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.
This study explores the modulatory role of Pumilio RNA-binding family member 1 (circ_PUM1) in the neuroprotective mechanisms of 6-gingerol against Alzheimer's disease (AD)-related neuronal injury, providing new insights into circRNA-mediated regulation of neurodegeneration. Variations in circRNA expression indirectly influenced by 6-gingerol (6-GIN) were comprehensively assessed within AD experimental frameworks. The AD phenotype was not absent when hippocampal amyloid-β (Aβ) was introduced into rats, nor when SK-N-SH and SK-SY5Y cells were subjected to Aβ challenge, jointly constructing complementary in vivo and in vitro paradigms for mechanistic exploration. Hippocampal injury was assessed by water content measurement, histological analysis, and TUNEL staining for apoptosis. In cell models, viability, apoptosis, and inflammatory cytokines (interleukin-6, inducible nitric oxide synthase, tumor necrosis factor-α) were quantified. The expression and localization of circ_PUM1 were examined, and its direct interaction with miR-340-5p was confirmed, revealing a regulatory axis potentially mediating the neuroprotective effects of 6-GIN. We found that administration of 6-GIN effectively counteracted Aβ1-42-induced neurotoxicity by alleviating neuronal apoptosis, oxidative injury, and inflammatory responses. These protective effects were evidenced by the reduction of neuronal damage and brain edema scores, decreased secretion of proinflammatory cytokines and lipid peroxidation products malondialdehyde (MDA), as well as the restoration of endogenous antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. Exposure to aβ resulted in a marked downregulation of circ_pum1 expression accompanied by elevated miR-340-5p levels; notably, 6-GIN administration reversed these molecular alterations. Mechanistic analyses further confirmed that miR-340-5p directly binds to the 3'-UTR of pleomorphic adenoma gene like-2 (PLAGL2), thereby regulating the estimated glomerular filtration rate (EGFR)/hypoxia-inducible factor-1α (HIF-1α)/hypoxia-inducible factor-2α (HIF-2α) signaling axis implicated in neuronal survival and metabolic adaptation. Collectively, these findings suggest that circ_PUM1 confers neuroprotection against Alzheimer's disease pathology by sequestering miR-340-5p and activating the PLAGL2/EGFR/HIF-1α-HIF-2α cascade, elucidating a critical pathway through which 6-GIN exerts its therapeutic potential in attenuating Aβ-associated neuronal degeneration. In conclusion: 6-GIN alleviates Aβ-induced apoptosis, oxidative stress, and neuroinflammation in AD through circ_PUM1/miR-340-5p/PLAGL2/EGFR-HIF1/2A signaling pathway.
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.
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.
Aldosterone, the principal mineralocorticoid, is critical for regulating electrolyte balance and blood pressure through its interaction with mineralocorticoid receptor (MR). This review traces the historical evolution of aldosterone research, from its discovery in the 1950s to current insights into its biosynthesis and signaling mechanisms. It details the enzymatic pathways of aldosterone production, emphasizing the role of cytochrome P450 11β2 (CYP11B2) in both adrenal and extra-adrenal tissues, and elucidates the structural basis for its specificity. The physiological roles of aldosterone are explored, highlighting its regulation of ion transport proteins and its impact on cardiovascular health, including vascular remodeling and myocardial fibrosis. The review examines the complex signaling pathways activated by aldosterone, encompassing MR-dependent genomic and non-genomic effects, as well as MR-independent mechanisms. It also addresses aldosterone-independent MR activation by glucocorticoids under conditions of reduced 11β hydroxysteroid dehydrogenase type 2 (11β-HSD2) expression. Furthermore, the review consolidates findings on regulatory factors influencing aldosterone synthesis, such as the renin-angiotensin-aldosterone system, adrenocorticotropic hormone, potassium, sodium, and glucose levels, emphasizing systemic and local regulation, as a foundation for future clinical interventions in disorders associated with dysregulated aldosterone signaling.
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.
The research focused on investigating the function and underlying mechanisms of Danggui Shaoyao San (DSS) in nephrotic syndrome (NS). The NS rat model was established using doxorubicin (Dox), and 24-hour urinary protein (UP) level was measured in NS rats. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were detected using an automatic biochemical analyzer; morphological changes of renal tissues were observed by HE staining; serum interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) levels were measured by ELISA; and the protein expression of interleukin 13 (IL-13), signal transducer and activator of transcription 6 (STAT6), phospho signal transducer and activator of transcription 6 (p-STAT6) was evaluated by Western blot. NS cell model was established using Dox. Cell viability was detected by MTT, and apoptosis was detected by flow cytometry. DSS reduced UP, BUN, and SCr levels and also decreased serum IL-6, IL-1β, and TNF-α levels in NS rats in a dose-dependent manner. Renal tissue injury in NS rats was significantly lessened by DSS. Finally, DSS increased cell viability and decreased apoptosis. In a dose-dependent manner, DSS led to a dose-dependent inhibition of IL-13 and p-STAT6 protein expression. DSS alleviates NS by inhibiting IL-13/STAT6 axis activation.
Metabolic dysfunction-associated steatohepatitis (MASH) is an inflammatory disorder that results in ongoing liver inflammation and injury. During the course of hepatitis, parthenolide (PAR) promotes the recovery of liver function. Using a mouse model of MASH, the present study aimed to assess the effect of PAR on the condition. The MASH mouse model was developed using a high-fat diet combined with high-carbohydrate drinking, and measurements were taken for body weight, liver-to-body mass ratio, non-alcoholic fatty liver disease activity score, and levels of alanine aminotransferase and aspartate aminotransferase. Subsequently, liver injury was detected using hematoxyling and eosin staining, hepatic lipid accumulation was evaluated with oil red O staining, and liver fibrosis was assessed through Masson staining. Macrophage infiltration and M1 polarization were assessed by immunofluorescence staining for F4/80; and lipid metabolic, fibrotic, and pro-inflammatory indicators were detected by RT-qPCR; nuclear factor-κB (NF-κB) signaling pathway was assessed by Western blot. We found that PAR alleviated liver injury, improved lipid metabolism, and reduced fibrosis in MASH mice,. It also lowered macrophage infiltration in the liver, particularly decreasing M1 macrophages and pro-inflammatory cytokines. PAR inhibited the activation of the NF-κB pathway, and the protective effects were attenuated by an NF-κB pathway activators. We conclude that PAR ameliorates liver injury, hepatic lipid metabolism, fibrosis and inflammation in MASH mice, likely by suppressing the NF-κB pathway and thereby inhibiting M1 polarization.
White mulberry (Morus alba L.) leaves have traditionally been used to improve glycemic control in diabetic and prediabetic individuals; however, their effects in hypertension remain insufficiently characterized. This study evaluated the impact of dietary mulberry leaf supplementation on blood biochemical parameters and on renal, cardiac, and vascular outcomes in spontaneously hypertensive rats (SHR). In addition, the content of the key bioactive compound 1-deoxynojirimycin (DNJ) was quantified. Male SHRs, aged 4 months (n=10 per group), were assigned to receive either standard rat chow or chow supplemented with ground mulberry leaves (7% w/w; ~4.0 g/kg body weight; 1.46±0.07 mg DNJ/rat/day) for eight weeks. Mulberry leaves contained 1.15±0.01 mg DNJ/g dry weight, as determined by RP-HPLC-DAD. Supplementation significantly reduced glycated hemoglobin (HbA1c: 2.23% vs. 1.98%, p=0.021) and attenuated postprandial glucose elevation during oral glucose tolerance testing (112 vs. 94 mg/dL at 120 min, 0.85-fold; p=0.005). No significant effects were observed on renal, cardiac, or vascular biomarkers, as assessed by ELISA and standard blood analyses. Kidney histology, including vascular thickness and density, was unchanged. Vascular reactivity to acetylcholine and noradrenaline did not differ between groups, and no differences were detected in the isolated perfused heart model. These findings suggest a potential role for Morus alba leaves in dietary strategies targeting glucose regulation in hypertension and underscore the need for longer-term and translational investigations.
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.
The growing percentage of people suffering from drug-resistant depression increases interest in alternative therapies, particularly the usage of psychedelics such as psilocybin. The main source of psilocybin is the Psilocybe cubensis species. Due to the potential therapeutic benefits of psilocybin and the legal restrictions on its possession and use in the form of fungal fruiting bodies, this research work documents an attempt to obtain in vitro P. cubensis mycelium in which psilocybin and other biologically active substances acting on the central nervous system would be present. It was hypothesized that chronic microdosing with whole in vitro - cultured P. cubensis mycelium, containing psilocybin together with other neuroactive secondary metabolites, could exert anti-anxiety and antidepressant effects through their combined action. For this purpose, the anti-anxiety and antidepressant activity of mycelium microdosing in male C57BL/6J mice was investigated. The tail suspension test (TST), novelty suppressed feeding test (NSFT), sucrose preference test (SPT), locomotor activity (LA), and female urine sniffing test (FUST) were used to examine animal behavior. The chemical analysis was performed using high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) method. Analysis of the studied extracts showed that psilocybin was present only in the mycelium of the Cambodian strain, at a concentration of 20.78 mg per 100 g dry weight. The experiment showed that mycelium supplementation significantly reduced anxious behavior in mice on day 22 but did not affect locomotor activity, depressive, anxiety-related, or anhedonic behaviors at later stages of the experimental protocol. Although the results suggest the potential of P. cubensis mycelial cultures in anxiety prevention, further studies using higher doses or alternative models are needed to confirm and extend these findings.
Orthodontically induced root resorption (OIRR), a common complication of orthodontic treatment exacerbated by excessive force application, is linked to pro-inflammatory M1 macrophage polarization. This study investigates whether periodontal ligament cells (PDLCs) under heavy compression force regulate macrophage polarization via the CCL7/CCR1 axis to exacerbate OIRR. In the animal experiment, male Wistar rats were subjected to heavy orthodontic force to establish the orthodontic tooth movement model, with the inhibitor group receiving CCR1 antagonist BX471. Histological and immunohistochemical analyses were conducted to assess root resorption and RAW 264.7 polarization in vivo. In the in vitro cell culture study, human PDLCs subjected to heavy compression force were analyzed via RNA-seq, RT-PCR, and Western blot for CCL7 and inflammatory markers. Conditioned media from force-loaded hPDLCs were applied to RAW 264.7 cells, with and without CCR1 inhibition. As a result, heavy compression force significantly increased CCL7 expression in hPDLCs, promoting M1 polarization (TNF-α, iNOS) and inhibiting M2 polarization (Arg-1). CCR1 inhibition reversed this imbalance, restoring the M1/M2 ratio. In vivo, BX471 treatment attenuated root resorption and macrophage polarization. The CCL7/CCR1 signaling pathway mediates the interaction between PDLCs and macrophages, promoting M1 polarization and OIRR under orthodontic force. Targeting CCL7/CCR1 may offer a promising therapeutic approach to mitigate OIRR during orthodontic treatment.
The effect of bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) on intervertebral disc degeneration (IVDD) repair and healing and its possible mechanism were investigated. Tail IVDD puncture was performed on mice, and BMSC-Exos were injected into the joint cavity. The disc morphology was observed by HE staining, apoptosis rate of nucleus pulposus (NP) tissues was determined by TUNEL, and polarization of macrophages and NP cell damage were detected by Western Blot. An in vitro experimental model was established by co-culture of nucleus pulposus (NP) cells and M1 macrophages in a conditioned medium, and the improvement effect of BMSC-Exos on the proliferation of damaged NP cells was detected by CCK-8 assay. NP cell apoptosis was determined by flow cytometry. Inflammatory factors in NP cell supernatant was measured by ELISA. In results: BMSC-Exos reversed the degenerative changes of IVDD in mice. BMSC-Exos promoted the transformation of THP-1 cells from M1 to M2 and inhibited the release of inflammatory cytokines. BMSC-Exos inhibited matrix metallopeptidase 13 (MMP-13), matrix metallopeptidase 3 (MMP-3), and Cleaved caspase-3 expression in damaged NP tissues. BMSC-Exos significantly increased NP cell proliferation and blocked apoptosis. The concentration of inflammatory factors in the supernatant of NP cells treated with BMSC-Exos was significantly down-regulated. Conclusion: BMSC-Exos have a regenerative effect on IVDD, encourage macrophages to transform from M1 to M2, suppress NP cell apoptosis and inflammatory responses, and improve degenerative alterations in the intervertebral disc.
The development of colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations, leading to the inactivation of tumor suppressor genes and activation of oncogenes. Aquaporin 1 (AQP1) has been shown to promote tumor angiogenesis; however, its specific role in CRC proliferation and migration remains unclear. This study aims to investigate the functions of miR-210-5p and AQP1 in CRC cell proliferation and migration. Using online datasets from the Cancer Genome Atlas (TCGA) and ten clinical samples, we examined AQP1 expression in CRC. Bioinformatic analysis was conducted to identify miRNAs potentially regulating AQP1. The effects of miR-210-5p and AQP1 on invasion and migration were further assessed in vivo in xenograft Balb/c nu/nu mice. Results showed that dysregulated AQP1 expression in CRC was correlated with advanced clinical stage and venous invasion. miR-210-5p was predicted to bind AQP1 and may target its expression. In vitro experiments revealed that miR-210-5p inhibits CRC proliferation and invasion by downregulating AQP1, which subsequently reduces the expression of vascular endothelial growth factor (VEGR), Wnt-7a, Matrix metallopeptidase 2 (MMP2), MMP9, and β-catenin. Targeting AQP1 led to suppressed proliferation and migration of CRC cells. In summary, AQP1 is upregulated in CRC and regulated by miR-210-5p. Downregulation of AQP1 by miR-210-5p attenuates CRC proliferation and migration through decreasing VEGR, Wnt-7a, MMP2, MMP9, and β-catenin expression.
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.
Cellular senescence is a stable and irreversible state of proliferative arrest triggered by diverse stressors, inclh3uding DNA damage, oncogenic signaling, oxidative stress, and metabolic imbalance. Once regarded as a culture artifact, senescence is now recognized as a fundamental biological program that governs tissue homeostasis, development, aging, and disease. Based on its origin, senescence can be divided into two principal categories: damage-induced, encompassing replicative, oncogene-induced, and therapy-induced forms, and developmentally programmed, which orchestrates tissue patterning and remodeling during embryogenesis. These processes converge on the activation of p53/p21 and p16/RB tumor suppressor axes, sustained DNA damage response (DDR), and the establishment of the senescence-associated secretory phenotype (SASP). Acute senescence serves beneficial roles in tumor suppression, wound healing, and embryonic morphogenesis by transiently activating SASP-mediated immune clearance. However, persistent senescence becomes detrimental, promoting chronic inflammation, tissue dysfunction, and cancer progression. Within the tumor microenvironment, chronic SASP signaling driven by nuclear factor kB (NF-κB), CCAAT/enhancer-binding protein beta (C/EBPβ), and Signal Transducer and Activator of Transcription 3 (STAT3) fosters epithelial-to-mesenchymal transition (EMT), invasion, and therapy resistance. Therapy-induced senescence (TIS) often leads to polyploidization and the emergence of polyploid giant cancer cells (PGCCs) that can escape arrest, regenerate proliferative progeny, and drive tumor relapses. Thus, senescence represents a biological paradox: a protective, transient process that maintains tissue integrity but, when unresolved, transforms into a driver of aging and malignancy. Understanding the molecular determinants, distinguishing beneficial from pathological senescence is crucial for developing targeted senotherapies.
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.
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.
This review focuses on analysing existing research to offer a comprehensive understanding of the complex role minerals play in the pathophysiology of ischaemia. By examining changes in mineral levels, we aim to uncover the mechanisms by which these elements influence the onset and severity of ischaemic heart disease (IHD). Imbalances in key minerals (biologically active metal ions present in blood plasma and/or cells in dissolved form) such as calcium, magnesium, zinc, manganese and copper have been closely associated with the onset and progression of IHD. Disrupted calcium and magnesium levels, particularly altered calcium/magnesium ratios, contribute to vascular calcification and elevated blood pressure. Deficiencies in magnesium have been linked to greater risks of arrhythmias and poorer outcomes following cardiac events. Additionally, abnormal zinc and copper levels, along with their ratio, affect oxidative balance and lipid metabolism, suggesting that proper mineral regulation is essential for cardiovascular protection and reducing IHD risk. Elevated manganese levels may contribute to oxidative damage, potentially increasing the risk of IHD. As a conclusion this review emphasizes the significant role of minerals in IHD, noting their potential to support pharmacological treatments by reducing oxidative stress and improving heart health. While minerals like magnesium and calcium show protective effects, excess iron and zinc may increase risk. Despite promising findings, further large-scale studies are needed to confirm their therapeutic value and to guide evidence-based dietary strategies for IHD management.
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.
