Post-operative cognitive dysfunction (POCD) is a cognitive disorder characterized by a decline in cognitive function following surgical procedures, with mitophagy identified as a significant underlying mechanism. Protein kinase C delta (PRKCD), localized within the mitochondria, is implicated in the regulation of PINK1/PRKN mitophagy pathway; however, the potential regulatory role of PRKCD in POCD through this pathway remains to be elucidated. Neurons and rats were exposed to sevoflurane (SEV) to illuminate the function and mechanism of PRKCD in POCD. Various methodologies were employed, including immunofluorescence, quantitative real-time PCR, CCK-8 assays, mitochondrial membrane potential (MMP) assessments, MitoSOX generation detection, Seahorse metabolic flux analysis, co-immunoprecipitation, western blotting and behavioural experiments like Morris water maze, novel object recognition and fear conditioning, along with haematoxylin and eosin and immunohistochemical staining. PRKCD was expressed in neurons and that SEV administration led to an upregulation of PRKCD expression. Furthermore, interference with PRKCD was found to restore cell viability in SEV-treated neurons. Additionally, inhibition of PRKCD resulted in the recovery of LC3 expression and the normalization of p62 levels in neurons subjected to SEV treatment. Suppressing PRKCD restored MMP and OCR, reduced MitoSOX in SEV-affected neurons and interacted with PRKN and PINK1, decreasing their expression. Overexpressing PRKN mitigated PRKCD inhibition's impact on mitochondrial damage. In vivo, SEV increased PRKCD, PINK1 and PRKN levels, but PRKCD knockdown improved behavioural and pathological outcomes, reversing changes in LC3-II, PINK1, PRKN and p62 expression. PRKCD enhanced SEV-induced POCD in aged rats via the regulation of PINK1/PRKN mitophagy pathway.

ETHNOPHARMACOLOGICAL RELEVANCE:Aucubin is one of the major bioactive iridoid glycosides present in Rehmanniae radix preparata, a traditional Chinese medicinal herb that has long been used to nourish the kidney, benefit the brain, and calm the mind, and is widely applied in the treatment of neurological and neuropsychiatric disorders. Modern pharmacological studies have demonstrated that aucubin exerts prominent anti-inflammatory and neuroprotective effects. Aucubin has been shown to ameliorate attention deficit hyperactivity disorder (ADHD)-like behaviors; however, the underlying mechanisms remain largely unknown. AIM OF THE STUDY:This study aimed to investigate the neuroprotective effects of aucubin against ADHD-like behaviors and to elucidate the underlying molecular mechanisms. METHODS:To elucidate the protective effects of Aucubin against ADHD through network pharmacology, molecular docking analysis, and experimental validation. An ADHD-like phenotype in offspring mice was established through intraperitoneal administration of S-ketamine in the middle and late trimesters of gestation. Aucubin (40 mg/kg) was intraperitoneally injected into offspring mice 14 days after birth, once daily for seven consecutive days. To assess behavioral, electrophysiological, and pathological changes in mice, several tests were employed, including the open field test (OFT), novel object recognition (NOR) test, elevated plus-maze (EPM) test, fear conditioning (FC), local field potential recording, and immunofluorescence assays. Furthermore, results in vitro have investigated the impact of aucubin on S-ketamine-induced astrocytic damage. RESULTS:Aucubin administration significantly reversed S-ketamine-induced ADHD-like behaviors, including decreased total distance in the OFT, increased recognition index in the NOR, reduced proportion of EPM's open-arm timing, and increased freezing time in the FC. Additionally, it decreased the glial fibrillary acidic protein intensity and theta (θ) oscillation power during NOR. In vitro studies demonstrated the neuroprotective effects of aucubin. Furthermore, NLRP3 activator Nigericin inhibited the neuroprotective effects of aucubin. CONCLUSIONS:Aucubin significantly improved ADHD-like behavior in mice by inhibiting NLRP3 activity in astrocytes.

Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children of school age. In mice with ADHD, glial fibrillary acidic protein (GFAP) levels were significantly higher, whereas glutamic acid decarboxylase 65 (GAD65) levels were lower. The goal of this study is to look at the potential function of GFAP and GAD65 antibodies (GAD65-Ab) in mice and children with ADHD by assessing GFAP and GAD65-Ab levels in the blood. An ADHD model was established in pregnant mice with 15 mg/kg of S-ketamine administration using intraperitoneal injection for 5 days from G14 to G18. Children were enrolled if they met in ADHD Rating Scale (ARS) in Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for ADHD based on clinical interviews. Venous blood was obtained from children and mice under aseptic conditions and the serum was centrifuged and preserved. Clear supernatants from mice and children were processed simultaneously in duplicate, side by side, for ELISA assay with the calibrators supplied in the GFAP and GAD65-Ab kit. In mice with ADHD-like behaviors, there was a strong positive connection between serum GFAP levels and open-arm times in the elevated plus maze, which corresponded with the association between serum GFAP levels and hyperactivity-impulsivity ratings (r [Spearman] = 0.496, P = 0.004). The optimal cut-off value of serum GFAP levels as an indicator for auxiliary diagnosis of ADHD was projected to be 28.8 ng/ml based on the receiver operating characteristic (ROC) curve, yielding a sensitivity of 28.6

Canagliflozin reduces albuminuria in patients with diabetic kidney disease (DKD) beyond its glucose-lowering effect, but the mechanisms remain unclear. We analyzed 85 patients treated with canagliflozin and 85 controls over 26 weeks to explore whether the gut microbiome and its metabolites contribute to renoprotection. Canagliflozin remodeled the gut microbiota, notably enriching Roseburia intestinalis and increasing plasma melibiose levels. In mice, canagliflozin alleviated glomerular endothelial injury and albuminuria. Similar effects were replicated by fecal microbiota transplantation, Roseburia intestinalis, or melibiose administration. Mechanistically, melibiose bound to and activated glyoxalase 1, reduced methylglyoxal, and suppressed the AGE-RAGE pathway, preserving glomerular endothelial integrity. Furthermore, oral melibiose precursor supplementation reduced albuminuria in patients with early-stage DKD. These findings suggest the involvement of a gut-kidney axis in the renoprotective effects of canagliflozin and indicate that melibiose may serve as a potential therapeutic strategy for DKD.

ObjectiveThis study aimed to assess the long-term results of the watch-and-wait (W&W) strategy in patients with clinical stage II/III mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) colorectal cancer (CRC) who received neoadjuvant anti-PD-1 monotherapy.MethodsThis retrospective study enrolled stage II/III dMMR/MSI-H CRC patients from four Chinese tertiary hospitals between August 1, 2020 and February 28, 2025. All participants received neoadjuvant anti-PD-1 monotherapy followed by W&W approach. post hoc, endoscopic complete response (eCR) was defined as no suspicious mucosal lesion on white-light or chromoendoscopy (flat scar or normal mucosa allowed) and negative targeted biopsies from the primary tumor site. The primary outcomes were disease-free survival (DFS) and overall survival (OS). The study is registered in the Chinese Clinical Trial Registry (www.chictr.org.cn ChiCTR2500100474).ResultsA total of 49 patients managed with W&W strategy were enrolled, and all met the post hoc eCR criteria. Radiological evaluation showed clinical complete response in 21 patients (44%), partial response in 17 (35%) and stable disease in 10 (21%). One patient lacked evaluable imaging. Median neoadjuvant treatment duration was 6 months (IQR 4-8), with a median of 12 treatment cycles (IQR 8-16). Treatment-related adverse events were grade 1–2 in 14 patients (29%); no grade 3–4 events occurred. At a median follow-up of 35 months (range 9-60), no local regrowth, distant metastasis, or death was recorded. The estimated 3-year DFS and OS are both 100%.ConclusionIn this cohort, patients with dMMR/MSI-H CRC who met eCR after neoadjuvant anti-PD-1 monotherapy had excellent long-term outcomes when managed with W&W strategy. These findings support the potential utility of endoscopic assessment for selecting candidates for organ preservation, but prospective validation of standardized criteria is warranted.

Neuropathic pain (NP) is frequently comorbid with anxiety and depression, yet the underlying molecular mechanisms in the brain remain poorly understood, hindering the development of targeted therapies. This study aimed to identify key transcriptional networks and regulatory pathways in the anterior cingulate cortex (ACC) associated with NP-induced anxiodepression. We analyzed transcriptomic data (GSE92718) from the ACC of a mouse model of chronic NP. By comparing differentially expressed genes at a time point manifesting anxiodepressive-like behavior (8-week post-injury) against those with pain alone (2-week), we constructed a weighted gene co-expression network (WGCNA). A key module (blue module) significantly correlated with the anxiodepressive phenotype was enriched for synaptic signaling (glutamatergic/GABAergic), neuroplasticity, and key pathways like MAPK and Ras. Within this module, we identified 7 pivotal lncRNAs and 5 hub mRNAs (Flt1, Slc38a2, Bmpr1b, Pdgfra, Gng2) via integrated lncRNA-mRNA-pathway and protein-protein interaction network analyses. Furthermore, we established a competing endogenous RNA (ceRNA) network, revealing a core regulatory axis comprising 3 hub lncRNAs, 5 hub mRNAs, and 40 miRNAs. The aberrant expression of the five hub mRNAs in the ACC was specifically validated in mice with anxiodepressive phenotypes using RT-PCR. Our findings unveil a critical ceRNA network and implicate dysregulated synaptic genes in the ACC as key drivers of NP-induced anxiodepression, providing novel insights into its molecular basis and highlighting potential diagnostic biomarkers and therapeutic targets.

Alzheimer’s disease (AD) is a worldwide neurodegenerative disorder and the leading cause of dementia. Despite decades of research which has improved the understanding of AD, an effective disease-modifying therapy has yet to be developed that can prevent, stop, or reverse neuropathological changes and cognitive deficits of AD. There has been keen interest in targeting the epigenetic protein histone deacetylase 6 (HDAC6) for various human conditions leveraging its pathophysiological functions. Particularly, the pathological hallmarks of AD are aging-related accumulation of β-amyloid (Aβ) plaques and tau protein-related neurofibrillary tangles. In preclinical studies, HDAC6 inhibitors may significantly improve Aβ clearance and decrease tau aggregation and genetic deficiency of HDAC6 ameliorates cognitive deficits in mouse models of AD. While some pan-HDAC inhibitors have been FDA-approved for certain clinical indications, many HDAC6 inhibitors exhibit therapeutic potentials in preclinical studies of AD, for which we prepare this article to review and discuss recent studies and offer prospectives. We envision that the field of drug discovery of HDAC6 in AD may benefit by leveraging multimodal approaches, including structural and computational biology, medicinal chemistry, neuropathology and biomarker discovery. Using these approaches, future research will be better poised to efficiently discover new and potent HDAC6-selective inhibitors with enhanced blood-brain-barrier penetration, desirable safety and anti-AD efficacy. Considering the accumulated findings of HDAC6 and the urgent need in the field of AD, we speculate that many new small molecule inhibitors of HDAC6 will move forward enabling translational and clinical evaluations as potential therapeutics of AD.

Background and Objectives Postoperative nausea and vomiting (PONV) is a common complication after laparoscopic cholecystectomy. Previous studies have shown that acupuncture at multiple acupoints could be effective in preventing PONV, but its efficacy in preventing PONV in patients after cholecystectomy remains unknown. Materials and Methods This study aims to observe the preventive effect of acupuncture at multiple acupoints on postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy, providing more evidence for the safety and effectiveness of acupuncture techniques. Results A total of 103 patients were included in the study, and after applying the inclusion and exclusion criteria, 100 patients were followed up, of whom 55 did not receive acupuncture treatment, while 45 underwent acupuncture therapy. The incidence of PONV was significantly lower in patients who received acupuncture at multiple acupoints compared (28.9%) to those who did not receive acupuncture (60.0%) [P = 0.001, relative risk: 0.45 (0.28-0.72)]. In the comparison of visual analog scale (VAS) scores at different postoperative time points, patients who received acupuncture had significantly lower VAS scores than those without acupuncture treatment. Additionally, the acupuncture group had significantly shorter hospital stays (6-7) compared with the group without acupuncture (6-9) [P = 0.014, beta coefficient: -1.23 (-2.20 to 0.25]. Conclusions Our results suggest that acupuncture at multiple acupoints may reduce the overall incidence of PONV in patients undergoing laparoscopic cholecystectomy, as well as shorten their postoperative hospital stay and alleviate postoperative discomfort which merits further clinical trials and application.

Macroautophagy/autophagy plays a crucial role in maintaining nervous system homeostasis but its role in chronic postoperative pain (CPOP) remains poorly understood. Here, we identify impaired autophagy and the accumulation of synaptic proteins in the anterior cingulate cortex (ACC) during the maintenance of CPOP after skin/muscle incision and retraction (SMIR). Lysosomal hydrolase levels are reduced upon SMIR, accompanied by a deficiency of the lysosomal trafficking protein transmembrane protein 251 (TMEM251, also named LYSET). TMEM251 overexpression alleviates impaired autophagy, accumulation of synaptic proteins within autophagy substrates, and maintenance of CPOP in SMIR mice. Conversely, TMEM251 knockdown induces autophagy impairment, accumulation of synaptic proteins, and chronic pain phenotypes in naive mice. Autophagy dysfunction is most pronounced in CaMKIIα-positive neurons in the ACC post-surgery, resulting in their activation, which is mitigated by TMEM251 overexpression. Chemogenetic activation of CaMKIIα neurons exacerbates autophagy impairment and CPOP, while their inhibition rescues SMIR-induced autophagy and pain phenotypes. Taken together, our study highlights the close relationship between impaired autophagy and neuronal activation in the promotion of chronic postoperative pain.

Osteosarcoma is the most common primary malignant bone tumor, and its occurrence and development are closely related to the bone microenvironment. Therefore, it is essential to understand the main factors that promote osteosarcoma progression in the bone microenvironment. Our study focused on the effect of BMP-9 on PD-L1 expression in osteosarcoma cells. The expression of PD-L1 was detected western blot and flow cytometry. Using RNA-seq analysis, we explored the mechanism that regulated PD-L1 mRNA expression. Our findings revealed that BMP-9 promoted PD-L1 protein expression in osteosarcoma cells. Further, BMP-9 induced the transcriptional expression of PD-L1 in osteosarcoma cells. RNA sequencing and TCGA database analysis showed that FOXO1 regulates the transcriptional expression of PD-L1. FOXO1 expression was significantly increased under BMP-9 action. Importantly, BMP-9 cannot increase the transcriptional and protein expression of PD-L1 in osteosarcoma cells when FOXO1 is knocked down. Additionally, the expression of BMP-9 was positively correlated with the expression of PD-L1 in clinical samples of osteosarcoma.

Atherosclerosis, a chronic inflammatory disorder and leading cause of cardiovascular disease, is characterized by macrophage-derived inflammation and foam cell formation. Emerging evidence suggests that metabolic reprogramming of macrophages represents a promising therapeutic approach for atherosclerosis management. In this study, the therapeutic potential of wogonin, a bioactive flavonoid isolated from Scutellaria baicalensis, in modulating macrophage metabolism and attenuating atherogenesis is investigated. Wogonin reduces lesion size and plaque vulnerability, accompanied by a reduction in foam cell formation and inflammation. Mechanistically, wogonin reprogrammes macrophage metabolism from glycolysis to fatty acid oxidation (FAO) by activating the PPARα-CPT1α pathway and acts as a mitochondrial protector by activating PPARα. Wogonin also promotes the KLF11 expression and KLF11 knockout exacerbated atherosclerosis and abolishes the inhibitory effect of wogonin on glycolysis and atherosclerosis. KLF11 forms a transcriptional complex with PPARα and YAP1, serving both as a brake on PPARα-YAP1-mediated glycolysis and a transcriptional activator of ABCA1/G1. Collectively, wogonin reprograms macrophage metabolism from glycolysis to FAO through activation of the PPARα-KLF11-YAP1 pathway, thereby reducing inflammation and foam cell formation, ultimately attenuating atherogenesis.

To explore the causal relationship between allergic rhino-conjunctivitis, asthma, and eczema and peripheral blood eosinophil count from the perspective of single nucleotide polymorphisms through two-sample Mendelian randomization analysis. Five methods, including inverse variance weighting, MR-Egger regression, median weighting, simple model, and weighted model, were used to evaluate the relationship between allergic rhino-conjunctivitis, asthma, and eczema and peripheral blood eosinophil count. Sensitivity analysis (pleiotropy, heterogeneity, and leave-one-out test) was used to evaluate the robustness of the results. There was a significant causal association between SNPs of allergic rhinitis , allergic conjunctivitis, asthma, and eczema and SNPs of peripheral blood eosinophil count. The sensitivity analysis of SNP instrumental variables showed no significant heterogeneity or pleiotropy, indicating that the results are robust. Evidence shows that peripheral blood eosinophil count is associated with an increased risk of allergic rhino-conjunctivitis, asthma, and eczema.

Ulcerative Colitis (Ulcerative Colitis, UC) is a chronic nonspecific inflammatory bowel disease with complex etiology and prone to recurrent episodes, significantly impacting patients’ quality of life. Although traditional Chinese medicine does not have a specific name for this condition, it categorizes it under conditions such as “dysentery,” “diarrhea,” and “intestinal inflammation.” This article begins with an analysis of the etiological and pathogenic mechanisms of UC from the perspective of traditional Chinese medicine, systematically examining common TCM syndromes. It focuses on the therapeutic characteristics of classic formulas like Shen Ling Bai Zhu San, Taohua Tang, Bai Tou Weng Tang, Si Shen Wan, and Bu Zhong Yi Qi Tang in different syndromes, along with their modern pharmacological research foundations. The article also explores their multi-target mechanisms in regulating immune function, repairing intestinal barriers, and maintaining microbial balance. Additionally, it summarizes the advantages and current limitations of TCM in treating UC, aiming to provide theoretical basis and reference for future clinical diagnosis and research.

Background: Neuropathic pain (NP) following spinal cord injury (SCI) remains a major clinical challenge with limited therapeutic options. This study investigated the mechanism by which repetitive transcranial magnetic stimulation (rTMS) alleviates SCI-induced neuropathic pain (SCI-NP) via the GATA-binding protein 3 (GATA3)-Perforin 1 (PRF1) signaling axis. Methods: Public transcriptomic datasets (GSE126611, GSE226238, GSE230149) were analyzed to identify candidate rTMSresponsive targets using protein-protein interaction (PPI) and functional enrichment analyses. In vivo, a contusive SCI model was induced in male Sprague-Dawley (SD) rats, followed by rTMS treatment (15 Hz, 6 weeks). Pain behaviors were assessed by Hargreaves and von Frey tests. Cytokine expression was quantified by enzyme-linked immunosorbent assay (ELISA), and GATA3/PRF1 expression was measured by Quantitative real-time polymerase chain reaction (qPCR) and Western blot. In vitro, binding of GATA3 to the PRF1 promoter was validated in rat spinal neurons using luciferase reporter assays and chromatin immunoprecipitation (ChIP). Functional rescue experiments were performed by intrathecal overexpression of GATA3. Results: Bioinformatic analyses identified a regulatory interaction between GATA3 and PRF1. rTMS treatment significantly reduced mechanical allodynia and thermal hyperalgesia (p G 0.05), downregulated pro-inflammatory cytokines (interleukin (IL)-13, IL-6, tumor necrosis factor-ca (TNF-ca); p G 0.001), upregulated IL-10 (p G 0.001), and suppressed expression of GATA3 and PRF1 (p G 0.001). Mechanistically, GATA3 directly bound the PRF1 promoter. GATA3 overexpression abolished rTMS-mediated analgesic and anti-inflammatory effects (p G 0.05). Conclusion: These findings suggest that rTMS alleviates SCI-NP by inhibiting GATA3-mediated transcriptional activation of PRF1, thereby reducing neuroinflammation.

Chronic postoperative pain (CPOP) remains a significant clinical challenge, with central sensitization being an important mechanism. However, the neuronal circuit-mediated mechanisms associated with this disorder are poorly understood. Here, we identified the nucleus accumbens core (AcbC) received excitatory projections from calcium/calmodulin-dependent protein kinase II (CaMKII)-positive neurons in the anterior cingulate cortex (ACC), playing an important role in the development of CPOP. We demonstrated that the AcbC neurons displayed the enhanced responses to both non-nociceptive and nociceptive stimuli following skin/muscle incision and retraction. Furthermore, fiber photometry and electrophysiological recordings confirmed that the activity of the ACCCaMKII-AcbC pathway was also elevated after surgery. Inhibition of AcbC neurons or the ACCCaMKII-AcbC pathway alleviated pain hypersensitivity in CPOP mice, whereas their activation induced pain phenotypes in naive mice. These findings reveal critical roles for the AcbC neurons and ACCCaMKII-AcbC pathway in CPOP pathogenesis, offering potential therapeutic targets for postoperative pain management.

Spontaneous intracranial hypotension (SIH) is a rare clinical condition that may occur due to cerebrospinal fluid leakage. The purpose of this study was to compare the safety and efficacy of single catheter multisite epidural blood patch(CA-EBP) with standard procedures, including blinded and targeted epidural blood patch (EBP) for the treatment of SIH, and to investigate the effectiveness of dexamethasone as an adjuvant. Clinical data of 68 patients with postoperative SIH who underwent EBP between March 2022 and May 2024. In this prospective cohort trial, 68 patients were allocated to four groups: blind EBP, targeted EBP, CA-EBP, and CA-EBP + dexamethasone, based on the procedure received. Patients were assessed for pain using the visual analog scale (VAS), anxiety and depression using the Hospital Anxiety and Depression Scale (HADS), and quality of life using the Headache lmpact Test (HIT-6). Adverse events were documented to evaluate the safety of the procedure. A total of 68 patients were recruited for the study, comprising 41 females and 27 males, with a mean age of 40.76 years. The participants were distributed as follows: 9 in the blind EBP group, 17 in the targeted EBP group, 20 in the CA-EBP group, and 22 in the CA-EBP + dexamethasone group. After a single treatment, the severity of headaches significantly decreased in 5 (55.56

ObjectiveTo compare the effects of different selective sodium-glucose cotransporter-2 inhibitors (SGLT2i) on hemoglobin and hematocrit in patients with type 2 diabetes mellitus (T2DM) with a network meta-analysis (NMA).MethodsRandomized controlled trials (RCTs) on SGLT2i for patients with T2DM were searched in PubMed, Embase, Cochrane Library, and Web of Science from inception of these databases to July 1, 2023. The risk of bias (RoB) tool was used to evaluate the quality of the included studies, and R software was adopted for data analysis.ResultsTwenty-two articles were included, involving a total of 14,001 T2DM patients. SGLT2i included empagliflozin, dapagliflozin, and canagliflozin. The NMA results showed that compared with placebo, canagliflozin 100mg, canagliflozin 300mg, dapagliflozin 10mg, dapagliflozin 2mg, dapagliflozin 50mg, dapagliflozin 5mg, empagliflozin 25mg, and dapagliflozin 20mg increased hematocrit in patients with T2DM, while canagliflozin 100mg, canagliflozin 200mg, canagliflozin 300mg increased hemoglobin in patients with T2DM. In addition, the NMA results indicated that canagliflozin 100mg had the best effect on the improvement of hematocrit, and canagliflozin 200mg had the best effect on the improvement of hemoglobin.ConclusionBased on the existing studies, we concluded that SGLT2i could increase hematocrit and hemoglobin levels in patients with T2DM, and canagliflozin 100mg had the best effect on the improvement of hematocrit, while canagliflozin 200mg had the best effect on the improvement of hemoglobin.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/#loginpage, identifier PROSPERO (CRD42023477103).

Aims/hypothesisSodium-glucose co-transporter 2 (SGLT2) inhibitors (SGLT2i) are antihyperglycaemic drugs that protect the kidneys of individuals with type 2 diabetes mellitus. However, the underlying mechanisms mediating the renal benefits of SGLT2i are not fully understood. Considering the fuel switches that occur during therapeutic SGLT2 inhibition, we hypothesised that SGLT2i induce fasting-like and aestivation-like metabolic patterns, both of which contribute to the regulation of metabolic reprogramming in diabetic kidney disease (DKD).MethodsUntargeted and targeted metabolomics assays were performed on plasma samples from participants with type 2 diabetes and kidney disease (n=35, 11 women) receiving canagliflozin (CANA) 100 mg/day at baseline and 12 week follow-up. Next, a systematic snapshot of the effect of CANA on key metabolites and pathways in the kidney was obtained using db/db mice. Moreover, the effects of glycine supplementation in db/db mice and human proximal tubular epithelial cells (human kidney-2 [HK-2]) cells were studied.ResultsTreatment of DKD patients with CANA for 12 weeks significantly reduced HbA1c from a median (interquartile range 25-75%) of 49.0 (44.0-57.0) mmol/mol (7.9%, [7.10-9.20%]) to 42.2 (39.7-47.7) mmol/mol (6.8%, [6.40-7.70%]), and reduced urinary albumin/creatinine ratio from 67.8 (45.9-159.0) mg/mmol to 47.0 (26.0-93.6) mg/mmol. The untargeted metabolomics assay showed downregulated glycolysis and upregulated fatty acid oxidation. The targeted metabolomics assay revealed significant upregulation of glycine. The kidneys of db/db mice undergo significant metabolic reprogramming, with changes in sugar, lipid and amino acid metabolism; CANA regulated the metabolic reprogramming in the kidneys of db/db mice. In particular, the pathways for glycine, serine and threonine metabolism, as well as the metabolite of glycine, were significantly upregulated in CANA-treated kidneys. Glycine supplementation ameliorated renal lesions in db/db mice by inhibiting food intake, improving insulin sensitivity and reducing blood glucose levels. Glycine supplementation improved apoptosis of human proximal tubule cells via the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway.Conclusions/interpretationIn conclusion, our study shows that CANA ameliorates DKD by inducing fasting-like and aestivation-like metabolic patterns. Furthermore, DKD was ameliorated by glycine supplementation, and the beneficial effects of glycine were probably due to the activation of the AMPK/mTOR pathway.

Diabetic nephropathy (DN) also known as diabetic kidney disease, is a major microvascular complication of diabetes and a leading cause of end-stage renal disease (ESRD), which affects the morbidity and mortality of patients with diabetes. Despite advancements in diabetes care, current diagnostic methods, such as the determination of albuminuria and the estimated glomerular filtration rate, are limited in sensitivity and specificity, often only identifying kidney damage after considerable morphological changes. The present review discusses the potential of metabolomics as an approach for the early detection and management of DN. Metabolomics is the study of metabolites, the small molecules produced by cellular processes, and may provide a more sensitive and specific diagnostic tool compared with traditional methods. For the purposes of this review, a systematic search was conducted on PubMed and Google Scholar for recent human studies published between 2011 and 2023 that used metabolomics in the diagnosis of DN. Metabolomics has demonstrated potential in identifying metabolic biomarkers specific to DN. The ability to detect a broad spectrum of metabolites with high sensitivity and specificity may allow for earlier diagnosis and better management of patients with DN, potentially reducing the progression to ESRD. Furthermore, metabolomics pathway analysis assesses the pathophysiological mechanisms underlying DN. On the whole, metabolomics is a potential tool in the diagnosis and management of DN. By providing a more in-depth understanding of metabolic alterations associated with DN, metabolomics could significantly improve early detection, enable timely interventions and reduce the healthcare burdens associated with this condition.

STUDY OBJECTIVES:We conducted a non-inferiority study to assess the postoperative quality of recovery (QoR) in elderly patients receiving ciprofol or propofol total intravenous anesthersia(TIVA)after elective laparoscopic major abdominal surgery, with QoR-15 scores as the main measure. DESIGN:A prospective, double-blind, randomized non-inferiority trial was conducted in the theater, post-anesthesia care unit (PACU), and the ward. PARTICIPANTS:144 elderly patients (age ≥ 65 years) were randomly assigned to either the ciprofol group or the propofol group. INTERVENTIONS:The ciprofol group received continuous infusion of ciprofol with remifentanil, and the propofol group received infusion of propofol with remifentanil. OUTCOME MEASURES:The primary outcome was the QoR-15 on the first postoperative day (POD1), assessed in both intention-to-treat and per-protocol populations, with the mean difference between groups compared to a non-inferiority threshold of -8. Additional assessments included QoR-15 scores on POD2, 3, and 5 for both analysis sets. Other evaluated perioperative value factors included hemodynamic parameters and injection discomfort in the intention-to-treat analysis. A linear mixed model was utilized to examine the impact of group-time interactions on hemodynamic data and QoR-15. MAIN RESULTS:The QoR-15 scores on POD1 in the ciprofol group were non-inferior to those in the propofol group both in intention-to-treat set (mean [95 %CI], 95.9[93.7-98.2] vs. 95.6 [93.3-97.8]; mean difference [95 % CI], 0.4 [-2.8-3.5]; P<0.001 for noninferiority) and per-protocol set (mean [95 %CI], 96.7 [94.4-99.0] vs. 95.7 [93.4-98.0]; mean difference [95 % CI], 1.0 [-2.2-4.3]; P<0.001 for noninferiority). Comparable outcomes were noted on postoperative days 2, 3, and 5 following the procedure in both analysis sets. Additionally: compared with propofol group, the occurrence of injection pain was lower (2.8 % vs. 27.8 %, P < 0.001); the hypotension was less frequent (33.3 % vs. 54.2 %, P = 0.012); the bradycardia was more common (38.9 % vs. 23.6 %, P = 0.048). CONCLUSIONS:Ciprofol is not inferior to propofol in QoR. Ciprofol can be suitably administered to elderly patients undergoing elective laparoscopic major abdominal surgery.