strategies represents a promising direction for improving eradication outcomes and limiting the further development of antimicrobial resistance.
Craniosacral therapy (CST) is a non-invasive, alternative therapeutic approach based on the concept of the craniosacral system and its inherent rhythm. This rhythm is a subtle, cyclical expansion and contraction of the dural membranes and cerebrospinal fluid (CSF), which regulates intracranial pressure and the physiological function of the craniosacral system (CS). The CS constitutes a semi-closed, physiological hydraulic network comprising the skull (cranium), the sacrum (tailbone), the associated membranes, and the circulating CSF. Within this system, CSF provides both protection and nourishment to the brain and spinal cord - the body's most vital organs. The craniosacral rhythm (CSR) refers to the physiological rhythm of expansion and contraction within the CS that regulates CSF pressure. Magnetic resonance imaging (MRI) studies have demonstrated the pulsatile nature of intracranial and spinal CSF circulation of approximately 6 to 12 cycles per minute. Experienced CST practitioners palpate this rhythm and assess it for abnormalities that may indicate dysfunction in the fascia, dural membranes, or CSF flow. CST techniques involve gentle manual palpation to release restrictions in dural and fascial structures and restore homeostasis. Some studies suggest that CST may provide therapeutic benefits for a range of conditions, including migraine headaches, non-specific low back pain, depression, anxiety, fibromyalgia, chronic pain, and improved overall quality of life. However, its efficacy for many other conditions remains controversial, and the scientific evidence supporting its physiological mechanisms is limited. This review presents a balanced overview of CST, highlighting its current clinical status, established and hypothesized mechanisms, and emerging directions for future research into both CST and the underlying pathophysiology of the craniosacral system. Notably, recent high-quality basic research has begun to elucidate potential neurophysiological pathways and pathophysiology relevant to CS. For example, new studies have revealed direct anatomical and functional connections between the dura mater and the brain. Furthermore, they demonstrated that in migraine models, trigeminal ganglion neurons are directly activated by CSF influx. Meningeal lymphatic calcitonin gene-related peptide (CGRP) signaling has been implicated in pain induction through CSF efflux and neuroinflammation. These findings opened new avenues for understanding the physiological underpinnings of CST and its potential impact on neural and autonomic regulation.
The optimal choice of general anesthesia technique for patients with obesity remains the subject of debate. At present, the anesthesia methods widely applied in clinical settings mainly consist of propofol-based intravenous anesthesia and sevoflurane-based inhalation anesthesia. For patients undergoing metabolic bariatric surgery, there is limited evaluation data concerning the overall recovery effect, and the conclusions are varied. This study aims to explore the difference between intravenous anesthesia and inhalation anesthesia in terms of the quality of early postoperative recovery in patients who undergo bariatric surgery. A total of 104 patients with obesity who underwent elective laparoscopic sleeve gastroplasty were randomly assigned two groups: the propofol (T) group and the sevoflurane (S) group. Five cases were excluded due to last-min changes in surgical plans, and finally 99 patients were included in the analysis (49 in Group S and 50 in Group P). In both groups, patients received propofol, remifentanil and rocuronium for induction. In Group P, anesthesia was maintained with intravenous propofol and remifentanil. In Group S, anesthesia was maintained with sevoflurane and remifentanil. The quality of recovery-40 (QoR-40) scale and the pain numerical rating scale (NRS), were used for evaluations before surgery and 24 and 48 h after surgery, and other relevant indicators were recorded. In results: compared with Group S, the QoR-40 score at 24 h in the Group P was significantly higher (161 and 150; P<0.001), indicating better recovery quality in the Group P than in the Group S. Among the five dimensions of the QoR-40, the Group P showed significantly better physical comfort, psychological support, and physical independence at 24 h postoperatively. No significant intergroup difference in QoR-40 scores was observed at 48 h postoperatively, and NRS scores were comparable between groups at both time points. The study results indicate that propofol intravenous anesthesia is associated with better recovery quality at 24 h after metabolic bariatric surgery, while the recovery difference between the two methods diminishes by 48 h.
The digestive system, comprising gastrointestinal (GI)-tract and connecting organs, such as liver or pancreas, has a wide autonomy in the human body due to the presence of specific nervous and endocrine systems of its own and can act voluntarily without stimulation from the rest of the body. This wide physiological autonomy of a digestive tract does not exclude connection with other organs and central as well as peripheral mechanisms controlling nervous and hormonal systems. The vagal nerve is a structure connecting GI-tract with brain centers. Both, the afferent and efferent components of the vagal nerve innervate the GI-tract and modify its functions. An example of stimulants affecting afferent fibers of vagal nerve are digestive hormones, such as cholecystokinin (CCK), because CCK is commonly recognized as the gut hormone that stimulates specific receptors located at the endings of vagal afferent fibers and promotes the vago-vagal reflex. Recent studies have documented that GI-tract is a source of abundant hormones regulating the hunger - satiety centers in the hypothalamus via afferent fibers of the vagal nerve, forming the brain-gut axis. In addition, local endocrine cells in the GI-tract can produce biogenic amines, such as serotonin or histamine which also can stimulate afferent component of this axis. The complexity of brain - gut axis is augmented by the participation of other factors, that can influence it, such as metabolites of gut microbiota, changes in the intestinal permeability, the proinflammatory cytokines and other immune responses, activity of the stress hormones, such as adrenaline, cortisol and aldosterone. In addition, the presence of the short chain fatty acids (SCFA) can modify the bidirectional brain-gut and gut-brain axes activity, indirectly, as nutrients for specific bacterial species, or directly, by stimulation of the specific receptors located within the GI wall. In this review, we focused on the brain-gut axis is involved in the strenghtening of the mucosal barrier via maintaining of oxidative balance. The main process reaction causing cellular destruction is lipid peroxidation. Lipid peroxides disrupt the structure of cellular lipids, making this barrier more permeable. Increased cellular permeability of GI-tract barrier contributes to the stimulation of the brain-gut axis. Pharmacological agents, affecting mucosal blood flow, such as cyclooxygenase (COX) products, COX inhibitors and pentoxifylline, are also able to modify functions of the brain-gut axis. We conclude that brain-gut axis plays a particularly important role in maintaining of mucosal barrier in GI-tract and alteration in its functions is implicated in pathogenesis of various diseases of the gut.
Myopia is one of the most prevalent refractive errors and one of the leading causes of visual impairment and blindness worldwide. It results from a mismatch between the axial length and optical power of the eye, resulting in a focal plane that lies in front of the retina. In children and young adults, myopia is most commonly caused by excessive elongation of the eyeball during development - a hallmark of school-age and some early-onset genetic forms of myopia. However, myopic refractive error can also result from other mechanisms, such as increased lens power in age-related nuclear cataracts or corneal steepening in keratoconus, which are not associated with axial elongation. The prevalence of myopia in young Asian adults has increased from 20-30% to 80-85% over the last 50 years. In contrast, recent meta-analytic data for European young adults, emphasizing studies with cycloplegic refraction essential for accuracy, indicate myopia prevalence rates of approximately 19-24%. The prevalence of high myopia (greater than or equal to-6.0 diopters) has increased disproportionately to myopia in the last 50 years, from 1-5% to 10-20% and became a global problem. The reason for this state of affairs is believed to be lifestyle and prolonged near vision activities. Although refractive error can be corrected, sight-threatening pathologies such as retinal detachment, macular degeneration, glaucoma, and cataracts are more challenging to control. Owing to years of research, the biological mechanisms of eye growth and refractive development are increasingly elucidated. The signaling cascade mechanisms that link the retinal image processing and alterations in choroidal thickness and scleral development have also been studied. While the retina can detect defocus and changes in defocus, decades of research have led to a growing understanding of the fundamental pathways in visually guided eye growth, yet the precise initial mechanisms by which the retina senses and transduces these optical signals continue to be an active and important area of investigation. Animal studies have demonstrated that the retina can locally regulate visually guided eye growth through intrinsic mechanisms, even in the absence of direct input from the brain. The precise molecular mechanisms underlying common forms of myopia, particularly those involving axial elongation, are yet to be fully elucidated. This reflects the complexity and multifactorial influences inherent even in these prevalent forms, alongside the challenges posed by experimental models in completely recapitulating all aspects of the human condition.
Proper placental angiogenesis is essential for fetal growth and maternal well-being during pregnancy. Imbalance between pro-angiogenic (placental growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A)) and anti-angiogenic (soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng)) factors underlies preeclampsia (PE), fetal growth restriction (FGR), and related complications. The primary scientific aim of this review is to comprehensively synthesize current evidence on the physiological mechanisms of placental angiogenesis, with a focus on VEGF/PlGF and endothelial nitric oxide synthase-nitric oxide (eNOS-NO) pathways, and to evaluate the diagnostic and predictive utility of the sFlt-1/PlGF ratio in placenta-related disorders (PE, FGR, intrauterine fetal demise, preterm birth). A secondary aim is to assess the clinical integration of angiogenic biomarkers into risk stratification and management algorithms according to international guidelines. Narrative review of literature from PubMed, Scopus, and Web of Science (2015-2025). Search terms: "placental angiogenesis", "VEGF", "PlGF", "sFlt-1", "sFlt-1/PlGF ratio", "preeclampsia", "fetal growth restriction", "spiral artery remodeling", "endothelial dysfunction". Key references were PROGNOSIS study (64) and two-stage model (2) and VEGF pathway (13). In normal pregnancy, PlGF enhances VEGF-A signaling via VEGFR-1, promoting spiral artery remodeling and villous angiogenesis. In PE and FGR, placental hypoxia drives sFlt-1 overexpression, reducing free PlGF and VEGF, leading to endothelial dysfunction. The sFlt-1/PlGF ratio<38 rules out PE within 1 week (negative predictive value [NPV] 99.3%); ratios≥85 (early-onset) and≥110 (late-onset)), predict adverse outcomes with high specificity. First-trimester screening combining PlGF with maternal factors and uterine artery Doppler detects 90% of preterm PE cases. The sFlt-1/PlGF ratio is a robust biomarker for early detection and risk stratification of PE and FGR. Repeat testing improves individualized management. Integration into clinical practice, per International Society for the Study of Hypertension in Pregnancy (ISSHP) 2021 and American College of Obstetricians and Gynecologists (ACOG) 2023 guidelines, supports timely intervention and reduces perinatal morbidity.
We undertook this study to investigate the effect of exosomal microRNA-143-3p (miR-143-3p) on the biological behavior and angiogenesis in breast cancer. We transfected human breast cancer cells (MDA-MB-231) with miR-143-3p Agomir or Agomir-NC, and we isolated the exosomes (ex) that were secreted and named these miR-143-3p Agomir-ex and Agomir-NC-ex, respectively. We performed real-time polymerase chain reaction (real-time PCR) to detect the level of exosomal miR-143-3p. We treated the MDA-MB-231 cells with exosomal miR-143-3p Agomir-ex and Agomir-NC-ex. We measured the cellular miR-143-3p concentration using real-time PCR, cell proliferation using the cell counting kit-8 (CCK-8), apoptosis using flow cytometry, the abilities of cell migration and invasion using FCM (flow cytometry), and the levels of vascular endothelial growth factor (VEGF) in cell supernatants using the enzyme-linked immunosorbent assay (ELISA). We constructed nude mouse MDA-MB-231 cell transplantation tumor models and injected Agomir-NC, miR-143-3p Agomir, Agomir-NC-ex, and miR-143-3p Agomir-ex intratumorally to observe the tumor growth. Next, we isolated the tumor tissues and measured the expression of miR-143-3p, pathological change, apoptosis, levels of Ki67, VEGF, and CD31, and microvessel density using real-time PCR, hematoxylin and eosin (HE) staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and immunohistochemistry, respectively. We found that, in comparison with Agomir-NC-ex, the expression of miR-143-3p was upregulated in miR-143-3p Agomir-ex, and miR-143-3p Agomir-ex increased the levels of miR-143-3p in breast cancer cells, inhibited the proliferation, migration, and invasion of breast cancer cells, promoted apoptosis, and decreased the levels of VEGF in the cell supernatant. Our experiments with the nude mouse transplantation tumor revealed that both miR-143-3p Agomir-ex and miR-143-3p Agomir reduced tumor growth and the expression of Ki67 protein, increased the levels of miR-143-3p, promoted tumor cell apoptosis, and inhibited the expressions of CD31 protein and VEGF, and angiogenesis. In our current study, we found that the exosomal miR-143-3p inhibited malignant biological behavior and angiogenesis in breast cancer.
Obesity contributes significantly to cancer development due to superfluous adipose tissue interfering with physiologic balance. The current narrative review outlines the molecular and physiological pathways linking obesity and cancer and highlights the role of natural products as preventive and therapeutic agents. Underlying processes intertwining obesity and cancer include chronic low-grade inflammation, insulin resistance, hormonal imbalance, adipokine dysregulation, oxidative stress, and changes in the gut microbiome. All of these are used to facilitate tumor-promoting microblood to increase tumor growth and help cancerous cells proliferate and metastasize. There are specific mediators that are important in the activation of oncogenic signalling pathways, such as tumor necrosis factor-alpha, interleukin 6, insulin-like growth factor-1, estrogen, leptin, and reactive oxygen species. Phytochemicals that have the potential to be used as natural anti-inflammatory, antioxidant, and anticancer agents include, but are not limited to, curcumin, resveratrol, epigallocatechin gallate (EGCG), quercetin, berberine, gingerol, and capsaicin. The compounds regulate major molecular pathways of the obesity-related cancers. A new method of delivery that automatically and involuntarily targets the delivery mechanism by use of nanotechnologies has demonstrated its capacity in increasing bioavailability and therapeutic effects of these bioactive agents. To reduce the burden of this impact of obesity on cancers, a strategy involving a blend of lifestyle changes, pharmacological treatment, and science-based natural solutions is required. We conclude that in order to increase the potential of natural products, there is a need to have clinical studies on oncology and public health, as well as regulatory advancement.
Matrine (MAT), a commonly employed Chinese botanical, has a long-standing history of application in the treatment of inflammation and cancer. Nevertheless, the precise molecular mechanism underlying MAT's impact on thymoma remains unresolved. Consequently, the objective of this investigation was to assess the influence of MAT on thymomas and ascertain the potential mechanisms through which it modulates the Wnt3a/β-catenin pathway. Thy0517 cells were treated with different doses of MAT to construct a thymoma cell therapy model in vitro, and given Wnt3a/β-catenin pathway agonist Laduviglusib for follow-up experiments. The effect of different doses of MAT on the proliferation, colony formation ability, apoptosis, migration, invasion, and stemness of Thy0517 cells was determined by MTT, colony formation assay, flow cytometry, wound healing assay, Transwell assay, and spheroid formation assay, respectively. Genes and proteins were evaluated by RT-qPCR and/or Western blot. High-dose MAT significantly inhibited the proliferation, migration, invasion, and stemness of Thy0517 cells, which also proved the anti-tumor effect of MAT. The suppressive impact of MAT on cellular function could potentially be augmented through the blockade of the Wnt3a/β-catenin pathway, thereby providing additional evidence for the pivotal role of MAT as a signaling pathway in governing the migratory and invasive capabilities of thymoma cells. We found that MAT has anti-tumor effects, inhibiting the proliferation, migration, invasion, and stemness of thymoma cells by regulating the Wnt3a/β-catenin pathway.
This research aimed to examine the clinical relevance and biological function of the tight junction protein claudin-2 (CLDN2) in gastric cancer, along with its regulatory interactions with lymphoid enhancer-binding factor 1 (LEF1) and the Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway. Analysis of CLDN2 expression and its prognostic implications in gastric cancer was conducted using data from the Cancer Genome Atlas (TCGA) database. The effects of CLDN2 or LEF1 on gastric cancer (GC) cells were detected by RT-qPCR, Western blot, cell-counting kit-8 (CCK-8), transwell assay, flow cytometry, CO-IP and immunofluorescence assays. The interactions between CLDN2 and LEF1 was predicted and validated using Gene MANIA and GEPIA. The functional association between CLDN2 and LEF1 was analyzed by rescue experiments. In GC tissues, CLDN2 was significantly upregulated and correlated with tumor stage, lymph node metastasis, and poor prognosis, showing elevated levels in young patients (21-40 years old) and individuals infected with Helicobater pylori (H. pylori). CLDN2 silencing inhibited GC cell proliferation, migration and invasion, induced G1-phase cycle block and apoptosis, and decreased cyclin D1 expression. CLDN2 and LEF1 were positively correlated and directly interacted, and suppressing LEF1 hindered the progression of GC. CLDN2 reduced KEAP1 expression and promoted NRF2 protein stability through post-transcriptional regulation. Silencing CLDN2 or LEF1 activated the KEAP1/NRF2 pathway and inhibited downstream p65, IkappaB kinase (IKK) and IκB protein expression. Reducing LEF1 levels counteracted the effects of CLDN2 on GC cell growth and KEAP1/NRF2 pathway. Increased levels of CLDN2, which modulate the LEF1 and KEAP1/NRF2 pathways, are correlated with GC progression and may be used as a marker for poor prognosis.
Vaspin, a visceral-adipose-tissue-derived serine protease inhibitor, is involved in the development of obesity, insulin resistance, energy metabolism, and reproduction. Its expression and regulation were studied in the human and rat placenta; however, the role of this adipokine in placental endocrine function has never been studied. The present study aimed to investigate the in vitro effects of vaspin on the endocrine function of the human placental syncytiotrophoblasts BeWo cell line and villous explants collected during the third trimester of pregnancy. BeWo cells (n=4) or villous explants (n=3) were cultured with vaspin at doses of 0.1, 1, and 10 ng/ml for 24, 48, and 72 h. The levels of progesterone (P4), estradiol (E2), human chorionic gonadotropin (hCG), and human placental lactogen (hPL) were determined in the culture medium via enzyme-linked immunosorbent assay (ELISA). In addition, the mRNA and protein expression of 3β-hydroxysteroid dehydrogenase (HSD3B1/3βHSD), aromatase (CYP19A1/CYP19), CGB3/hCG, and CSH1/hPL were determined via real-time PCR and Western blotting, respectively. We analyzed the role of pharmacological inhibitors of extracellular signal-regulated kinase (ERK1/2) and protein kinase A (PKA) in the vaspin action on hormone secretion. We observed that vaspin has a modulatory effect on the secretion and expression of placental hormones in BeWo cells and placentas from physiological pregnancies. However, in most cases, the effect was inhibitory on the parameters examined. Moreover, we noted that PKA participates in reducing E2 secretion, while ERK1/2 is involved in hCG level. These findings indicate that vaspin is a new regulator of human placental endocrine function.
Pancreatic cancer remains one of the most aggressive malignancies with limited therapeutic options and poor prognosis. Erlotinib (OSI-774), a small-molecule tyrosine kinase inhibitor (TKI), is clinically used in combination with gemcitabine, yet its efficacy is limited by modest improvements in overall survival (OS) and significant side effects. The aggregation of erlotinib in aqueous solutions further restricts its bioavailability. This study investigates the potential of Congo red (CR), a supramolecular carrier, to enhance the therapeutic impact of erlotinib against pancreatic cancer cells. Biophysical analyses using UV-visible spectroscopy (UV-Vis) and dynamic light scattering (DLS) confirmed the formation of stable CR-erlotinib co-aggregates with optimal molar ratio of 5:1. The effects of erlotinib alone and in combination with CR (CR:OSI-774) were evaluated on two pancreatic cancer cell lines (PANC-1 and BxPC-3). CR:OSI-774 complexes demonstrated significantly lower IC50 and IC90 values compared to erlotinib monotherapy, indicating enhanced anti-proliferative effects. While erlotinib induced apoptosis, CR:OSI-774 primarily triggered necrotic cell death. Importantly, both compounds significantly inhibited cancer cell migration and invasion, with CR:OSI-774 showing superior inhibition of invasive capacity. CR alone did not negatively affect cell viability or apoptosis/necrosis rates. Nanomechanical measurements using atomic force microscopy revealed an increase in cellular stiffness after treatment, particularly in cells exposed to the CR-erlotinib complex, suggesting changes in cytoskeletal organization associated with reduced motility. Furthermore, quantitative protein analysis using the Jess capillary electrophoresis system revealed a decrease in AKT phosphorylation without significant changes in total AKT levels, indicating effective modulation of EGFR signaling via supramolecular aggregation. These findings suggest that supramolecular aggregation with CR represents a promising strategy to enhance erlotinib efficacy in pancreatic cancer therapy while potentially reducing systemic toxicity. The approach opens new avenues for personalized medicine and targeted anti-cancer therapy.
Adriamycin (ADR)-induced nephrotic syndrome (NS) is a common renal disease model characterized by proteinuria, glomerular damage, and inflammatory responses. Baicalin, a bioactive flavonoid derived from Scutellaria baicalensis, demonstrates anti-inflammatory and anti-fibrotic properties. This study aims to investigate whether baicalin alleviates ADR-induced NS by regulating the transforming growth factor-beta (TGF-β)/Smad signaling pathway and the NOD-like receptor family, pyrin domain-containing protein 3 (NLRP3) inflammasome. A murine NS model in vivo was established by administering 10 mg/kg ADR to male C57BL/6J mice. Experimental groups were treated orally with 20 mg/kg or 40 mg/kg baicalin for 6 weeks. The following parameters were measured in each group: 24-h urinary protein, serum creatinine (Scr), blood urea nitrogen (BUN), total protein, albumin, total cholesterol, and triglycerides. In vitro, a cellular NS model was established by treating mouse podocyte cells (MPC5) with 0.75 µmol/L ADR, and the protective effects of baicalin were evaluated. Protein expression levels of the TGF-β/Smad signaling pathway and NLRP3 inflammasome were analyzed by Western blot. The secretion levels of interleukin-4 (IL-4), interleukin-8 (IL-8), interleukin-1β (IL-1β), and interleukin-18 (IL-18) were assessed by enzyme-linked immunosorbent assay, and the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) were measured in cells. ADR reduced MPC5 cell viability to below 50% and increased MDA levels (≥6 nmol/mg prot). The expression of NLRP3 (upregulated by 4-fold), α-smooth muscle actin (upregulated by 3-fold), N-cadherin (upregulated by 3-fold), and IL-8/IL-1β/IL-18 (all upregulated by more than 1-fold) was significantly elevated. Treatment with 12.5 µmol/L baicalin markedly reversed these changes, restoring cell viability to over 85% and bringing pathway protein and cytokine levels close to those of the control group. In vivo, ADR-induced NS mice exhibited doubled 24-h urinary protein, Scr, and BUN levels, along with renal interstitial inflammatory infiltration and a 60% downregulation of podocin expression. Treatment with 40 mg/kg of baicalin restored these indicators to levels comparable to those in untreated mice, with effects similar to irbesartan (P<0.05). We concluded that baicalin demonstrated significant renoprotective effects in both in vivo and in vitro models of ADR-induced NS by regulating the TGF-β/Smad pathway and NLRP3 inflammasome, mitigating renal injury and inflammation. These results offer experimental support for the potential use of baicalin as a therapeutic agent for NS.
Patients with Crohn's disease (CD) often exhibit low serum zinc levels. Experimentally, colitis models induced by intrarectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS) have shown exacerbated pathogenesis with zinc deficiency. Zinc, which is regulated by transporters (zip and znt), plays a crucial role in maintaining intestinal integrity. Zip transports zinc into the cytoplasm from the extracellular spaces or organelles, while znt moves it out of the cytoplasm into the extracellular space or into organelles. Although CD is an intractable gastrointestinal inflammatory condition that is developed predominantly in the terminal ileum, few studies have focused on the ileitis. Therefore, we aimed to identify zinc transporters related to ileitis using the TNBS/ethanol-induced ileitis model. Ileitis was induced in mice by ileal luminal injection of TNBS (1.5 mg/0.8 mL/mouse) in 50% ethanol. The mice were euthanized 6, 24, or 48 h after the injection for histological and physiological analyses. Serum zinc levels and the expression of zinc transporters in duodenal and ileal tissues were also evaluated. Ileal luminal injection of TNBS/ethanol significantly increased tumor necrosis factor alpha (TNF-α) and interleukin 1beta (IL-1β) mRNA expression at 24 h, then caused ileal epithelium detachment at 48 h. Serum zinc levels were significantly decreased, accompanied by reduced expression of zip4 and znt1 in the ileum, 6 and 24 h after the injection. The expression of zip4 and znt1 in the duodenum was significantly increased at 24 and 48 h, respectively, and serum zinc levels recovered to around normal levels. Furthermore, zip7 expression in the ileum significantly decreased at 24 h but recovered slightly at 48 h, coinciding with re-epithelialization. Overall, the pathogenesis of TNBS/ethanol-induced ileitis involves dynamic changes in zinc transporters.
Although enzalutamide (ENZA) has improved the overall survival of patients with metastatic prostate cancer, ENZA resistance (ENZA-resistant) inevitably develops, largely limiting its efficacy. Alternative oncogenic pathways may bypass androgen receptor (AR) signaling to promote ENZA-resistant. Glutamyl-tRNA synthetase 2 (EARS2) is involved in mitochondrial biogenesis and is associated with cancer, but its action mechanism in prostate cancer (PCa) is not well defined. EARS2 expression was detected in primary PCa and castrate-resistant prostate cancer samples, ENZA-resistant cell lines, and ENZA-resistant xenograft models, and the prognostic relationship of EARS2 in patients with PCa was analyzed. In AR-sensitive LNCaP cells, changes in EARS2 expression were explored before and after stimulation with dihydrotestosterone (DHT) or bicalutamide. AR was knocked down in AR-positive LNCaP and C4-2B cells to explore the relationship between EARS2 and AR. The effect of EARS2 on PCa cells was further explored. ENZA-resistant xenograft model was built to explore the effect of EARS2 on tumorigenesis in vivo. EARS2 was knocked down in C4-2B-ENZA-resistant, and the relationship between EARS2 and mitochondrial biogenesis and reactive oxygen species (ROS) homeostasis was investigated in PCa cells. Finally, the relationship between EARS2 and striatin 4 (STRN4) was explored. EARS2 expression was elevated in PCa and correlated with ENZA-resistant, and high EARS2 expression was associated with poorer patient prognosis. In androgen-sensitive LNCaP cells, DHT inhibited EARS2 expression, and silencing AR increased EARS2 expression. Suppressing EARS2 inhibited the proliferation, colony formation, migration and invasion ability, down-regulated the IC50 of ENZA in ENZA-resistant cells, and promoted apoptosis. Stable EARS2 downregulation in C4-2B-ENZA-resistant significantly inhibited tumor growth. Suppressing EARS2 in ENZA-resistant cells may lead to increased mitochondrial biogenesis and ROS generation. Mechanistically, EARS2 inhibited mitochondrial biogenesis and ROS generation in PCa cells by targeting STRN4. EARS2 targets STRN4 to modulate mitochondrial biogenesis and ROS homeostasis mediating ENZA-resistant.
Lower limb arterial disease is among the most common vascular disorders, with its incidence rising significantly in aging populations, thus posing a major social and healthcare challenge. Currently, L-arginine is considered by vascular surgery experts as a compound with therapeutic potential in intermittent claudication, though its clinical efficacy remains insufficiently confirmed. The aim of this study was to evaluate the efficacy and safety of oral L-arginine supplementation in patients with atherosclerotic lower limb ischemia, with particular regard to lipid metabolism disorders. A randomized study included 100 patients (62 men and 38 women) over 50 years of age with Fontaine stage II ischemia. The study group received oral L-arginine at a dose of 6 g/day for 30 and 60 days. Clinical parameters were assessed, including the ankle-brachial index (ABI) and pain-free walking distance (PFWD), along with oxidative stress markers (serum nitric oxide (NO) concentration, total antioxidant status (TAS)) and lipid profile (total, HDL, and LDL cholesterol, and triglycerides). In both study and control groups, subgroups with hypertriglyceridemia, hypercholesterolemia, and mixed hyperlipidemia were additionally identified. Evaluations were performed at baseline, day 30, and day 60. After 30 and 60 days, significant increases in NO and TAS levels (p<0.001), as well as extended PFWD (p<0.001), were observed across all subgroups receiving L-arginine compared with controls. No significant effects were observed on ABI (right or left) or on cholesterol and triglyceride concentrations. These findings support the potential role of L-arginine as a supportive therapy in the management of atherosclerotic complications, particularly by improving oxidative balance and exercise tolerance.
Gastric cancer (GC) is one of the most prevalent malignant cancers, with currently unsuccessful treatment strategies for patients. Increased PI3K/AKT/STAT-3 pathway activity has been observed in patients with GC. Morin (MRN), which is a flavonoid, exhibits significant anticancer activity by inhibiting the PI3K/AKT signaling pathway. However, monotherapy with MRN has faced challenges due to poor bioavailability and rapid elimination. This study investigated the combined effects of MRN and paclitaxel (PTX) on apoptosis induction and their molecular mechanisms in GC cells (HGT-1). After 24 h of MRN and PTX exposure, various assays were performed to assess the suppression of HGT-1 cell proliferation. These included cytotoxicity assessments, reactive oxygen species (ROS) level measurements, apoptotic morphological features, mitochondrial membrane potential (ΔΨm), nuclear fragmentation, and cell cycle analysis. Further, the effect of MRN and PTX on STAT-3 expression and various proliferation and apoptotic proteins was investigated using western blotting. The results revealed that the MRN and PTX combination significantly induced cytotoxicity, increased ROS levels, and altered ΔΨm, resulting in HGT-1 cell apoptosis (P<0.05). Furthermore, MRN and PTX treatment decreased the expression of oncogenic proteins, such as C-Fos, KRAS, and p-ERK1, in HGT-1 cells (P<0.05). The combination treatment inhibited PI3K, AKT, and STAT3 expressions, thereby suppressing proliferation and inducing proapoptotic protein expression in HGT-1 cells. Therefore, the combination of MRN and PTX could serve as a therapeutic approach for malignant GC treatment.
Among many different types of vaginal therapy for women suffering from urogynecological disorders, we may distinguish hormonal vaginal treatment with oestrogens. Lately, there has been a new option of treatment- prasterone. It is prohormone which can be further metabolized and acts like both estrogens and androgens. The purpose of the study is to analyze the effect of short-term vaginal application of prasterone. We checked 39 women of age 28-85 suffering from prolapse or stress incontinence that consented to surgical treatment and hadn't used vaginal estrogens before. We analyzed vaginal maturation index (VMI), biocenosis, endometrial thickness, and blood level of estradiol and dehydroepiandrosterone sulfate (DHEA-S) The analyses were performed before and after eight weeks of vaginal preparation with prasterone 6.5 mg once daily, administered intravginally. Results of the main variables before and after treatment were as follows: estradiol [pg/mL] 63.25±101.85 vs. 49.62±99.85 (p=0.94); DHEA-S [µmol/L] 3.93±2.19 vs. 4.28±2.55 (p=0.02); endometrial thickness [mm] 3.65±3.79 vs. 3.97±3.42 (p=0.97); biocenosis score [1-4] 2.95±0.94 vs. 2.50±0.76 (p=0.02). The study showed a significant increase in the DHEA-S levels after treatment and decrease in the degree of biocenosis. No substantial differences were found in relation to estradiol levels, or endometrium size. Moreover, a notable increase in the VMI was observed. Prasterone preparation has the effect of improving vaginal maturation and bacterial flora in both patients with stress urinary incontinence and female organ prolapse. In addition, these parameters are improved in both reproductive and menopausal women.
Ulcerative colitis (UC) belongs to inflammatory bowel disease (IBD), a group of chronic disorders of the gastrointestinal (GI) tract with unknown etiopathogenesis. The prevalence of IBD is increasing, and available therapeutic options do not lead to complete remission; therefore, there is a need to identify novel pharmaceutical strategies for UC. The aim of our study was to evaluate the suitability of the PSB-KK-1415, the G protein coupled receptor 18 (GPR18) receptor agonist, in the treatment of intestinal inflammation in mice. The impact of PSB-KK-1415 on the viability of human epithelial cell line CCD 841 CON was assessed using MTT assay. Dextran sodium sulfate (DSS) was used to induce colitis in mice. Colonic samples were collected at different stages of disease and Gpr18 expression was determined using real time RT-PCR. In the DSS model, the mice were treated with PSB-KK-1415 (5 mg/kg once daily) by different routes of administration. The anti-inflammatory potential of PSB-KK-1415 in vivo was evaluated based on macroscopic and microscopic scoring systems. As a result PSB-KK-1415 did not affect the viability of CCD 841 CON cells after 24 and 48 hours. The mRNA expression of GPR18 was significantly increased in the early and moderate stages of colitis as compared to the control group and decreased in severe colitis and during recovery. In the acute mouse model of UC, 5 mg/kg PSB-KK-1415 injected intraperitoneally tended to reduce the area of inflammation and improved the intestinal wall thickness as compared to mice with colitis. PSB-KK-1415 decreased MPO activity. No significant differences in anti-inflammatory effect were found with regard to the route of administration. In the chronic model of DSS-induced colitis, PSB-KK-1415 demonstrated anti-inflammatory properties, evidenced by a decreased area of inflammation in the colon and improved intestinal thickness as compared to inflamed animals. Our findings indicate that activation of the GPR18 receptor may be a potential target for modulation the course of chronic colitis in mice.
This study investigated the mechanism of the RNA-binding protein Epiplakin 1 (EPPK1) in ovarian cancer (OC). EPPK1 expression in OC tissues was analyzed using gene expression profiling interactive analysis (GEPIA). The association between EPPK1 expression and patient overall survival (OS) and progression-free survival (PFS) was evaluated through Kaplan-Meier analysis. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot were performed to quantify EPPK1 levels in 25 clinical OC specimens. An EPPK1-knockdown xenograft model was established to examine tumor growth and distant metastasis in vivo. The roles of EPPK1 and Yes-associated protein (YAP) in OC cell proliferation, migration, and immune escape were assessed in vitro. The EPPK1-YAP interaction was characterized. Analysis of the GEPIA database revealed elevated EPPK1 expression in ovarian serous cystadenocarcinoma, with Kaplan-Meier survival curves demonstrating significantly shorter OS and PFS in patients with high EPPK1 expression over a 5-year period. RT-qPCR and Western blot analyses confirmed EPPK1 upregulation in clinical OC specimens. Functional studies demonstrated that altered EPPK1 and YAP expression modulated OC cell proliferation, migration, invasion, and immune escape capabilities both in vitro and in vivo. Mechanistically, EPPK1 binds to and enhances YAP mRNA stability. Notably, YAP overexpression rescued the inhibitory effects of EPPK1 knockdown on OC cell proliferation, migration, invasion, and immune evasion in vitro. The results indicate that EPPK1 promotes immune evasion and distant metastasis in OC by stabilizing YAP RNA.