Neuroinflammation driven by activated microglia is a major contributor to secondary brain damage following ischemic stroke. Targeting microglial activation has thus emerged as an important therapeutic strategy. Methylnissolin (ML), a pterocarpan-type isoflavonoid with documented anti-inflammatory activity and predicted ability to cross the blood-brain barrier, represents a potential modulator of microglial responses.

Chronic stress and prolonged glucocorticoid exposure may lead to impaired neuroplasticity and cellular dysfunction, which are key contributors to depression-like conditions. Sonic hedgehog (Shh) signaling plays a crucial role in neurogenesis, and its dysregulation has been implicated in reduced neurite outgrowth, proliferation, and cytoskeletal stability. Dexamethasone, a synthetic glucocorticoid, is widely used to model stress-induced neuronal dysfunction. However, the precise mechanisms through which dexamethasone impairs neuroplasticity and neuronal survival remain unclear as well as the therapeutic strategies to counteract such effects remain underexplored. This study explores whether activation of Shh signaling can mitigate stress-associated molecular changes resulting from dexamethasone-induced suppression of neuroplasticity. For induction of stress-induced neuroplasticity deficits model, N2a cells were treated with dexamethasone (1μM) for 24 h. In treatment strategy, cells were co-treated with purmorphamine (1μM) alongside dexamethasone for 24 h to activate Shh signaling. Dexamethasone suppressed glucocorticoid receptor phosphorylation, Shh signaling, and the expression of neurogenic and cytoskeletal markers. These changes were accompanied by reduced neuritic complexity and cell proliferation. Purmorphamine co-treatment significantly restored glucocorticoid receptor activity, Shh pathway components, and the expression of BDNF, profilin1, and SOX2. Morphological analyses revealed partial rescue of neurite architecture and enhanced proliferation. Our findings highlighted that purmorphamine mitigates dexamethasone-induced neuronal dysfunction by reactivating GR and Shh signaling and restoring transcriptional programs governing neuroplasticity. These findings highlight its potential as a neuroprotective agent against stress-related neural impairment.

Motion sickness (MS) is a complex syndrome characterized by a spectrum of autonomic and behavioural symptoms, often accompanied by emesis. Suncus murinus has become a primary species in which to study the mechanisms of emesis control, yet the behavioural profile associated with motion-induced malaise of this animal has not been thoroughly assessed. In this study, we exposed 129 animals to provocative motion (1 Hz, 4-cm horizontal reciprocating displacement, 30 min) to induce MS and systematically recorded spontaneous behaviours, retching and/or vomiting (R/V), and changes in body surface and tail temperatures. A non-biased MS symptom score was developed based on stepwise multiple linear regression, incorporating nine observable behaviours and physiological variables, namely scratching, stretching, chin on the floor, burrowing, chewing the bedding, micturition, defecation and/or tenesmus, remaining stationary, and body surface and tail temperature changes. Administration of two anti-MS drugs, diphenhydramine (30 mg/kg, s.c.) and scopolamine (10 mg/kg, s.c.), significantly reduced the MS symptom score from 14.25 ± 1.89 to 7.84 ± 0.85 and from 18.11 ± 2.28 to 11.91 ± 0.87 respectively, indicating the validity of the scoring system as a quantitative measure of motion-induced 'sickness', 'malaise', and even 'nausea' in this species. Shapley additive explanation (SHAP) analysis further indicated the contributions of two individual spontaneous behaviours, stationary duration and chin on the floor episode, to MS prediction. Our findings suggest that this behavioural scoring system provides a reliable and translationally relevant tool for studying MS and screening potential anti-emetic treatments for humans.

Stroke remains a leading cause of death and long-term disability worldwide. Although revascularization therapies have transformed acute care, effective neuroprotective strategies are still lacking. Intercellular mitochondrial transfer has recently gained attention as a promising endogenous repair mechanism. Through tunneling nanotubes, extracellular vesicles, or cell fusion, healthy mitochondria can be transferred from donor to recipient cells, helping restore bioenergetic homeostasis in injured neurons. This phenomenon, functionally comparable to organelle-level metabolic rescue, offers several advantages. It avoids the ethical concerns associated with genetic manipulation, leverages intrinsic intercellular communication for targeted delivery, and provides mitochondrial DNA complementation to correct metabolic defects. Here, we integrate current evidence on the cellular sources, transfer routes, and regulatory mechanisms underlying poststroke mitochondrial exchange; delineate the coordinated contributions of astrocytes, mesenchymal stem cells, microglia, and endothelial cells to this process; and critically evaluate its translational promise alongside the key barriers that must be addressed for successful clinical application.

Cardiac microvascular injury from hyperlipidaemia and hyperglycaemia is associated with increased major adverse cardiovascular events (MACE). Semaglutide, a long-acting GLP-1 receptor agonist, reduces diabetic cardiovascular complications beyond its glycaemic and weight-lowering effects. However, the impact of semaglutide on diabetes-induced coronary microvascular injury and the integrated mechanisms involved remain unclear.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer (CRC) and promotes tumor invasion and metastasis. Although 5-fluorouracil (5-FU) serves as a first-line CRC therapeutic, its clinical utility is constrained by dose-dependent toxicity. This study demonstrated that combining 5-FU with the EGFR inhibitor aumolertinib (AUM) synergistically suppressed CRC progression while reducing effective 5-FU doses. Transcriptomic and functional analyses linked this synergy to cellular senescence and autophagic flux blockade. Mechanistically, reactive oxygen species (ROS) accumulation drives senescence and autophagy inhibition, which inactivates the PI3K/AKT/mTOR pathway, thereby inhibiting CRC cell proliferation, invasion, and migration. Notably, ROS scavenging with N-acetylcysteine reversed these effects. The synergistic tumor growth inhibition was confirmed in HCT116 xenografts using low-dose combination therapy (5-FU 15 mg/kg + AUM 10 mg/kg). Collectively, these findings establish an ROS-dependent autophagic senescence axis as the molecular basis for 5-FU/AUM synergy, offering a novel strategic approach for CRC treatment.

Since neurological diseases are on the rise and current treatments have problems such as side effects, dependency, and, in cases such as stimulation methods, costs, and reduced patient compliance, efforts to find specific treatment options with fewer of the aforementioned problems continue. In recent years, arrestins have emerged as key modulators of various intracellular pathways implicated in neurodegeneration, neuroinflammation, and synaptic plasticity, making them a focus of interest in neurological disease and neurodegenerative disorders research.

Renal fibrosis is a common feature of chronic kidney disease (CKD) and is characterized by interstitial fibrotic tissue deposition, impaired renal function, and interstitial inflammation. To date, there are no clinically effective therapeutic agents specifically approved for the treatment of renal fibrosis. Sevelamer, as a phosphate binder, was approved to treat hyperphosphatemia and was recently shown to have antifibrotic effects in preclinical studies. In this study, we established a folic acid (FA)-induced renal interstitial fibrosis mouse model and an in vitro model using human kidney-2 (HK-2) cells to evaluate the therapeutic effects and mechanisms of sevelamer in renal fibrosis. Our results revealed that sevelamer reduced serum phosphate levels in fibrotic mice and improved renal function by restoring serum creatinine (Scr), blood urea nitrogen (BUN), and uric acid (UA) levels. Sevelamer significantly alleviated tubular injury, reduced extracellular matrix (ECM) accumulation, decreased the expression of inflammatory cytokines (IL-1β, IL-6, and TNF-α) in the serum, and mitigated renal inflammation. In vitro, sevelamer-induced phosphate deprivation inhibited HK-2 cell migration and epithelial‒mesenchymal transition (EMT), reducing the expression of fibrosis-associated proteins. Mechanistic studies revealed that low-phosphate stress induced by sevelamer suppressed the phosphorylation of IκBα and NF-κB-p65, inhibiting nuclear factor kappa B (NF-κB) signaling both in vivo and in vitro. As a result, sevelamer-mediated low-phosphate stress improved renal function, reduced ECM deposition, suppressed the expression of EMT markers in mouse kidneys and HK-2 cells, decreased inflammatory cytokine release, and attenuated NF-κB pathway activation. Sevelamer may be a potential therapeutic agent for the treatment of renal fibrosis.

Osteosarcoma is the most common primary malignant bone tumor, predominantly affecting young individuals. Despite standard chemotherapy and surgical resection, the overall survival rate has reached a plateau, emphasizing the need for more effective treatments. Flavonoids are antioxidant molecules with recognized anti-inflammatory and anticancer properties. In this study, we aimed to investigate the therapeutic potential of five flavonoids against four different osteosarcoma cell lines (MG-63, Saos-2 HOS, and 143B). Among the five structurally different flavonoids, robinetin exhibited the highest toxicity against osteosarcoma cells while sparing healthy human lung fibroblasts (MRC-5). Robinetin synergized with doxorubicin, reducing 143B cell viability, delaying migration, and downregulating metastasis-related transcription factors c-Jun, Snail, Slug, and Twist2. In vivo, robinetin inhibited the growth of osteosarcoma tumor xenografts in a chick chorioallantoic membrane model. Our study highlights and reports for the first time the therapeutic value of robinetin and demonstrates the potential of robinetin in osteosarcoma treatment.

This study aimed to compare the effects of indobufen and aspirin on platelet function, neurological recovery, and adverse reactions in acute ischemic stroke patients with early neurological deterioration.

Observational studies show significant differences in plasma lipid profiles between ischemic stroke (IS) patients and healthy individuals, but the causal relationships are unclear. This study aimed to explore the causal links between 179 plasma lipid species and IS and investigate the role of inflammatory proteins as mediators in this relationship. We also analyzed inflammatory protein expression in the brain before and after stroke.

This study aimed to determine whether topical and/or oral administration of an nucleotide-binding oligomerization domain- (NOD-) like receptor (NLR) protein 3 (NLRP3) inflammasome blocker can reduce signs of chronic inflammation in experimental autoimmune uveitis (EAU) mice. Mice were treated daily with the inflammasome blocker, tonabersat, orally, topically or in combination in comparison to topical dexamethasone over a period of 12 weeks. Ocular assessments using fundus and optical coherence tomography (OCT) images were carried out weekly. At the end of the study, ocular tissues were collected, and immunohistochemistry was performed to assess general retinal inflammation (cluster of differentiation (CD)45, CD68 and interleukin (IL)-17A), inflammasome activation (NLRP3 and cleaved caspase-1 (CC1)), and microglial activation and infiltration (glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule-1 (Iba-1)). Results showed that all treatments reduced the severity of ocular inflammation in fundus and OCT images with the tonabersat combination therapy being superior compared to oral or topical tonabersat alone, and as effective as topical dexamethasone. Interestingly, immunohistochemical analysis suggested that while dexamethasone reduced general inflammatory markers, it had minimal effect on the inflammasome pathway. All tonabersat treatment regimens, on the other hand, were effective in not only reducing general inflammation but also significantly inhibiting the inflammasome pathway. This study supports the idea that blocking the inflammasome pathway is a potential way to resolve the underlying cause of chronic inflammation potentially reducing disease relapse often seen with non-infectious uveitis.

Ever since its discovery in the early 20th century, chemotherapy has been the mainstream therapy for almost all cancers. Though several cycles of chemotherapy significantly reduce the proliferation and spread of the disease, they cause deleterious side effects. The adverse effects on the immune system imposed by these non-specific cytotoxic chemo drugs forced scientists to focus and give importance to boosting the immune system with a series of specific biological therapies. Stimulating or modulating the immune system to recognize and strike cancer cells (immunotherapy), combining with the application of gene knock down through RNA interference (RNAi) have spearheaded the cancer biotherapies, propelling them towards a more targeted and efficacious therapy regimen. Immunotherapy uses drugs like monoclonal antibodies, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cell therapy to enhance the immune response. These immune-based therapies can improve the specificity of cancer targeting and overcome immune evasion mechanisms employed by cancer cells. Further, soon after RNAi discovery, efforts have been made to adopt RNAi for its clinical applications in treating cancer. Different non-coding RNAs (ncRNAs) exert a distinct influence on gene expression and its regulation, offering a diversified toolkit for manipulating cellular pathways in the fight against cancer. This review article summarizes the currently used chemo drugs and their adverse effects and the shift of focus towards small RNA based bio-drugs as future cancer therapeutics.

Colitis-associated cancer (CAC) is a subtype of colorectal cancer (CRC). The persistent inflammatory stimulation caused by ulcerative colitis (UC) can worsen intestinal damage and promote the development of cancer. Anemoside B4 (B4), an active component of Pulsatilla chinensis, has previously been shown to have beneficial effects against UC, which sets the stage for investigating its potential in preventing and treating CAC. Therefore, we explored the mechanism of B4 in the treatment of CAC based on RNA sequencing (RNA-seq). The results demonstrated that B4 treatment significantly improved weight loss, inhibited colon shortening, reduced both the number and size of tumors, alleviated colon tissue damage, and lowered mRNA levels of IL-1β, IL-6, and TNF-α in CAC mice. RNA-seq revealed that B4 can regulate the expression of key genes in the Wnt/β-catenin signaling pathway, thereby interfering with the development and progression of CAC. Molecular docking predicted that B4 binds to key targets with a high affinity, specifically Wnt6, Ctnnb1, and Ccnd1. And these findings were verified by RT-qPCR and Western blot analysis. Overall, B4 can alleviate the occurrence and development of colitis associated cancer via inhibiting the activity of the Wnt/β-catenin signaling pathway.

Metabolic alterations, resulting from obesity, drive chronic kidney disease (CKD) through mechanisms including lipotoxicity, inflammation, and fibrosis. Oleoylethanolamide (OEA), an endogenous compound belonging to the N-acylethanolamine family, has been widely studied for its metabolic properties. However, emerging evidence highlights its anti-inflammatory and anti-fibrotic effects. Here, we explored the effect of OEA on high-fat diet (HFD)-induced renal damage associated with obesity in mice. OEA treatment improved kidney function by restoring urine output and reducing proteinuria and albuminuria in obese mice. Moreover, OEA normalized serum creatinine and blood urea nitrogen levels, which were altered by HFD feeding, and decreased the transcription of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin, associated with renal damage. OEA also counteracted renal glucose dysmetabolism by reducing glycogen content and modulating the protein expression of glucose transporters. Furthermore, OEA exerted marked anti-inflammatory and antifibrotic effects in kidney, further confirmed by a reduction in the transcription of pro-inflammatory and pro-fibrotic markers. OEA reduced renal steatosis, improving lipid metabolism through increased peroxisome proliferator-activated receptor-α and fibroblast growth factor 21 transcription and reduced triglyceride trafficking by the downregulation of diacylglycerol O-acyltransferase 1. Finally, to highlight the direct effect of OEA in the kidney, we confirmed its protective activity against lipotoxicity and demonstrated its ability to improve mitochondrial bioenergetics in human proximal tubular epithelial cells (HK-2). These results indicate that OEA may be a promising therapeutic molecule for restraining CKD-related alterations associated with obesity and metabolic disorders.

Hyperuricemia is an important independent risk factor for poor prognosis following myocardial ischemia-reperfusion injury (MI/RI), yet its precise molecular mechanisms remain incompletely understood.This study aimed to determine whether hyperuricemia aggravates MI/RI by promoting ferroptosis through enhanced oxidative stress and disrupted iron metabolism. Using both in vivo models (hyperuricemia- myocardial ischemia-reperfusion mice,MI/R) and in vitro systems (HL-1 cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation, OGD/R), we found that elevated uric acid (UA) levels led to increased reactive oxygen species production, mitochondrial dysfunction, and altered expression of key ferroptosis-related proteins. Specifically, nuclear receptor coactivator 4(NCOA4) expression was upregulated, while the levels of SLC7A11 (xCT), glutathione peroxidase 4(GPX4), and ferritin heavy chain 1(FTH1) were significantly reduced. Notably, treatment with ferroptosis inhibitors such as deferoxamine(DFO) and ferrostatin-1(Fer-1) effectively mitigated these pathological changes, underscoring the contribution of NCOA4-FTH1 and xCT- glutathione (GSH)-GPX4 signaling to hyperuricemia-aggravated MI/RI .

Aggression is one of the most common adverse events that negatively impacts quality of life and leads to anti-seizure medications (ASMs) discontinuation in patients with epilepsy. Pediatric patients may be more susceptible to aggression with ASMs. However, very few studies have systemically evaluated aggression associated with ASMs in a large sample of pediatric patients with epilepsy.

Skp2 plays a critical role in regulating cell cycle progression by promoting the ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27. Numerous studies have implicated Skp2 overexpression in cancer chemoresistance; however, its impact on sensitivity to camptothecin (CPT), a clinical topoisomerase I inhibitor, in non-small cell lung cancer (NSCLC) remains unclear. In this study, we identified that CPT can markedly induce the accumulation of p27. Mechanistically, CPT can directly bind to Skp2 protein and inhibit Skp2-SCF E3 ubiquitin ligase activity, as evidenced by decreased p27 ubiquitination level upon CPT treatment. Ectopic Skp2 expression in NSCLC cells abrogated CPT-induced p27 accumulation. Of note, Skp2 overexpression markedly increased CPT-induced DNA damage and apoptosis in NSCLC cells, and pharmacologic inhibition of Skp2 with SZL P1-41 partially reversed the cytotoxicity of CPT. Skp2-overexpressing A549 cell xenografts were also more sensitive to CPT than A549 cell xenografts with empty vector; tumors with high Skp2 levels exhibited lower p27 expression and greater DNA damage after CPT treatment. Collectively, our study demonstrated that the CPT induces p27 accumulation by targeting Skp2, whereas Skp2 overexpression can modulate the off-target effects and enhance CPT sensitivity in NSCLC, supporting the potential use of Skp2 as a predictive biomarker for CPT-based therapy.

The impact of sex on metformin (METF) activity has been largely overlooked. This pilot study investigates sex influences metabolic and microRNA (miRNA) profiles in diabetic patients treated with METF therapy compared to those not treated with METF. Fifty-six outpatients with type 2 diabetes mellitus (29 men and 27 women), Caucasian, non-smokers, normotensive, normolipidemic, in good metabolic control, and free from diabetic complications were recruited. They were divided into two groups, drug-naïve and METF-treated, and stratified by sex. Serum samples were collected and analyzed for amino acids (AA) and acylcarnitines (AC), advanced glycation end products (AGEs), malondialdehyde (MDA), and 8 selected circulating miRNA. Women treated with METF (W-METF) showed lower MDA than the W-drug-naïve, while AGEs were reduced in both the W-METF and men treated with METF (M-METF). In the W-METF, five miRNA were upregulated compared to the W-drug-naïve, whereas three miRNA were upregulated in the M-METF group compared to the M-drug-naïve. AA and AC are sex-dependent: W-METF showed more differences than W-drug-naïve, while men had fewer changes. METF impacted women's AC profiles more, with 23 out of 39 AC being significantly reduced, compared to only 4 AC being reduced in men. METF amplifies sex differences increasing their number from 11 in the drug-naïve patients to 39 in the METF-treated patients. MiR-223-3p was upregulated only in W-METF. This pilot study highlights that METF induces significant sex-dependent changes in the blood metabolome and 8 circulating miRNA, paving the way for large-scale studies and suggesting that METF therapy could be personalized based on sex.

Detrusor underactivity (DU) is a prevalent bladder dysfunction for which effective treatment is lacking. A series of studies have shown that the 5-HT receptor is involved in the regulation of micturition, but its role in DU remains unknown. Besides, transient receptor potential vanilloid 4 (TRPV4) agonist has been demonstrated to improve bladder function in BPNI rats by increasing afferent signals and the 5-HT/5-HT receptor are functionally associated with TRPV4 in several pathophysiological processes. In the current study, we established a bilateral pelvic nerve injury (BPNI) model. Tissue staining and cystometry were performed and the results showed that the BPNI model exhibited DU in both histological and urodynamic manifestations. Intrathecal injection of the 5-HT receptor agonist TCB2 could facilitate the micturition reflex in BPNI rats, reducing intercontraction interval (ICI), residual volume (RV), and bladder capacity (BC), which could be reversed by the TRPV4 antagonist HC-067047. Western blot and immunofluorescence analyses revealed there was no significant difference in the expression of the 5-HT receptor in the L6-S1 dorsal root ganglia (DRG) and spinal dorsal horn between sham-operated and BPNI rats, whereas the expression of TRPV4 was significantly decreased in BPNI rats. Calcium imaging of DRG neurons showed an increased calcium influx induced by TCB2, which was blocked by HC-067047. These findings suggest that the 5-HT receptor agonist can improve bladder dysfunction in BPNI rats by regulating the micturition reflex via TRPV4. The 5-HT receptor may be a potential therapeutic target for the treatment of DU.

Normal platelet activation is critical for proper hemostasis, while abnormal activation can lead to thrombotic diseases. Therefore, searching for substances that can regulate platelet activation will be helpful in preventing and treating thrombotic diseases. Studies have pointed out that SHIP1 can regulate platelet activation, affecting clot retraction and integrin αIIbβ3 activation. Nevertheless, the role of the SHIP1 agonist rosiptor in regulating platelet functions has not been investigated. This study aimed to investigate the antiplatelet and antithrombotic effects of rosiptor. Human platelets were isolated and used to evaluate the regulatory effect of rosiptor on platelet functions. The results showed that rosiptor significantly inhibits platelet activation, including aggregation, secretion, integrin αIIbβ3 activation, and Ca mobilization. Moreover, rosiptor inhibited FeCl-induced mesenteric artery occlusive thrombus formation in mouse models in vivo. Notably, rosiptor did not significantly prolong tail bleeding time in mice. Mechanistically, the levels of cGMP and cAMP were measured using ELISA kits, and protein expression was detected by immunoblotting. Rosiptor enhanced cGMP and cAMP-dependent signal transduction and inhibited agonist-induced PI3K/PKC signaling pathway. In conclusion, our study suggests that rosiptor may have a potential therapeutic role in thrombotic diseases with a reduced risk of bleeding complications.