Osteoarthritis (OA), a highly prevalent degenerative joint disease worldwide, is defined by articular cartilage degradation, abnormal bone remodeling, and persistent chronic inflammation. It severely compromises patients’ quality of life, and currently, there is no radical cure. Abnormal mechanical stress is widely regarded as a core driver of OA pathogenesis, and the exploration of mechanical signal perception and transduction mechanisms has become crucial for deciphering OA’s pathophysiological processes. Piezo1, a key mechanosensitive cation channel belonging to the Piezo protein family, has recently gained significant attention due to its pivotal role in mediating cellular responses to mechanical stimuli in joint tissues. This review systematically examines Piezo1’s expression patterns, regulatory mechanisms, and pathological functions in OA, with a particular focus on its dual roles in modulating chondrocyte homeostasis and bone metabolism disorders, while also delving into the underlying molecular signaling pathways and potential therapeutic implications. Piezo1, consisting of approximately 2 500 amino acids and forming a unique trimeric propeller-like structure, is widely expressed in chondrocytes, osteocytes, mesenchymal stem cells, and synovial cells. It exhibits permeability to cations such as Ca²⁺, K⁺, and Na⁺, and directly responds to membrane tension changes induced by mechanical stimuli like fluid shear stress and mechanical overload. In OA patients and animal models, Piezo1 expression is significantly upregulated, especially in cartilage regions subjected to abnormal mechanical stress (e.g., human temporomandibular joint cartilage). This overexpression is closely associated with aggravated cartilage degeneration, increased chondrocyte apoptosis, accelerated cellular senescence, and intensified inflammatory responses. Mechanical overload and pro-inflammatory cytokines (e.g., IL-1β) are key inducers of Piezo1 upregulation: IL-1β activates the PI3K/AKT/mTOR signaling pathway to enhance Piezo1 expression, forming a pathogenic positive feedback loop that inhibits chondrocyte autophagy, promotes apoptosis, and further accelerates joint degeneration. Mechanistically, Piezo1 mediates OA progression through multiple interconnected pathways. When activated by mechanical stress, Piezo1 triggers excessive Ca²⁺ influx, leading to endoplasmic reticulum stress (ERS) and mitochondrial dysfunction, which directly induce chondrocyte apoptosis. This process involves the activation of downstream signaling cascades such as cGAS-STING and YAP-MMP13/ADAMTS5. YAP, a transcriptional regulator, upregulates the expression of matrix metalloproteinase 13 (MMP13) and aggrecanase (ADAMTS5), thereby accelerating cartilage matrix degradation. Additionally, Piezo1-driven Ca²⁺ overload promotes the accumulation of reactive oxygen species (ROS) and upregulates senescence markers (p16 and p21), accelerating chondrocyte senescence via the p38MAPK and NF-κB pathways. Senescent chondrocytes secrete senescence-associated secretory phenotype (SASP) factors (e.g., IL-6, IL-1β), further amplifying joint inflammation. In terms of bone metabolism, Piezo1 maintains joint homeostasis by promoting the differentiation of fibrocartilage stem cells into chondrocytes and balancing bone formation and resorption through regulating the FoxC1/YAP axis and RANKL/OPG ratio. Therapeutically, targeting Piezo1 shows promising potential. Preclinical studies have demonstrated that Piezo1 inhibitors (e.g., GsMTx4) can reduce joint damage and alleviate pain in OA mice. Simultaneously, siRNA-mediated co-silencing of Piezo1 and TRPV4 (another mechanosensitive channel) decreases intracellular Ca²⁺ concentration, inhibits chondrocyte apoptosis, and promotes cartilage repair. Conditional knockout of Piezo1 using Gdf5-Cre transgenic mice alleviates cartilage degeneration in post-traumatic OA models by downregulating MMP13 and ADAMTS5 expression. Despite existing challenges, such as off-target effects of inhibitors, inefficient local drug delivery, and interindividual genetic variability, strategies like developing selective Piezo1 antagonists, optimizing targeted nanocarriers, and combining Piezo1-targeted therapy with physical therapy provide viable avenues for clinical translation. The authors propose that Piezo1 serves as a critical therapeutic target for OA, and future research should focus on deciphering its context-dependent regulatory networks, developing tissue-specific intervention strategies, and validating their efficacy and safety in clinical trials to address the unmet medical needs of OA patients.

OBJECTIVE To investigate the improvement effect and mechanism of processed Oxytropis falcata on renal fibrosis （RF） in rats. METHODS RF model was induced by adenine. After modeling， the rats were divided into the model group， positive control group （colchicine， 0.45 mg/kg）， and processed O. falcata low-， medium- and high-dose groups （0.5， 1， 2 g/kg）， respectively. Additionally， a blank group without modeling was set up， with 8 rats in each group. The positive control group and the various dosage groups of processed O. falcata were given the corresponding medicinal solutions intragastrically， while the blank group and model group were given equal volume of normal saline intragastrically， once daily for 28 consecutive days. The appearance and histopathological morphology of the rats’ kidneys were observed. Serum levels of renal function indexes [bl ood urea nitrogen （BUN）， creatinine （Cr） ] and inflammatory factors [interleukin-6 （IL-6） and tumor necrosis factor-α （TNF-α） ] in rats were detected. Protein expressions of fibronectin （FN）， α -smooth muscle actin （ α -SMA） and collagen type Ⅰ （Col-Ⅰ） in renal tissue of rats were determined. mRNA expressions of transforming growth factor-β 1 （TGF-β 1 ）， Smad3 and extracellular signal-regulated kinase 1/2 （ERK1/2） in renal tissues were measured. Protein expression of TGF-β 1 and phosphorylation levels of Smad3 and ERK1/2 in renal tissues were detected. RESULTS Compared with the blank group， the rats in the model group exhibited enlarged kidneys with pale color， rough and uneven surface. There was a significant infiltration of inflammatory cells and vacuolated cells in the renal tubules， along with marked proliferation of collagen fibers. Serum levels of BUN， Cr， IL-6 and TNF-α， protein expressions of α -SMA， Col-Ⅰ and FN in renal tissues， mRNA expressions of TGF-β 1 ， Smad3， ERK1 and ERK2 and protein expression of TGF-β 1 as well as phosphorylation levels of Smad3 and ERK1/2 in renal tissues were increased significantly （ P ＜0.05）. Compared with the model group， renal pathological changes of rats were alleviated in processed O. falcata groups， with reduced infiltration of inflammatory cells and proliferation of collagen fibers. The levels of the aforementioned quantitative indicators were all significantly reversed （ P ＜0.05）. CONCLUSIONS Processed O. falcata can improve renal function in RF rats， alleviate inflammatory responses， and reduce abnormal collagen fiber deposition. Its mechanism of action may be related to the inhibition of the activity of the TGF-β 1 /Smad signaling pathway.

Background: High-mobility group box protein 1 (HMGB1) is a chromatin-binding protein involved in arthritis, ischemia, sepsis, atherosclerosis, neurodegenerative disorders, meningitis, and cancer. HMGB1 exhibits dual roles in cancer, acting as either a tumor suppressor or oncoprotein depending on context. Objective: This research aimed to elucidate HMGB1’s functional significance in cutaneous squamous cell carcinoma (cSCC). Methods: We overexpressed HMGB1 in cSCC cell lines using recombinant adenovirus and examined its effects on cell proliferation, colony formation, and cell migration. Results: Immunohistochemical analysis revealed elevated HMGB1 expression levels in cSCC tissue relative to normal epidermis. To assess the influence of HMGB1, we employed recombinant adenoviruses expressing HMGB1 to transduce SCC cell lines (SCC12 and SCC13). Enhanced HMGB1 expression significantly promoted cellular proliferation and colony formation capacity.Notably, HMGB1 overexpression elevated the levels of proliferation regulators, including P63, SOX2, CDK4 and CDK6. Furthermore, HMGB1 overexpression substantially enhanced tumor invasiveness, accompanied by upregulation of epithelial-mesenchymal transition (EMT) biomarkers. Mechanistically, overexpression of HMGB1 enhanced transforming growth factor-β signaling by increasing phosphorylation of SMAD2/3, the key mediators of EMT. Conclusion These data imply that HMGB1 acts as a tumor-promoting factor in cSCC.

Cancer is one of the most lethal and burdensome diseases worldwide. Its progression not only causes irreversible damage to the body, but also imposes a substantial psychological burden on patients due to its complex prognosis. Immune imbalance, a hallmark of the tumor microenvironment (TME), accelerates tumor invasion and metastasis by impairing the function of effector immune cells, promoting the abnormal infiltration of immunosuppressive cells, and disrupting cytokine homeostasis, thereby constituting a major barrier to the efficacy of cancer immunotherapy. Compared with conventional chemotherapy and radiotherapy, aerobic exercise has shown considerable potential in antagonizing tumor progression through relatively mild but effective immunomodulatory mechanisms. On the one hand, regular aerobic exercise enhances the number and activity of key effector immune cells, such as CD8⁺ T cells, thereby strengthening their ability to recognize and eliminate tumor cells and alleviate immune imbalance. On the other hand, aerobic exercise promotes tumor vascular normalization, improves vascular maturity, and stimulates the secretion of irisin and other anti-inflammatory myokines, thereby remodeling the TME and relieving its immunosuppressive state to delay tumor progression. However, psychological stress following a cancer diagnosis can not only act as an independent disruptive factor that exacerbates immune imbalance within the TME, but also amplify the effects of other detrimental factors, such as reduced treatment adherence, thereby further weakening the antagonistic effect of aerobic exercise on tumor growth. Psychological stress, as a chronic stressor, promotes the excessive secretion of emotion-related hormones, including glucocorticoids (GCs) and norepinephrine (NE), which further suppress the activation and effector functions of antitumor immune cells such as CD8⁺ T cells and natural killer (NK) cells, while facilitating the recruitment of protumor immune cells such as regulatory T cells (Tregs). These changes ultimately disrupt immune homeostasis in the TME, promote tumor immune evasion, accelerate tumor invasion and metastasis, and offset the beneficial effects of aerobic exercise on tumor control. In addition, psychological stress induces hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis and abnormal excitation of the sympathetic nervous system (SNS), thereby maintaining elevated levels of GCs, NE, and related stress hormones, suppressing inflammatory chemokine expression and immune cell recruitment, and further disturbing immune homeostasis in the TME, which accelerates tumor progression. More importantly, prolonged psychological stress can also disrupt the homeostasis of central neurotransmitters, such as 5-hydroxytryptamine (5-HT) and glutamate (Glu). This not only directly inhibits the activation and effector functions of antitumor immune cells and promotes the establishment of an immunosuppressive microenvironment, but also impairs cellular energy metabolism and continuously provides energy for tumor cells through metabolic reprogramming, thereby sustaining rapid tumor growth and adaptation to a hostile TME. Ultimately, these alterations contribute to the dysregulation of “neuro-endocrine-immune” axis and weaken the protective effect of aerobic exercise against tumor progression. Therefore, this review focuses on the interaction between psychological stress and the “neuro-endocrine-immune” axis, with particular emphasis on the mechanisms by which psychological stress induces immune imbalance and weakens the antagonistic effect of aerobic exercise on tumor progression. We further highlight the important role of psychological stress in tumor progression and propose that combining psychotropic interventions, aerobic exercise, and clinical antitumor immunotherapy may help restore the tumor-killing capacity of the immune system. Such a multimodal strategy may exert synergistic effects at multiple levels, including psychological stress relief, neuroendocrine regulation, and reconstruction of immune homeostasis, thereby providing new perspectives for identifying therapeutic targets in solid tumors, enhancing the efficacy of cancer immunotherapy, and improving patient prognosis.

ObjectiveMigraine is a leading neurological disorder and the fourth most common cause of years lived with disability worldwide, affecting nearly 116 million individuals. Although pharmacological treatments are available, their efficacy is often limited by side effects and variable response rates. Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) offers a safe, non-invasive alternative for migraine management. However, the neurophysiological mechanisms, particularly how rTMS modulates local cortical excitability and distributed pain-related circuits, remain poorly understood. Elucidating these mechanisms is essential for optimizing treatment protocols and improving clinical outcomes. MethodsThis study employed concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate neuroplastic and neurocircuitry mechanisms of DLPFC-rTMS in migraine. Study 1 compared 30 migraineurs and 28 healthy controls to identify abnormalities in TMS-evoked potentials (TEPs) and significant current density (SCD) within sensory-discriminative regions including the primary somatosensory cortex (S1) and posterior insula (pINS), cognitive-affective regions including the anterior insula (aINS) and midcingulate cortex (MCC), and a descending modulatory region, the periaqueductal gray (PAG). Study 2 used a single-blind, crossover, sham-controlled design in 34 healthy participants. Each participant received both active (10 Hz, 80% RMT, 1 500 pulses) and sham DLPFC-rTMS in counterbalanced order. TMS-EEG and cold pain tolerance were assessed before and after each session. ResultsIn Study 1, migraineurs showed a significantly less negative N120 amplitude compared to healthy controls (P=0.027, Cohen’s d=0.60), indicating local intracortical disinhibition. No group differences were observed for N40, P60, or P180 components. At the source level, migraineurs exhibited significantly higher SCD in the S1, pINS, aINS, and MCC (allQ<0.05), but not in the ventroposterior thalamus (vpTHAL), mediodorsal thalamus (mdTHAL), or PAG. In Study 2, active rTMS significantly reduced SCD from pre- to post-stimulation in the S1, aINS, and MCC (all Q<0.05). Sham stimulation also reduced SCD in the S1 (Q<0.05) but not in the aINS or MCC. Although no significant group-level analgesic effect was observed between active and sham conditions (P=0.107), correlation analyses revealed that greater SCD reductions in the S1 and MCC were significantly associated with higher post-rTMS pain tolerance (R=-0.487 and -0.495, both Q<0.01) and larger improvements in pain tolerance(R=-0.487 and -0.451, both Q<0.05). No such correlations were found following sham stimulation, suggesting that the behavioural relevance of neural changes is specific to active rTMS. ConclusionThis study provides novel evidence that migraineurs exhibit both local neuroplastic abnormalities (reduced N120 amplitude) and hyperactivity in key pain-processing regions (S1, pINS, aINS, MCC). A single session of DLPFC-rTMS reduced hyperactivity in the aINS, MCC, and S1. Notably, greater reductions in the S1 and MCC were associated with improved pain tolerance. These findings identify distinct cortical circuitries, particularly within the cognitive-affective pain network, that may serve as potential biomarkers for optimizing rTMS treatment in migraine and other chronic pain conditions. Future studies should validate these results in patient populations experiencing spontaneous migraine attacks and explore multi-session or accelerated rTMS protocols.

AIM: To investigate the effects of high-concentration glucose on the cell viability of retinal pigment epithelialcells(ARPE-19)/ human umbilical vein endothelial cells(HUVEC)cells, as well as on the expression levels of sirtuin 6(SIRT6).

METHODS:ARPE-19 and HUVEC cells were cultured for 48 h in media containing various glucose concentrations(5.5, 25, 50, 75, 100 mmol/L)and cellular morphology was observed under an optical microscope.Cell viability was assessed using the CCK-8 assay. Flow cytometry was utilized to evaluate apoptosis levels, and Western blot analysis was conducted to measure the expression of Bcl-2 and SIRT6. ARPE-19/HUVEC cells were treated with 50 mmol/L glucose for 48 h, after which immunofluorescence staining was performed to determine the subcellular localization and expression level of SIRT6 protein. In parallel, cells receiving the same treatment were harvested at different time points(0, 6, 12, 24, 36, 48, and 72 h), and the temporal changes in SIRT6 protein expression were assessed by Western blot analysis. SIRT6 overexpressing stable ARPE-19/HUVEC cell lines were constructed. Western blot was performed to detect the effects of SIRT6 overexpression on the expression levels of glucose transporters in ARPE-19/HUVEC cells treated with high glucose(50 mmol/L glucose).

RESULTS:Compared with the 5.5 mmol/L glucose group, cell number was decreased and cell viability was significantly reduced in ARPE19/HUVEC cells with increasing glucose concentrations(all P<0.01). Meanwhile, the protein expression level of SIRT6 was markedly downregulated(P<0.05). Such inhibitory effects exhibited both concentration-and time-dependent patterns(all P<0.05). Furthermore, high glucose induced cell apoptosis and downregulated the protein expression of Bcl-2(P<0.05). Immunofluorescence staining revealed that SIRT6 protein was predominantly localized in the nucleus after 48 h of high-glucose treatment, accompanied by pyknosis and nuclear fragmentation. After incubation with highg-lucose medium(50 mmol/L glucose)for different durations, long-term high-glucose intervention was found to reduce SIRT6 protein expression in ARPE19/HUVEC cells. Successful construction of the SIRT6-overexpressing stable ARPE-19/HUVEC cell lines was confirmed via immunofluorescence and Western blotting. Western blot analysis revealed that, compared with the HG+LV-con group, the HG+LV-SIRT6 group exhibited no significant differences in GLUT1 or GLUT4 expression in ARPE-19 cells, whereas GLUT3 expression was elevated(P<0.05). Compared with the HG+LV-con group, the HG+LV-SIRT6 group showed no significant change in GLUT1 expression, while GLUT3 and GLUT4 levels were increased(both P<0.05).

CONCLUSION:High-concentration glucose-reduce the proliferative activity of ARPE-19/HUVEC cells, induce apoptosis, and downregulate SIRT6 expression. SIRT6 may alleviate high glucose-induced retinal cell damage by promoting the expression of glucose transporters.

A growing body of research points out that gut microbiota plays a key role in tumor immunotherapy. By optimizing the composition of intestinal microbiota, it is possible to effectively improve immunotherapy resistance and enhance its therapeutic effect. This article comprehensively analyzes the mechanism of intestinal microbiota influencing tumor immunotherapy resistance, expounds the current strategies for targeted regulation of intestinal microbiota, such as traditional Chinese medicine and plant components, fecal microbiota transplantation, probiotics, prebiotics and dietary therapy, and explores the potential mechanisms of these strategies to improve patients' resistance to tumor immunotherapy. At the same time, the article also briefly discusses the prospects and challenges of targeting intestinal microbiota to improve tumor immunotherapy resistance, which provides a reference for related research to help the strategy research of reversing tumor immunotherapy resistance.

The development of organ transplantation has brought new hope to many patients with organ failure and their families， but it has also raised numerous ethical issues. How to balance the rights and interests between organ donors and recipients， as well as ensure the fairness and transparency of the transplantation process has become an urgent problem to be solved. Based on the latest Regulations on Organ Donation and Transplantation and the Working Rules of the Ethics Committee for Human Organ Transplantation， the current difficulties and challenges in organ transplantation ethics were deeply analyzed. Taking the ethical review practice of Shenzhen Third People’s Hospital as an example， this paper explored issues such as full informed consent of both donors and recipients， risk assessment of marginal donors， and the review of relationships between donors and recipients. It also explored and constructed a set of complete ethical review models for organ transplantation through refined management. This model improved the efficiency and quality of ethical review as well as enriched the related knowledge system. It is expected that the implementation of this model can provide a reference for promoting effective ethical review nationwide， advancing the improvement and development of ethical review work in organ transplantation. Meanwhile， more medical ethics experts and practitioners are called upon to focus on and engage in the research and practice of ethical review in organ transplantation， jointly promoting progress in this field.

Objective To explore the feasibility and clinical experience of the middle hepatic vein splitting-reconstruction technique in split liver transplantation from low-age donor livers. Methods A retrospective analysis was conducted on the cases of two low-age donor livers that underwent middle hepatic vein splitting-reconstruction, which were transplanted into four child recipients at the Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University from January 2017 to July 2023. The surgical and postoperative conditions were summarized and analyzed. Results Donor 1 was a 6-year-old and 4-month-old girl with a body weight of 21 kg, and the obtained donor liver weighed 496 g. After splitting, the left and right liver weights were 201 g and 280 g, and transplanted into a 9-month-old boy weighing 6.5 kg and a 9-month-old boy weighing 7.5 kg, respectively. The graft to recipient weight ratio (GRWR) was 3.09% and 3.73%, respectively. Donor 2 was a 5-year-old and 8-month-old boy with a body weight of 19 kg, and the donor liver weighed 673 g. After splitting, the left and right liver weights were 230 g and 400 g, and transplanted into a 13-month-old girl weighing 9.5 kg and a 15-month-old boy weighing 12 kg. The GRWR was 2.42% and 3.33%, respectively. Both donor livers were split ex vivo, with the middle hepatic vein being completely split in the middle and reconstructed using allogeneic iliac vein and iliac artery vascular patches. According to GRWR, none of the 4 transplant livers were reduced in volume. Among the 4 recipients, one died due to postoperative portal vein thrombosis and non-function of the transplant liver, while the other three cases recovered smoothly without early or late complications. Regular follow-up was conducted until July 31, 2023, and liver function recovered well. Conclusions Under the premise of detailed assessment of the donor liver and meticulous intraoperative operation, as well as matching with suitable child recipients, low-age donor livers may be selected for splitting. The complete splitting and reconstruction of the middle hepatic vein in the middle may effectively ensure the adequate venous return of the left and right liver and provide sufficient functional liver volume.