This study aimed to investigate the effects of avasopasem manganese (AVA), a superoxide dismutase (SOD) mimetic, on endoplasmic reticulum stress (ERS) in isoproterenol (ISP)-induced ischemic heart injury in type 1 diabetic male mice. Oxidative stress (OS) and ERS are known to play important roles in the progression of cardiac damage, and diabetes mellitus (DM) itself exacerbates ERS. It is postulated that agents capable of inhibiting ERS many alleviate ischemic heart injury. This study investigated the effects of AVA on ischemic heart injury in type 1 diabetic mice via ERS-related proteins (GRP78, PERK, IRE1, ATF4, XBP1, Nrf2, and CHOP/caspase 12). A power analysis determined that 96 male BALC-c mice, aged 6 to 8 weeks, were utilized and randomly allocated into six groups: control, DM, ISP, DM+AVA (10 mg/kg), ISP+AVA (10 mg/kg), and DM+ISP+AVA (10 mg/kg). In diabetic and ischemic mice, AVA treatment raised the levels of glutathione (GSH) and the activities of the enzymes superoxide dismutase (SOD) and catalase (CAT). It also lowerd the levels of malondialdehyde (MDA) and the activity of myeloperoxidase (MPO). Cardiac markers creatine kinase-muscle type/brain type isoenzyme (CK-MB) and cardiac troponin T (cTnT) levels were also decreased following treatment. In the diabetic and ischemic mice, mRNA expression of ERS-related proteins (GRP78, PERK, IRE1, ATF4, XBP1, and Nrf2) was elevated but significantly reduced after AVA administration. AVA treatment improved cardiac outcomes by reducing OS and inflammation and downregulating ERS-related protein expression in diabetic and ischemic mice.

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.

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.

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

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.

Crocetin, a major compound of saffron, exhibits various biological activities, including neuroprotective properties. Our study sought to evaluate the effect of crocetin on epileptiform discharges in the primary somatosensory cortex (S) neurons following microinjection of penicillin in urethane anesthetized rats. Electrocorticographic (ECoG) recordings were performed for a 180-min period. The frequency and amplitude of spikes were recorded in 30-min intervals for 180-min. The areas under the curve (AUC) of the above-mentioned spike alterations were calculated. Biochemical parameters of the cerebrum were also determined. Intraperitoneal (IP) injection of crocetin and intracerebroventricular (ICV) administration of diazepam and flumazenil (an agonist and an antagonist of GABA-benzodiazepine receptors, respectively) were done before penicillin administration. Infusion of penicillin (500 IU/2.5 μL) into the S of the brain triggered epileptiform activity with spike wave patterns. Prior administration of crocetin (20 and 40 mg/kg, IP) and diazepam (4 μg/μL, ICV) alleviated the frequency and amplitude of spikes. Microinjection of flumazenil (4 μg/μL) prevented the reducing effects of crocetin (40 mg/kg) and diazepam (4 μg/μL). The AUC results supported the impact of the aforementioned treatments. On the other hand, IP urethane injection and intracortical penicillin microinjection reduced superoxide dismutase (SOD) activity and total antioxidant capacity (TAC) content, while it simultaneously increased malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) levels. Crocetin (20 and 40 mg/kg) ameliorated biochemical alterations. These results showed that crocetin could reduce penicillin-induced epileptiform activity through GABA-benzodiazepine receptor, as well as anti-oxidative and anti-inflammatory mechanisms.

In Alzheimer's disease (AD), the hippocampus and cerebral cortex are primarily affected, showing degeneration of cholinergic neurons and Aβ plaques accumulation. These changes are strongly associated with oxidative stress, neuroinflammation, and impaired autophagy. In our study simvastatin (Simva), a lipid-lowering statin, was investigated against aluminum chloride (AlCl)-induced rat model of AD and showed potential neuroprotective effects. Nano-delivery systems were used to enhance Simva's brain pharmacological activity. Adult male Sprague Dawley rats were designated into four groups: Control group (normal saline, IP, 28 days), AlCl group (25 mg/kg AlCl, IP for 28 days), Simva group (Simva 10 mg/kg, orally for 28 days 1 h before AlCl injection) and Simva-Nano group (Simva nanocarrier 10 mg/kg, orally for 28 days 1 h before AlCl injection). Simva and its nanocarrier enhanced autophagy by upregulating p-AMPK, p-ULK1, and LC3-II while downregulating ULK1. They showed strong antioxidant and anti-inflammatory effects by decreasing MDA, TNF-α, IL-1β and increased GSH. Additionally, they increased ACh levels and suppressed AChE gene expression. Immunohistochemical staining revealed substantial reduction in Aβ plaques in the Simva group, while in Simva-Nano group, Aβ plaques were not detected under our assay conditions. Aβ immunostaining was quantified as the number of Aβ deposits per field (6 fields). Histopathological analysis confirmed reduced neuronal degeneration and glial activation, with the Simva-Nano group demonstrating near-normal hippocampal architecture. In conclusion, Simva exhibits notable neuroprotective effects in the AD rat model via antioxidative, anti-inflammatory, and autophagic pathways. Nanocarrier delivery further improves Simva's pharmacological effects, offering a promising AD therapeutic strategy.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease. It is currently difficult to treat, with limited treatment options available. Recent evidence implicates ferroptosis-an iron-dependent form of regulated cell death-as a critical pathogenic mechanism in pulmonary fibrogenesis. Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitors, which have been proven to have anti-fibrotic effects on various organ systems, however, there are few studies on the mechanism of action of the drug in pulmonary fibrosis. Utilizing a bleomycin-induced murine model and MLg fibroblasts/MLE12 alveolar epithelial cells, we conducted multi-parametric assessment of fibrotic markers (Alpha smooth muscle actin (α-SMA), Collagen I), ferroptosis markers (intracellular iron, lipid peroxidation), and key regulatory proteins. Empagliflozin treatment significantly attenuated pulmonary collagen deposition and myofibroblast activation in vivo, while demonstrating dual anti-ferroptotic effects in vitro: reducing excessive iron accumulation and lipid peroxidation in MLg cells, while restoring glutathione peroxidase 4 (GPX4) expression in ferroptosis-sensitive MLE12 cells. Mechanistically, empagliflozin upregulates the expression of transcription factor EB (TFEB) post TGF-β1 challenge, initiating coordinated regulation of ferroptosis mediators. TFEB knockdown exacerbated ferroptosis through GPX4 suppression and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) induction, whereas TFEB overexpression reversed these effects. We confirmed TFEB-mediated transcriptional upregulation of GPX4 coupled with ACSL4 suppression as the molecular basis for empagliflozin's anti-fibrotic action. These findings establish empagliflozin as a novel therapeutic strategy for IPF through TFEB-driven modulation of ferroptosis pathways, providing experimental basis for repurposing SGLT2 inhibitors in fibrotic lung diseases.

Reelin is an essential extracellular matrix glycoprotein that regulates cortical layers formation and has been implicated in several neuropsychiatric conditions, including schizophrenia (SCZ). To explore its role in brain function and its potential involvement in SCZ, we developed a Reln heterozygous deletion (Reln) mouse model that replicates a genetic deletion identified in a Japanese patient with SCZ. In previous studies, we demonstrated that Reln mice exhibit cognitive impairments in a visual discrimination test. In the present study, we found that Reln mice displayed impairments in social novelty recognition and social odor responses, whereas social preference and non-social odor responses remained intact. Immunohistochemical analyses revealed a significant decrease in the numbers of calcium/calmodulin-dependent protein kinase II-positive glutamatergic pyramidal neurons, gamma-aminobutyric acid-ergic interneurons, parvalbumin-positive interneurons and somatostatin-positive interneurons in the medial prefrontal cortex (mPFC) of Reln mice. Furthermore, Reln mice exhibited significant deficits in excitatory spine density and morphology, along with a reduced number of PV boutons in the mPFC compared to wild-type (WT) controls. Finally, we demonstrated that injection of adeno-associated virus (AAV)-R36-Myc into the mPFC improved social novelty impairments in Reln mice, with no observable effects in WT controls. These findings indicate that Reln mice provide a valuable model for exploring the neurobiological mechanisms underlying cognitive and social impairments in SCZ. Furthermore, the efficacy of AAV-R36-Myc highlights the therapeutic potential of Reelin replacement, warranting further investigation as a targeted treatment strategy for SCZ.

Leishmaniasis remains a major global health problem, especially in tropical and subtropical regions, where current treatments are limited by toxicity, cost, and drug resistance. The disease affects more than 98 endemic countries, causing approximately 1.3 million new cases and 30,000 deaths each year. Despite occasional advances, its global burden remains substantial and demands sustained attention. Piperine, a bioactive alkaloid from Piper species, shows promising antileishmanial effects, but its clinical use is limited by poor solubility and bioavailability. This review evaluates the potential of piperine and its derivatives as therapeutic agents against leishmaniasis, focusing on their mechanisms of action, effectiveness in experimental models, and drug delivery advancements. A systematic literature review gathered in vitro, in vivo, and in silico studies on piperine alone or combined with standard therapies. Findings show that piperine disrupts parasite mitochondria, induces cell cycle arrest, and modulates immune responses. Structural modifications, such as tetrahydropyridine and piperidine derivatives, improve potency, while novel delivery systems (as nanoparticles, liposomes, lipid nanospheres) enhance bioavailability and treatment outcomes. Piperine also exhibits synergistic effects with meglumine antimoniate and amphotericin B, potentially reducing toxicity and increasing effectiveness. In summary, piperine and its derivatives are promising candidates for leishmaniasis therapy. However, further studies, especially clinical trials, are necessary to confirm these benefits and enable clinical translation.

Existing meta-analyses of anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration focus mainly on ranibizumab and aflibercept, with limited data on newer agents (faricimab, conbercept). This network meta-analysis (NMA) comprehensively compares all four key agents.

Sepsis, a life-threatening systemic inflammatory syndrome caused by dysregulated host responses to infection, frequently originates from Gram-negative pathogens such as Escherichia coli (E. coli). While antibiotics remain the mainstay treatment, rising antimicrobial resistance necessitates alternative therapeutic strategies. Formononetin (FMN), a bioactive isoflavone derived from traditional Chinese medicine, exhibit potent anti-inflammatory and antioxidant properties. This study employed an integrative approach combining in vivo pharmacodynamic evaluation, network pharmacology, and experimental validation to systematically investigate FMN's therapeutic potential against E. coli induced sepsis. In vivo studies in a murine sepsis model showed FMN significantly reduced E. coli sepsis induced body weight loss, clinical manifestations, histopathological changes, and suppressed proinflammatory cytokines (e.g. IL-6 and TNF-α). Network pharmacology identified 28 putative targets interacted with the E. coli sepsis-related site and molecular docking suggested possible interactions between FMN and key inflammatory mediators such as Toll-like receptor 4 (TLR4) and tumor necrosis factor (TNF). qRT-PCR indicated that FMN modulated the transcription of TLR4/MyD88-related genes, with downstream reductions in the mRNA levels of TLR4, MyD88, iNOS and IL-6. These findings suggest that FMN may be a promising candidate for further investigation as a multi-target modulator in sepsis.

Immune thrombocytopenia (ITP) is an autoimmune condition characterized by the destruction of platelets or their inadequate production due to immune system dysregulation. Ursodeoxycholic acid (UDCA) exhibits anti-inflammatory and immunomodulatory effects; however, its specific mechanism of action in the context of ITP remains to be fully elucidated. The present study aimed to examine the impact of UDCA on monocyte migration and to elucidate the underlying molecular mechanisms through transcriptomic analyses complemented by both in vivo and in vitro experiments. The findings revealed that UDCA markedly inhibited the migration of monocytes from the bone marrow into the peripheral circulation in an ITP murine model, concomitantly reducing the population of M1 macrophages within the spleen and their capacity for platelet phagocytosis. In vitro assays demonstrated that UDCA suppressed the migration of THP-1 monocytes, an effect contingent upon the CCL2-CCR2 chemokine axis. Mechanistic investigations indicated that UDCA downregulated the expression of CCR2 (C-C chemokine receptor 2) and modulated the activity of the p38/ERK and AKT signaling pathways. This study provides the first evidence that UDCA attenuates the pathological progression of ITP by inhibiting monocyte migration via the CCL2-CCR2 chemokine pathway, thereby offering novel theoretical insights to support its clinical application.

Anti-tuberculosis drug-induced liver injury (ADLI) is a serious complication of tuberculosis treatment, yet its molecular mechanisms remain poorly understood. Disruptor of telomeric silencing 1-like (DOT1L) is a unique histone methyltransferase that catalyzes monomethylation (me1), dimethylation (me2) and trimethylation (me3) of histone H3 at lysine 79 (H3K79), despite lacking a SET domain. Beyond its methyltransferase activity, DOT1L participates in various biological processes-including the cell cycle, DNA damage response, and gene transcription-both in a methylation-dependent and -independent manner. Notably, dysregulation of DOT1L has been closely associated with the pathogenesis of liver diseases. In this study, we established an ADLI mouse model using a combination of isoniazid, rifampicin, and pyrazinamide, and observed significant upregulation of DOT1L expression in the liver tissues of ADLI mice. Intervention with the specific DOT1L inhibitor SGC0946 markedly alleviated liver injury. Mechanistically, we found that DOT1L catalyzes H3K79 hypermethylation at the p53 gene promoter, leading to activation of the p53-Bax/Bcl-2 apoptosis signaling pathway and subsequent apoptosis of hepatocytes. In contrast, SGC0946 treatment reduced H3K79 methylation levels at the p53 promoter and suppressed the p53-Bax/Bcl-2 pathway, thereby attenuating liver injury. Our findings highlight the importance of DOT1L expression homeostasis in liver physiology and reveal a novel epigenetic mechanism by which DOT1L participates in ADLI progression through transcriptional regulation of p53. These results position DOT1L as a potential therapeutic target for the prevention or treatment of ADLI.

Helicobacter pylori (H. pylori) infection is a common bacterial disease of the gastric mucosa, affecting more than 40% of the global population, and it is classified by the World Health Organization (WHO) as a Group 1 carcinogen for gastric cancer (GC). H. pylori promotes gastric carcinogenesis through complex molecular mechanisms and modulates host immunity via virulence factors (e.g., CagA and VacA), remodeling of the tumor microenvironment (TME), and substantial effects on the gut microbiota-processes that together influence responses to GC immunotherapy. This review synthesizes the multidimensional interplay among H. pylori, host immune responses, and GC immunotherapy across three domains: virulence factors, TME remodeling, and microbiota dysbiosis. We also highlight emerging therapeutic strategies, including nanotechnology-enabled TME reprogramming, stem-cell engineering to derive immune effector cells, and targeted immunomodulation. These approaches offer mechanistic insights and technical platforms for precision immunotherapy in H. pylori-associated GC and may improve prevention and treatment outcomes.

Mounting evidence highlights flavonoids as multitarget candidates for central nervous system disorders because they can cross the blood-brain barrier and modulate diverse neurotransmitter pathways. Echinatin, a chalcone-type flavonoid from Glycyrrhiza species, has not previously been evaluated in behavioral models relevant to mood disorders. Here, we examined whether echinatin exerts antidepressant-like effects in validated rodent tests and explored the underlying monoaminergic mechanisms using pharmacological manipulations. Male BALB/c mice received echinatin (20 or 30 mg/kg), fluoxetine (10 mg/kg) or reboxetine (20 mg/kg). Antidepressant-like activity was assessed in the tail-suspension and modified forced-swimming tests, while motor performance was evaluated with the Rota-rod and the activity-meter. To delineate monoaminergic involvement, mice were pretreated with p-chlorophenylalanine (PCPA; serotonin synthesis inhibitor), α-methyl-p-tyrosine (AMPT; catecholamine synthesis inhibitor), WAY-100635 (serotonin 5-HT1A receptor antagonist), phentolamine (α-adrenoceptor antagonist), propranolol (β-adrenoceptor antagonist), SCH-23390 (dopamine D1 receptor antagonist), sulpiride (dopamine D2/D3 receptor antagonist) or ketanserin (serotonin 5-HT2A/5-HT2C receptor antagonist). Echinatin at 30 mg/kg markedly reduced immobility in both behavioral tests, producing effects comparable to reference antidepressants, without affecting locomotor activity or motor coordination. The anti-immobility effect was reversed by serotonergic (PCPA, WAY-100635), noradrenergic (AMPT, phentolamine, propranolol) and dopaminergic (SCH-23390, sulpiride) interventions, but was not altered by ketanserin. These findings provide the first pharmacological evidence that echinatin elicits antidepressant-like effects through broad monoaminergic modulation and support its further evaluation as a potential lead compound for antidepressant drug development.

Astrogliosis is thought to be a potential factor in the neuroinflammatory response associated with fibromyalgia (FM); however, the role of A1/A2 astrocyte polarization remains underexplored. Several metabolic processes have been reported to influence astrocyte activation and function. The current study was designed to assess the potential regulatory role of apigenin (API), a natural flavonoid, on astrocytes polarization via modulation of the kynurenine pathway (KP) in rats with FM-like symptoms. Reserpine (Res) (1 mg/kg/day, s.c.) was injected into the rats for three consecutive days to induce FM, after which they were given oral API (25 mg/kg/day) for 14 days. API ameliorated spinal cord degeneration as well as allodynia and hyperalgesia as demonstrated in the Randall-Selitto, Von Frey, and hot plate tests. It restored monoaminergic balance and reduced the contents of glutamate and substance P. API suppressed aryl hydrocarbon receptors (AHR), kynurenine (KYN), indoleamine 2,3-dioxygenase (IDO), and nuclear factor kappa B (NF-κB) overexpression in the spinal cord. API hampered astrogliosis as evidenced by reduced GFAP immunohistochemical expression and its associated neuroinflammation and oxidative stress. Consequently, it inhibited A1 astrocytes polarization as evidenced by diminished their markers, namely C3, C1q, and S100β, contrary to upleveling S100A10, an A2 phenotype's marker. In conclusion, API mitigated FM-like pain symptoms by driving astrocyte polarization towards the neuroprotective A2 through modulating the KYN/AHR axis and its interaction with NF-κB signaling.

Age-related macular degeneration (AMD) is a chronic retinal disorder that occurs when oxidative damages are gradually accumulated to the center of retina. Oxyresveratrol (OxyR), a naturally occurring stilbene found in many plants, has been reported to exhibit anti-inflammatory and anti-oxidative activities. To fill this gap, we explored the effect of OxyR on retinal pigment epithelial cells in response to oxidative stress and on a mouse model of AMD and further dissected the molecular mechanism underlying OxyR's actions. In this study, we demonstrated that OxyR efficiently impeded both apoptosis and ferroptosis of a human ARPE-19 cells induced by sodium iodate (NaIO). Such protective effect of OxyR on NaIO-induced ARPE-19 cells was accompanied with altered expression levels of NRF2, KEAP1, and several ferroptosis-related proteins. Moreover, OxyR treatment, coupled with silencing of NRF2, ferroptosis inhibitor (ferrostatin-1) or depletion of ROS, enhanced the protection of ARPE-19 cells from NaIO-induced damages. Consistently, oral gavage of OxyR restored the reduction of retinal thickness and attenuated the upregulation of NRF2 in retinal pigment epithelium layers of NaIO-treated mice. These results demonstrated that OxyR mitigates NaIO-induced ARPE19 cell death via targeting NRF2-ferroptosis signaling. Our findings provided potential avenues for the use of OxyR in controlling AMD.

β-Hydroxybutyrate, a metabolic substrate and signaling molecule, exerts neuroprotective effects against various neurodegenerative diseases, including retinal diseases. However, mechanisms underlying these neuroprotective effects are currently not fully understood. In this study, we examined the effects of β-hydroxybutyrate against N-methyl-D-aspartic acid (NMDA)-induced retinal injury in rats and the underlying mechanisms. The intravitreal injection of NMDA (200 nmol) resulted in a decrease in neuronal cells, an increase in apoptotic cells, and activation of microglial cells. Simultaneous intravitreal injection of β-hydroxybutyrate (50 nmol) and NMDA significantly attenuated these NMDA-induced responses. The protective effects of β-hydroxybutyrate against NMDA-induced retinal injury were suppressed by Compound C (an inhibitor of AMPK), but not AR-C155858 (an inhibitor of monocarboxylate transporters). These findings suggest that β-hydroxybutyrate exerts protective effects against NMDA-induced retinal excitotoxicity through inhibition of neuronal cell apoptosis and microglial cell activation. β-Hydroxybutyrate is transported across the plasma membrane via monocarboxylate transporters; however, the mechanisms associated with these transporters are unlikely to be involved in its protective effect. Instead, activation of AMPK pathway may contribute to β-hydroxybutyrate-mediated protection.

Univariate and multivariate Cox analyses revealed a correlation between diabetes and the prognosis of gastric cancer patients (p < 0.05). Using bioinformatics, Serine/threonine-protein kinase pim-1 (PIM1) was identified as the core target gene of triptolide in the treatment of gastric cancer patients with diabetes. Cell Counting Kit-8 (CCK8), cell scratch and plate cloning experiments revealed that triptolide can inhibit the proliferation and migration ability of AGS and HGC-27 cells in a high-glucose environment. Western blot and flow cytometry analysis revealed that triptolide can inhibit PIM1 protein expression, reduce JAK2/STAT3 phosphorylation, and promote apoptosis in AGS and HGC-27 cells under high-glucose conditions. Diabetes is an independent prognostic risk factor for patients with gastric cancer. Triptolide reverses the malignant phenotype of gastric cancer cells induced by high glucose by targeting the PIM1-JAK2/STAT3 signalling axis, providing an experimental basis for the precise treatment of patients with gastric cancer with diabetes.

Ferroptosis is an important pathological factor in sepsis-induced cardiomyopathy (SIC). Zinc finger protein 36 (ZFP36) is an RNA-binding protein regulating cellular biological processes by degrading target genes. Studies have shown that ZFP36 is highly associated with ferroptosis. BALB/c mice were administered lipopolysaccharide (LPS) intraperitoneally to establish an SIC model. After LPS exposure for 24 h, mice showed myocardial damage and ferroptosis, and an elevated protein level of ZFP36 was detected in the myocardium. H9c2 cells were transfected with plasmid-carrying short hairpin RNA to knock down ZFP36. The mRNA-sequencing data suggested that ZFP36 may be involved in the ferroptosis process of SIC. After inhibiting ZFP36 expression, H9c2 cell viability was reduced, and we detected an increase in lipid peroxides by C11-BODIPY581/591. ZFP36 knockdown intensified LPS-induced ferroptosis and cell injury. ZFP36 expression was inhibited in mice by recombination adeno-associated virus 9-containing shRNA. SIC mice with ZFP36 knockdown showed left ventricular systolic dysfunction aggravatingly. In SIC mice with ZFP36 knockdown, disruption of myocardial structure and increased immunological infiltration. After ZFP36 downregulation, the SIC hearts displayed massive 4-HNE and malondialdehyde accumulation, decreased glutathione content and superoxide dismutase activity, and elevated iron-positive myocardium by Prussian blue staining. The alteration of ferroptosis markers evidenced the activation of ferroptosis in ZFP36-deficient SIC mice. In addition, we observed that the level of solute carrier family 7 member 11 was downregulated after the ZFP36 knockdown both in vivo and in vitro. In conclusion, deficiency of ZFP36 exacerbates SIC by activating ferroptosis.