Insomnia is closely associated with immune dysregulation, yet the overall pattern of peripheral-central immune disequilibrium and its underlying molecular basis remains incompletely understood. To characterize the peripheral-central immune features associated with insomnia, identify key immune cell populations and core molecular programs, and prioritize candidate therapeutic compounds with preliminary experimental validation. Peripheral blood bulk transcriptomic dataset GSE208668 was analyzed using differential expression analysis, weighted gene co-expression network analysis (WGCNA), and functional enrichment analysis to identify insomnia-associated genes. Protein-protein interaction network analysis and machine learning models were then applied in independent peripheral blood datasets to refine core genes. Immune deconvolution and peripheral blood single-cell transcriptomic dataset GSE213496 were used to determine the immune-cell context, cell-type localization, and intercellular communication features of these genes. The brain single-cell transcriptomic dataset GSE137665 was further analyzed to assess central alterations. Drug prediction, molecular docking, and molecular dynamics simulations were performed to prioritize candidate compounds, followed by in vitro validation of resveratrol in an LPS-induced THP-1 macrophage model. A total of 5,321 differentially expressed genes associated with insomnia were identified, and weighted gene co-expression network analysis highlighted the turquoise and blue modules as key insomnia-related modules. Integrative analysis yielded 390 intersecting genes enriched mainly in immune, inflammatory, and oxidative stress-related pathways. Protein interaction analysis and machine learning further identified six refined core genes: FN1, HMOX1, HSP90AA1, IL10, MYD88, and NFE2L2. Because IL10 was not stably detected in the single-cell datasets, the remaining five genes were used for downstream single-cell analyses. Immune deconvolution suggested selective peripheral immune remodeling in insomnia, characterized by increased resting CD4 memory T cells and M2 macrophages, together with reduced activated NK cells. Peripheral single-cell analysis showed that HMOX1, HSP90AA1, MYD88, and NFE2L2 were mainly enriched in neutrophils, inflammatory macrophages, conventional dendritic cells, and selected lymphocyte populations, whereas FN1 showed a more restricted distribution pattern. CellChat analysis indicated enhanced intercellular communication under the sleep deprivation-related condition. In contrast, brain single-cell analysis revealed comparatively modest but detectable central alterations, including enrichment of ependymal cells, slight increases in excitatory neurons, brain endothelial cells, and choroid plexus stromal fibroblasts, together with heterogeneous expression of the core hub genes and selective rewiring of intracerebral communication networks. Drug prediction consistently prioritized quercetin and resveratrol, and structural analyses supported stable interactions with key targets. In THP-1 macrophages, resveratrol downregulated MYD88 and HSP90AA1 while further upregulating HMOX1. Insomnia appears to be associated predominantly with a peripheral-centered immune disequilibrium pattern, characterized by selective remodeling of innate immune-related populations, enhanced inflammatory and oxidative stress programs, and increased intercellular communication. The MYD88-HMOX1-HSP90AA1-NFE2L2 axis may represent a key molecular program linking inflammatory activation and oxidative stress adaptation. Resveratrol was identified as a potential compound and has been validated through preliminary in vitro experiments.
While Cisplatin remains a cornerstone of oncological intervention, its induction of systemic oxidative stress arranges a deleterious cascade that compromises male reproductive homeostasis. Selenium nanoparticles (SeNPs) may protect against oxidative stress and capping them with Arab gum (AG) could enhance their therapeutic efficacy. This study investigated the comparative gonadoprotective potential of Selenium Nanoparticles (SeNPs) and Arab gum (AG)-coated SeNPs (AG-SeNPs) against Cis-induced testicular dysfunction. Forty-five male Wistar rats were randomized into nine experimental groups: four baseline controls (Normal, AG, SeNPs, and AG- SeNPs) and five treatment groups receiving AG, SeNPs, AG-SeNPs, or a physical mixture of AG + SeNPs following Cis administration. Assessment parameters included the gonadosomatic index, biochemical markers of oxidative stress (CAT, GPX, MDA), and pro-inflammatory cytokines (TGF-beta, TNF-α and IL-6). Testicular integrity was further evaluated via histopathology, PCNA protein expression (cellular proliferation), and DNA fragmentation analysis using the Comet assay and apoptotic markers (Caspase-3 and Cytochrome C release). Administration of AG-SeNPs demonstrated superior gonadoprotective efficacy compared to uncoated SeNPs or physical mixtures. AG-SeNPs significantly restored redox homeostasis, via augmenting antioxidant enzyme activities (CAT, GPX) and reducing lipid peroxidation (MDA). Furthermore, AG-SeNPs significantly downregulated inflammatory signaling (TGF-beta, TNF-α and IL-6) and mitigated DNA damage. The treatment preserved genomic stability and inhibited the intrinsic apoptotic pathway by suppressing Cytochrome C release and Caspase-3 activation. Histological examination confirmed the restoration of seminiferous tubular architecture and enhanced cellular proliferation (PCNA expression). These findings suggest that AG-coating enhances the therapeutic index of SeNPs, likely due to improved bioavailability and synergistic antioxidant properties. AG-SeNPs represent a promising nanomedicine-based strategy for mitigating the gonadotoxic side effects of cisplatin-based chemotherapy.
Nutritional therapy is a key component of critical care management, yet optimal strategies remain debated due to the heterogeneity of ICU patients, dynamic metabolic alterations, and the profound influence of inflammation on nutrient utilisation. Evidence from recent trials has challenged traditional one-size-fits-all approaches, emphasising the need for individualised, phase-specific nutrition throughout the continuum of critical illness and recovery. This manuscript summarises current concepts and emerging evidence in nutrition therapy presented at the 39th Annual Conference of the German Society for Nutritional Medicine (DGEM). Experts reviewed and critically discussed inflammation-driven metabolic changes, personalised energy and protein prescriptions, micronutrient management, macronutrient adaptation, ketogenic strategies in neurocritical care and sepsis, and nutritional considerations in post-ICU syndrome and outpatient recovery. This overview does not claim to be exhaustive; interpretations of individual study results partly reflect the views of the experts. Together with the inclusion of newer therapeutic approaches, this is intended to stimulate discussion and, at the same time, provide a basis for further studies. Inflammation and high disease severity strongly influence nutritional responsiveness, with highly inflamed patients demonstrating reduced benefit and heightened risk of overfeeding. Personalised strategies, including indirect calorimetry, fat-free mass-based protein dosing, and metabolic biomarkers such as the urea-creatinine ratio, offer a rational framework for tailoring therapy. Micronutrient deficiencies are common due to redistribution, pre-existing deficits, and extracorporeal losses, necessitating structured assessment and supplementation. Macronutrient delivery should be progressively escalated and regarded as a pharmacologic intervention aligned with disease phase and organ function. Early standardised ketogenic diet protocols show feasibility and potential clinical benefit in refractory status epilepticus and sepsis. Post-ICU and outpatient phases remain nutritionally vulnerable, with persistent catabolism and underfeeding common; structured, multidisciplinary rehabilitation and transitional nutrition programs may improve long-term outcomes. Future personalised nutrition strategies may rely on metabolic phenotyping and biomarker-informed stratification rather than uniform protein, energy and micronutrient targets for all ICU patients. Integrating individualised energy and protein prescription, targeted micronutrient management, emerging metabolic therapies, and coordinated post-ICU rehabilitation may optimise recovery and functional outcomes. Robust clinical trials are needed to confirm the impact of these personalised strategies on long-term patient-centred endpoints.
The present study reports a case of limb-girdle muscular dystrophy (LGMD) associated with a pathogenic lamin A/C (LMNA) mutation (c.1622G>A). Notably, this case expands the phenotypic and genotypic spectrum of LMNA-related LGMD, and provides novel familial clinical and genetic evidence for this rare mutation. Genetic sequencing revealed a heterozygous mutation in both the proband and the mother of the proband, suggesting autosomal dominant inheritance. Electromyography (EMG) revealed reduced nerve conduction velocity and abnormal potentials in the proband and mother, indicating muscle weakness and atrophy. Magnetic resonance imaging (MRI) results showed symmetric muscle atrophy in the proximal muscles of the lower legs, with fatty tissue replacement. Both the proband and mother had elevated creatine kinase levels, whereas the father had normal levels. Transthoracic echocardiography ruled out severe heart disorders in the proband and mother. In conclusion, EMG and MRI findings indicated myopathic changes in the proband and the mother of the proband, confirming the significance of this mutation in LGMD. This familial case adds novel clinical, electrophysiological and imaging data to the existing literature on LMNA-associated LGMD. Further genetic and clinical evaluations are required to understand the long-term prognosis and potential treatment strategies for LMNA-related LGMD.
NDRG1 protein engages with the orphan nuclear receptor NR4A1, effectively suppressing the transcriptional activity of NF-κB and influencing the inflammatory response. However, the specific roles of the NDRG family and NR4A transcription factors in inflammatory bowel disease (IBD) remain poorly defined, particularly regarding potential differential mechanisms between ulcerative colitis (UC) and Crohn's disease (CD). We hypothesize that NDRG-NR4A interactions are differentially regulated in UC versus CD, contributing to disease-specific modulation of NF-κB signaling and inflammatory responses. Therefore, the aim was to analyze gene and protein expression of both protein families (NDRGs: NDRG1, NDRG2, NDRG3, and NDRG4; and NR4A: NR4A1, NR4A2, and NR4A3), their contributions to UC and CD, and their association with disease severity. In this cross-sectional and comparative study, we assess gene and protein expression of NR4A and NDRG1-4 in 38 UC patients, 10 CD patients, and 18 controls. Gene and protein expression levels were measured by RT-PCR (mucosa) and immunohistochemistry (colonic tissue), respectively. The colonic mucosa from remission UC patients showed upregulation of NDRG2 and the nuclear receptor genes NR4A1-3 compared with controls. NDRG4 was upregulated in active UC patients compared with controls. NDRG1 was downmodulated in active and remission UC patients compared with controls. All differences were statistically significant (p < 0.05). Decreased NR4A2 gene expression was associated with high-sensitivity C-reactive protein (p = 0.030) and erythrocyte sedimentation rate levels (p = 0.001). Our results provide the first evidence of differential alterations in the NDRG-NR4A axis in UC and CD, which could modulate NF κB signaling and the inflammatory profile differently in each disease, opening the possibility of new therapeutic options.
Background/Objectives: Exploiting the metabolic properties of postbiotics is a novel strategy for managing metabolic disorders, including diabetes. Inactivated microorganisms, a major class of postbiotics, improve glycemic control in preclinical and clinical studies. Here, we examined whether heat-killed (HK) Mycobacterium aurum (M. aurum) exerts prophylactic or therapeutic anti-hyperglycemic effects in diabetic mice. Methods: Diabetes was induced in male BALB/c mice by streptozotocin (STZ; 150 mg/kg) injection. HK M. aurum (1 mg) was given orally (three prophylactic doses before STZ) or intradermally (six weekly therapeutic doses after STZ). We assessed glycemic parameters, serum C-peptide/insulin (ELISA), and tissue protein expression (Western blot). Results: Neither route altered body weight or glucose homeostasis in non-diabetic mice. In STZ-diabetic mice, oral prophylactic treatment significantly attenuated hyperglycemia (39-60% reduction weeks 5-8 post-STZ) and showed a trend toward improved serum C-peptide, but did not affect dysregulated expression of skeletal muscle (SM), hepatic, pancreatic and renal proteins involved in glucose transport (GLUT2, GLUT4, and SGLT2), glycolysis (α-LDH), mitochondrial uncoupling (UCP2 and UCP3), and antioxidant defense (CAT). Therapeutic intradermal administration significantly decreased blood glucose (~30% at week 5, ~40% at week 6) and modestly enhanced insulin secretion. Hepatic UCP2 and α-LDH and SM UCP3 protein levels were normalized toward non-diabetic levels, whereas hepatic GLUT2 and SM GLUT4 remained largely unchanged. These correlative findings suggest effects independent of insulin-dependent glucose transport, but do not demonstrate direct functional improvement in mitochondrial or redox status. Conclusions: HK M. aurum exerts partial anti-hyperglycemic effects in STZ-induced diabetic mice, but the associated protein changes require functional validation before its role as a postbiotic in β-cell dysfunction can be established.
Antibiotic-associated diarrhea (AAD) remains a common complication of antibiotic therapy. While probiotics show therapeutic potential, the novel strain Bacillus subtilis THC1I has not been previously evaluated for AAD treatment. This study aimed to assess the effects of B. subtilis THC1I on intestinal barrier integrity and gut microbiota dysbiosis in an AAD mouse model. Fifty mice were randomized into five groups (n = 10): control, model, positive control (Enterogermina®, B. clausii), and a B. subtilis THC1I spore suspension at 0.82 × 10⁹ and 1.64 × 10⁹ CFU/kg/day. AAD was induced with gentamycin sulfate and cefradine for five consecutive days. Outcomes included clinical symptoms, hematological and biochemical parameters, colonic macroscopic and histopathological indices, inflammatory cytokines, and gut microbiota analyzed by 16S rRNA sequencing. B. subtilis THC1I significantly improved body weight, water intake, fecal scores, and fecal water content. Treatment restored electrolyte balance (sodium and potassium), reduced white blood cell counts, and decreased relative colon weight and inflammation scores. Histopathological analysis revealed restored epithelial architecture and increased goblet cell density. Pro-inflammatory cytokines (TNF-α, IL-1β) were significantly reduced. B. subtilis THC1I partially improved microbial diversity (Shannon index) and modulated microbiota composition at both phylum and genus levels, decreasing pathogenic bacteria (Proteobacteria phylum: Escherichia-Shigella, Klebsiella, Salmonella; Firmicutes phylum: Clostridioides), and modulating the dysbiotic overgrowth of the beneficial commensal Blautia, while promoting beneficial bacteria (Bacteroidota phylum: Bacteroides, Muribaculaceae; Firmicutes phylum: Lachnospiraceae, Lactobacillus). B. subtilis THC1I demonstrates restorative effects on intestinal barrier damage and gut microbiota dysbiosis in AAD mice, supporting its potential as a therapeutic candidate for clinical application.
Foodborne pathogen Listeria monocytogenes causes listeriosis, a rare but deadly condition. Internalin A (InlA) and Listeriolysin O (LLO), its main virulence factors, facilitate adhesion, invasion, intracellular survival, and intercellular spreading, making them interesting therapeutic targets. L. monocytogenes infections are becoming harder to treat because of antibiotic resistance; hence, flavonoids are being considered. An integrated in-silico technique was used to test plant-derived flavonoids' inhibitory efficacy against these proteins. For both targets, three modes of docking (HTVS, SP, and XP docking) were used for the preliminary screening from a library of 1,254 flavonoids. While CIDs 441667, 15126294, and 187808 showed favorable in-silico profiles for InlA with scores of -8.461, -7.578, and -7.521 kcal/mol, respectively, CIDs 441699, 443648, and 442868 showed the best affinity for LLO with values of -7.446, -5.991, and -5.852 kcal/mol, respectively. Admet analysis predicted the drug-likeness and safety characteristics of the compounds. Subsequently, the QM calculation was employed to examine the interaction of these compounds with the receptor, alongside their MEP and NBO characteristics. The selected ligands and the control ampicillin for both proteins were utilized to build protein-ligand complexes, subsequently assessed via a 100 ns molecular dynamics simulation. Subsequent post-simulation MM-GBSA, PCA and DCCM analysis of the trajectories evaluated their dynamic stability concerning InlA and LLO. CIDs 441667 and 15126294 for InlA, as well as CIDs 441699 and 443648 for LLO, have been identified as potential inhibitors, establishing a basis for future in vivo investigations and experimental validation.
Hydroxysafflor Yellow A (HSYA), the major bioactive component from Carthamus tinctorius L., exerts significant protective effects against myocardial ischemia-reperfusion injury (MIRI). Mitophagy is pivotal in the pathological process of MIRI, yet the specific molecular mechanism underlying HSYA-mediated mitophagy regulation remains unclear. This study aimed to investigate the association between HSYA treatment and mitochondrial autophagy in murine MIRI and to explore the potential mechanistic role of the SIRT1-FOXO3-BNIP3 signaling pathway using functional loss-of-function and rescue experiments. These findings may provide preliminary evidence supporting the clinical translational potential in MIRI therapy. Mouse myocardial ischemia-reperfusion injury (MIRI) model and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced AC16 cardiomyocyte injury models were established. Metabolomics, molecular docking, and surface plasmon resonance (SPR) techniques were combined to screen the potential targets of HSYA. The SIRT1 inhibitor EX527 and SIRT1 siRNA were used to verify the underlying mechanism. Cardiac function, myocardial infarct size, mitochondrial function, the expression of autophagy-related proteins, and protein-protein interaction were detected and analyzed. Compared with the MIRI group, HSYA significantly improved cardiac function in mice, as evidenced by increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (p < 0.01), attenuated ST-segment elevation, and improved myocardial perfusion. HSYA also markedly reduced myocardial infarct size (p < 0.01) and serum levels of CK-MB, LDH, and cTnI (all p < 0.01) and ameliorated myocardial histopathological damage and mitochondrial ultrastructural integrity. Mechanistic studies revealed that HSYA significantly upregulated the expression of SIRT1, FOXO3, BNIP3, Beclin-1, and the LC3II/I ratio while downregulating p62 expression (p < 0.01), consistent with enhanced mitophagy-related activity. Furthermore, these protective effects were markedly attenuated upon SIRT1 inhibition or siRNA-mediated silencing, whereas HSYA intervention partially reversed these alterations. Additionally, co-immunoprecipitation (Co-IP) and pull-down assays demonstrated that HSYA promoted protein-protein interactions between SIRT1-FOXO3, FOXO3-BNIP3, and BNIP3-LC3B. These findings highlight that HSYA is associated with improved cardiac function, enhanced mitophagy-related activity, and upregulated SIRT1-FOXO3-BNIP3 signaling, providing robust experimental evidence for its clinical translational application in MIRI treatment.
Several medications are available for rapid tranquilisation in psychomotor agitation, but choosing among them varies across local practices and this variation is compounded by inconsistent guidelines. We performed a systematic review with individual participant data network meta-analysis to inform evidence-based recommendations. In this systematic review and individual participant data meta-analysis, we searched multiple databases from database inception to Nov 14, 2025, for randomised trials comparing intramuscular or intravenous treatments for rapid tranquilisation (primary outcome defined as sedation within 15-30 min) in patients with psychomotor agitation in general or psychiatric emergency settings. Anonymised individual participant data were collected and harmonised into a common dataset. Risk of bias was assessed using the RoB 2 tool. We performed Bayesian one-stage random-effects individual participant data network meta-regressions, accounting for between-study heterogeneity, drug classes, prognostic factors, and subgroup effects based on agitation severity. We combined individual participant data and aggregate data to evaluate side-effects. Confidence in the evidence was assessed using the Confidence In Network Meta Analysis (CINeMA) framework. People with lived experience were involved in the design and interpretation of the findings. The protocol was registered with PROSPERO (CRD42023402365). We included 18 trials across eight regions (3411 participants; 1988 [58·3%] men, 1423 [41·7%] women; mean age 36·0 [SD 11·7] years), of which 13 trials (2705 participants) provided individual participant data for antipsychotics, benzodiazepines, and their combination. In moderate agitation, odds of achieving sedation relative to haloperidol monotherapy were higher with antipsychotic-benzodiazepine combinations (odds ratio [OR] 12·93, 95% credible interval [95% CrI] 3·00-50·91; relative risk [RR] 1·58), benzodiazepines (5·52, 1·37-21·02; 1·49), and other antipsychotics (4·54, 1·35-14·45; 1·45). In severe agitation, antipsychotic-benzodiazepine combinations were more effective than haloperidol (4·86, 1·28-17·54; 1·73), whereas results were uncertain for benzodiazepines (2·09, 0·58-6·99; 1·38) and other antipsychotics (1·70, 0·62-4·59; 1·28). Confidence in these estimates was very low, mainly due to imprecision and heterogeneity. Haloperidol monotherapy was associated with higher risk of extrapyramidal side-effects and benzodiazepines, alone or in combination, with hypotension. Antipsychotic-benzodiazepine combinations might be among the most effective options for rapid tranquilisation in patients with psychomotor agitation but carry a risk of hypotension, whereas haloperidol monotherapy appeared among the least effective and is associated with extrapyramidal side-effects. These findings should be contextualised to the specific setting and patient characteristics, including the underlying agitation aetiology. Large trials are needed to provide more precise recommendations. German Ministry of Research, Technology and Space and Swiss National Science Foundation.
Tranexamic acid is an antifibrinolytic agent reducing mortality when administered to trauma patients with haemorrhagic shock. This mortality reduction is time sensitive. Increased intramuscular dose administration has proven an effective alternative to intravenous administration in several studies and is used by some emergency medical services. However, subcutaneous administration has not been studied. Previous research indicates that subcutaneous tissue blood flow is more compromised during shock than muscle perfusion. Determining subcutaneous absorption is crucial to evaluate its potential as an alternative route and to assess the effect of accidental subcutaneous injection during intended intramuscular administration. In this experimental study using historical intramuscular and intravenous control groups, a total of six Norwegian Landrace pigs (40-50 kg) used in a trauma surgery course were subjected to various abdominal and thoracic traumas. After 1 h of surgery, the animals received tranexamic acid 30 mg/kg subcutaneously. Serum was sampled at 0, 5, 15, 25, 35, 45, 60, and 85 min after administration. Tranexamic acid serum concentration was measured using liquid chromatography-tandem mass spectrometry and compared to intramuscular and intravenous groups from previous studies, in which animals had received tranexamic acid 30 mg/kg intramuscular (n = 7) or 15 mg/kg intravenous (n = 8). There was no statistical difference in serum concentrations between subcutaneous and intramuscular administration. Mean (±standard deviation) concentration after administration at 10, 45, and 85 min were 41.4 μg/mL (±19.0), 39.1 μg/mL (±8.9), and 33.4 μg/mL (±5.8), and for IM concentrations were 41.8 μg/mL (±18.9), 39.9 μg/mL (±7.8), and 44.2 μg/mL (±21.8). At 5 min, the concentration of both SC and IM administration was approximately half those observed after IV administration, but all concentrations were well above the 10-17 μg/mL concentration needed to inhibit fibrinolysis. Although subcutaneous blood flow is sensitive to shock, serum tranexamic acid concentrations after subcutaneous administration in shocked pigs were comparable to those achieved after intramuscular administration. Intramuscular administration should remain the preferred secondary route after the standard intravenous route, but inadvertent subcutaneous injection is likely to achieve therapeutic serum concentrations. This observational study in pigs undergoing hemorrhagic shock compared subcutaneous tranexamic acid administration to historical intravenous and intramuscular controls and found that plasma concentrations were comparable between routes. This suggests that inadvertent subcutaneous dosing during intramuscular injection likely achieves therapeutic levels. While promising, these results rely on historical controls and warrant further confirmatory studies. Intramuscular administration remains the preferred alternative to intravenous dosing for now.
Cerebral ischemia/reperfusion (I/R) injury represents a major pathological component of ischemic stroke and is driven by a complex cascade of neurochemical and molecular events, including excitotoxicity, oxidative and nitrosative stress, neuroinflammation, blood-brain barrier (BBB) disruption, mitochondrial dysfunction, and regulated cell death pathways such as apoptosis and ferroptosis. Tanshinones, a class of lipophilic diterpenoid quinones derived from Salvia miltiorrhiza (Danshen), have attracted increasing attention as multi-target neuroprotective agents in experimental models of cerebral I/R. Accumulating evidence demonstrates that major tanshinones, including tanshinone I, tanshinone IIA, tanshinone IIB, cryptotanshinone, and dihydrotanshinone I, modulate key neurochemical processes underlying cerebral I/R injury, including redox homeostasis, inflammatory signaling cascades, mitochondrial function, BBB integrity, and cell death regulatory networks. In parallel, recent advances in formulation strategies, including chemically modified derivatives (e.g., sodium tanshinone IIA sulfonate and the cryptotanshinone derivative DST-3), as well as microemulsions, liposomes, and nanoparticle-based delivery systems, have markedly improved aqueous solubility, pharmacokinetic behavior, and brain bioavailability of tanshinones, thereby potentially enhancing their neuroprotective effects in experimental models. This review comprehensively summarizes current evidence on the neurochemical and molecular mechanisms of tanshinones and their formulations in cerebral I/R injury, with an emphasis on signaling pathway modulation, redox regulation, mitochondrial protection, and formulation-driven improvements in brain delivery, and discusses remaining mechanistic challenges and future research directions.
Immune checkpoint inhibitors (ICIs) are widely applied in the treatment of various malignant tumors, leading to notable improvements in patient prognosis. However, with their increased use, various immune-related adverse events (irAEs), including ICI-induced inflammatory arthritis (ICI-IA), may develop, affecting clinical evaluation and treatment decisions. The present report presents 3 cases of ICI-IA and reviews the literature on its clinical features, diagnosis and therapeutic approaches. The first patient, who had been diagnosed with metastatic bladder cancer, developed limb joint pain after undergoing combination therapy involving ICIs and chemotherapy. Laboratory tests showed elevated levels of C-reactive protein and interleukin (IL)-6. Bone scintigraphy excluded bone metastasis, and the symptoms of the patient improved following corticosteroid therapy. The second patient had advanced cervical cancer and a history of rheumatoid arthritis. Following multiple cycles of ICI combined with anti-angiogenic treatment, the patient experienced recurrent joint swelling and pain, accompanied by elevated IL-6 and IL-10 levels. Bone scintigraphy excluded bone metastasis, and the symptoms were controlled with corticosteroid therapy. The third patient had advanced lung cancer and developed persistent pain in the shoulders, knees and ankles during immunotherapy. Corticosteroid therapy effectively controlled the symptoms after bone metastases and autoimmune diseases were excluded. These cases illustrate that ICI-IA is a clinically relevant irAE. Early recognition and management are crucial for improving patient prognosis. A thorough understanding of the pathogenesis of ICI-IA is essential for optimizing treatment strategies and improving quality of life.
Cisplatin, a chemotherapeutic drug, produces severe nephrotoxicity and at present, there are no effective drugs to clinically prevent or treat it. In the Dai nationality, BaiYangJie is used to treat poisoning caused by chemicals or drugs. Previous research has demonstrated that the methanolic extract of BaiYangJie (MEAG) can treat cisplatin-induced nephrotoxicity; however, its mechanism of action remains unclear. The aim of the present study was therefore to identify the potential mechanism of action of MEAG in cisplatin nephrotoxicity using a combination of network pharmacology and serum metabolomics. Initially, network pharmacology analysis was used to identify hub targets and signalling pathways involved in the renoprotective effects of MEAG. Subsequently, plasma metabolomics profiling utilising ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry technology revealed key metabolic alterations and pathway modulations associated with MEAG treatment. Finally, integrated analysis uncovered key molecular mechanisms, which were subsequently validated by western blotting and immunohistochemistry. A total of 13 endogenous metabolites were identified in serum metabolomics, primarily involved in phenylalanine metabolism and in the biosynthesis of phenylalanine, tyrosine and tryptophan. The treatment of MEAG in cis-induced acute kidney injury primarily involved regulating the inflammatory response, responses to lipid and chemical stress, the FoxO signalling pathway, arachidonic acid metabolism and the NF-κB signalling pathway. Animal experiments showed that MEAG can inhibit inflammation and the expression of the migration inhibitory factor (MIF)/NF-κB pathway. Through integrated network pharmacological analysis, metabolomic profiling and experimental validation, it was systematically elucidated that MEAG exerted its therapeutic effects through dual regulatory mechanisms: Suppressing inflammatory responses by inhibiting overactivation of the MIF/NF-κB signalling pathway and restoring phenylalanine metabolic homeostasis. These findings thus provide a mechanistic foundation for developing targeted therapeutic strategies against chemotherapy-associated nephrotoxicity.
Retroperitoneal laparoscopic resection is the preferred minimally invasive surgery for adrenal tumors. Patients vary greatly in postoperative drain output, but no clear criteria exist to select candidates for a drainage-free strategy. The objective of the present study was to establish clinical screening criteria for identifying patients eligible for a drainage-free strategy after retroperitoneal laparoscopic adrenal tumor resection and verify the clinical value of the criteria. A retrospective analysis was first conducted on 126 patients who underwent the aforementioned surgery. Patients were divided into two groups based on total postoperative drain output: The drainage-free group (≤60 ml, 40 cases) and the drain group (>60 ml, 86 cases). Indicators such as age and tumor diameter were compared with identify factors influencing postoperative drain output. Subsequently, a prospective validation study was carried out involving 54 patients, with 20 patients meeting the preliminary screening criteria assigned to the experimental group and 34 ineligible patients to the control group. Perioperative data and complication rates of the two groups were compared. The retrospective univariate analysis identified seven indicators (including age and tumor diameter) associated with postoperative drain output (P<0.05). Multivariate logistic regression confirmed five independent risk factors for postoperative drain output: Age [odds ratio (OR)=1.062; 95% confidence interval (CI) 1.005-1.123; P=0.033], tumor diameter (OR=2.199; 95% CI: 1.162-4.159; P=0.015), locking clip application for adrenal tissue or central vein (OR=12.081; 95% CI: 1.772-82.385; P=0.011), saponification and adhesion of adipose tissue in the surgical area (OR=0.092; 95% CI: 0.026-0.319; P<0.001) and intraoperative blood loss (OR=10.48; 95% CI: 1.025-1.072; P<0.001). In the prospective validation study, only one patient in the experimental group had postoperative drain output >60 ml (recovered with conservative treatment). The experimental group also had significantly less total drain output, shorter drain removal time and shorter hospital discharge time than the control group (P<0.05), with no significant difference in complication rates (P>0.05). In conclusion, the established screening criteria may accurately identify eligible patients. This strategy appears to safely shorten hospital stays and facilitate stratified management and may have clinical value.
Elderly patients with chronic obstructive pulmonary disease (COPD) complicated with type II respiratory failure (RF) have high morbidity and poor prognosis. Conventional therapy shows limited efficacy, while high-dose glucocorticoids easily cause adverse reactions, and targeted data on low-dose regimens are insufficient. To investigate the pharmacological application value of low-dose methylprednisolone sodium succinate (LD-MSS) in elderly patients with COPD complicated with respiratory failure (RF). A total of 96 COPD patients with RF admitted to 3201 Hospital were analyzed by propensity score matching. The patients were divided into experimental group (n=48) and control group (n=48), and received LD-MSS treatment and conventional treatment respectively. The RF correction time and APACHE II score of both groups were recorded, and pre- and post-treatment lung function, blood gas function, and inflammatory factor levels were measured. Compared with the control group, the LD-MSS group had a significantly shorter RF correction time and a significantly lower APACHE II score (P<0.05). In addition, the experimental group had better pulmonary and blood gas functions and lower levels of inflammatory factors than the control group (P<0.05). Finally, no marked difference was identified between groups in the incidence of adverse reactions (P>0.05). LD-MSS is effective in anti-inflammation and in improving blood gas function, and has a good safety profile.
Sodium-glucose co-transport protein inhibitor Sotagliflozin (SOTA) has demonstrated cardiovascular benefits in diabetic patients, while doxorubicin (DOX) is widely used to generate cardiomyopathy experimental models. The present study investigated the cardioprotective mechanisms of SOTA on DOX-induced heart failure in vitro and in vivo. First, C57BL/6 mice were injected with multiple doses of DOX (total 15 mg/kg), and the in vivo impact of SOTA on cardiac function and cardiomyopathy-related biochemical signaling was assessed. Next, H9C2 cells were treated with DOX in the presence of SOTA to examine the changes in cell viability, mitochondrial function, inflammation, oxidative stress and cell death-related signal pathways. SOTA treatment in vivo alleviated cardiac dysfunction and fibrosis while reducing cardiomyocyte apoptosis, inflammation, oxidative stress and mitochondrial dysfunction. In vitro, H9c2 cells exposed to DOX in the presence of SOTA exhibited enhanced cell viability and mitigated apoptosis, inflammation, oxidative stress and mitochondrial damage. Furthermore, cleaved caspase-3 and inflammatory cytokine (IL-6, IL-1β and TNF-α) levels were decreased. Reactive oxygen species and mitochondrial Ca2+ loading were reduced. Mitochondrial dysfunction was also improved, as indicated by increased JC-1 aggregates and Bcl-2/Bax ratios. Notably, SOTA activated 5' AMP-activated protein kinase (AMPK) and inhibited mTOR signaling while protecting from DOX-induced cardiomyopathy, suggesting SOTA as a promising therapeutic for heart failure treatment.
Gastric cancer (GC) is one of the main causes of cancer-related global mortality. The emergence of drug resistance and toxicity in current therapies highlights the need for novel treatment strategies. Quercetin, a natural flavonoid, has demonstrated anticancer activity; however, its molecular mechanism, particularly its effect on key targets in GC, remains underexplored. A comprehensive in silico and in vitro methods were used to elucidate the anticancer potential of Quercetin. Network pharmacology analysis was used to identify potential GC-related targets, followed by molecular docking and 200 ns molecular dynamics (MD) simulations to evaluate the binding affinity and stability of the Quercetin-target complex. In vitro experiments, including gene expression analysis and fluorescence binding assays, were conducted using AGS gastric cancer cells to validate the computational findings.nsulin-like growth factor 1 (IGF1) emerged as a key hub gene associated with GC progression. Molecular docking predicted a favorable interaction between Quercetin and IGF1, with a docking score of - 6.3 kcal/mol and multiple hydrogen-bond interactions. MD simulations confirmed the stability of the Quercetin-IGF1 complex, with reduced RMSD values (0.48 nm vs. 0.63 nm for unbound IGF1), favorable free energy profiles, and stable hydrogen bonding. In vitro studies demonstrated a significant downregulation of IGF1 mRNA expression (p < 0.001) and a dose-dependent inhibition of IGF1 activity by Quercetin. The integration of network pharmacology, computational modeling, and experimental validation suggests that Quercetin may modulate the IGF1 signaling axis and influence IGF1-associated pathways in gastric cancer. The stable binding and significant inhibitory effect observed suggests that Quercetin may interrupt IGF1-mediated signaling pathways involved in tumor growth and survival. This study identifies Quercetin as a potential modulator of IGF1-associated signaling pathways with significant therapeutic promise for gastric cancer. The findings provide mechanistic insights supporting the further development of Quercetin as a targeted therapy for IGF1-driven malignancies.
Mitochondria-targeted antioxidants (MTAs) accumulate in mitochondria to mitigate mitochondrial oxidative stress. The present study investigates the anticancer therapeutic potential of two MTAs, MitoQ, and Mito-TEMPO, in rodent N-nitrosodiethylamine-induced hepatic cancer. Tumor-bearing male Wistar rats were treated with MitoQ (0.125 mg/kg b.w. orally), Mito-TEMPO (0.100 mg/kg b.w. intraperitoneally), or their combination for 6 weeks. The therapeutic effects of these MTAs were assessed in terms of total tumor number, multiplicity, and dielectric properties. Inflammatory level, DNA damage, apoptotic, and cell proliferation markers were assessed using ELISA and immunohistochemistry. Mitochondrial oxidative stress, activities of mitochondrial antioxidant enzymes, and electron transport chain enzymes were assessed using biochemical methods. Results revealed a significant (p ≤ 0.05) reduction in total number of tumors and tumor multiplicity, improved mitochondrial antioxidant system, electron transport, membrane potential and a significant (p ≤ 0.05) decrease in mitochondrial LPO and mitochondrial ROS when compared to untreated Tumor group. Furthermore, treatment significantly (p ≤ 0.05) modulated the levels of IL-6, TNF-α, 8-OHdG, bax, caspase-3, PCNA, Ki67, connexin, and cadherin proteins in tumors. In conclusion, both MitoQ and Mito-TEMPO have appreciable anticancer therapeutic potential against N-nitrosodiethylamine-induced hepatic cancer. The combination treatment of these two MTAs also exhibited additive anticancer therapeutic potential on tumor profile. Therefore, MTA-based anticancer therapy approach holds a promising future.
Opioids are the mainstay of cancer-related pain management but are limited by adverse effects and clinical complexity. Cannabinoids have been proposed as adjunctive, opioid-sparing agents, yet their impact on opioid consumption in cancer patients remains uncertain. This systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines and registered in PROSPERO (CRD420251175971). Randomized and nonrandomized clinical studies involving adult cancer patients receiving opioids for pain and treated with cannabinoids were included. Outcomes comprised total opioid consumption, maintenance/background opioid dose, and breakthrough/rescue opioid use. Placebo-controlled comparisons were analyzed separately from within-group baseline changes. Risk of bias was assessed using RoB 2 and ROBINS-I, and certainty of evidence using GRADE. Fifteen studies met inclusion criteria, with ten eligible for meta-analysis. Placebo-controlled analyses showed no significant differences between cannabinoids and placebo for total, maintenance, or breakthrough opioid use. Baseline-change analyses demonstrated heterogeneous and formulation-dependent effects, with modest reductions in maintenance opioid dose observed primarily in THC-predominant regimens, driven by isolated studies. Overall certainty of evidence was low due to heterogeneity and methodological limitations. Cannabinoids are not associated with consistent or clinically meaningful opioid-sparing effects in cancer pain under controlled conditions. Observed benefits in uncontrolled analyses are variable and not reliably reproduced. Cannabinoids should not be considered a dependable opioid-sparing strategy in cancer pain management.