Tianjin First Center Hospital

Metanephric mesenchymal cells (MMCs) hold therapeutic potential for acute kidney injury (AKI), but their efficacy is limited, and the mechanisms underlying their action remain unclear. This study aimed to investigate whether catalpol-pretreated MMCs (MMCs-cata) could enhance the efficacy of AKI treatment by regulating key signaling pathways. An AKI model was established in C57BL6 mice via intraperitoneal injection of cisplatin, and the therapeutic effects of MMCs-cata were compared with those of untreated MMCs. RNA-Seq was performed to analyze differentially expressed genes, Western blotting and ELISA were used to measure VEGF-A levels in MMC-cata and the supernatants. An in vitro model of cisplatin-induced renal tubular epithelial cell injury was developed to investigate the signaling pathways upstream and downstream of VEGF-A. The role of VEGF-A/VEGFR2 was confirmed through experiments involving gene silencing, neutralizing antibodies, and VEGFR2 blockade. Additionally, molecular docking simulations and Western blotting were performed to explore the effects of catalpol on the Wnt signaling pathway. MMCs-cata significantly improved renal function in AKI model mice by suppressing inflammation, oxidative stress, and necroptosis. RNA-Seq, Western blotting and ELISA revealed the activation of VEGF-related genes in MMCs-cata along with elevated intracellular and supernatant VEGF-A levels. In both the in vivo and in vitro models, silencing VEGF-A in MMCs-cata, neutralizing VEGF-A in the supernatant, or blocking VEGFR2 in tubular epithelial cells abolished the protective effects of MMCs-cata, while exogenous VEGF-A supplementation alone exerted protective effects. Mechanistic studies indicated that MMCs-cata activated the p38 pathway and suppressed the STAT3 pathway. Molecular docking and Western blotting confirmed that catalpol binds to Wnt3A, activating the canonical Wnt pathway to drive VEGF-A secretion. Catalpol pretreatment enhances the therapeutic efficacy of MMCs by activating the canonical Wnt pathway to promote VEGF-A secretion. VEGF-A interacts with VEGFR2 on renal tubular epithelial cells, likely through both p38 pathway activation and STAT3 pathway inhibition, thereby suppressing inflammation, oxidative stress, and necroptosis to alleviate AKI. This study provides novel insights into the integration of traditional Chinese medicine components with stem cell therapy for AKI management.

ABSTRACT Diabetic wound infections are a common complication of diabetes, which severely impact patients' quality of life. Effective treatment of diabetic wound infections remains one major challenge in the clinic, partially due to the formation of bacterial biofilm and antibiotic resistance. It is imperative to develop non‐antibiotic‐dependent strategies to efficiently eradicate biofilm infections in diabetic wounds. In this work, an innovative nanospray (CDs‐HM) was successfully prepared by linking one acoustic sensitizer (hematoporphyrin monomethyl ether, HMME) to CDs fabricated with hemin, nickel(II) chloride, and polymer ethylene imine. CDs‐HM exhibited catalase‐enhanced sonodynamic properties and photothermal‐enhanced chemodynamic properties. In vitro experiments and transcriptomic analysis demonstrated that CDs‐HM successfully killed the bacteria and destroyed bacterial biofilm by disrupting bacterial cell membrane integrity, inducing oxidative stress, and inhibiting ATP production through synergistic photothermal therapy/chemodynamic therapy/sonodynamic therapy (PTT/CDT/SDT) effects. In the diabetic wound infection mouse model, CDs‐HM remarkably eradicated MRSA biofilm, reduced inflammation levels, and promoted angiogenesis/collagen deposition so as to accelerate wound healing. It is noteworthy that CDs‐HM displayed superior bacteria killing and wound healing effects compared with conventional vancomycin and nanosilver dressing interventions. The practicality and efficiency of CDs‐HM endowed it with broad clinical translation prospects. It paved the way for developing novel strategies for combating diabetic wound infections.

Biliary strictures (BS) remain a common and serious complication after pediatric liver transplantation (pLT), potentially leading to recurrent cholangitis and graft failure. Prompt diagnosis and appropriate management are essential to improve outcomes. This retrospective, single-center study included 1454 pediatric liver transplants performed between January 2013 and December 2021. BS were classified as anastomotic strictures (AS), non-anastomotic strictures (NAS), or intraoperative technical misadventure (ITM). Cases involving both AS and NAS were classified under the BOTH group. A standardized percutaneous transhepatic cholangiography drainage (PTCD)-based protocol was applied: mild strictures were treated with PTCD alone, whereas severe strictures required balloon dilatation (BD) with external drainage. Surgical revision was performed when guidewire passage failed. Outcomes included stricture resolution, recurrence, and graft survival. BS occurred in 120 patients, with AS accounting for 63.3%, NAS & BOTH for 31.7%, and ITM for 5.0%. The overall incidence of BS declined significantly from 12.38% (2013-2016) to 7.07% (2017-2021). PTCD ± BD achieved an 85.7% resolution rate in AS, while surgical reanastomosis was successful in all refractory cases. NAS & BOTH were associated with significantly lower graft survival and showed limited response to both minimally invasive and surgical treatments. Minimally invasive approaches, particularly PTCD ± BD, combined with timely surgical intervention, is effective for AS after pLT. However, NAS & BOTH remain challenging and are associated with inferior graft outcomes, underscoring the need for improved early detection and the development of novel therapeutic strategies.

Renal interstitial fibrosis (RIF) is the cardinal pathological hallmark of chronic kidney disease (CKD). Although the stem-cell factor (SCF)/c-kit axis has been implicated in kidney fibrogenesis, its cell-specific role and downstream mechanism in tubular epithelial cells (TECs) remain undefined. We investigated whether TEC-derived SCF/c-kit signaling propels RIF after unilateral ureteral obstruction (UUO) via Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (NF-κB) activation. Using the Cre-loxP system, a renal tubular epithelial cell-specific c-kit gene knockout mouse model (Ggt1-Cre c-kit−/−) was established. Renal interstitial fibrosis was induced in both C57BL/6J (WT) and Ggt1-Cre c-kit−/− mice via UUO surgery. The extent of fibrosis was evaluated by assessing renal function indicators (serum creatinine and blood urea nitrogen), renal histopathology (PAS and Sirius red staining), and the expression of fibrosis markers (α-SMA, Vimentin, and Collagen I). Western blot and immunofluorescence techniques were employed to detect the expression of fibrosis markers, key proteins of the NF-κB pathway (p-p65, p65, p-IκBα, and IκBα), and inflammatory cytokines (Interleukin (IL)-6 and IL-1β). Primary renal tubular epithelial cells were isolated and cultured ex vivo, and treated with SCF and the NF-κB-specific inhibitor SC-75741 to evaluate the degree of cellular fibrosis and the activation status of the NF-κB pathway. Fourteen days after UUO, renal SCF and c-kit expression paralleled the rise in fibrotic markers. TEC‑specific deletion of c‑kit ameliorates the initial decline in renal function, attenuates tubular injury, reduces collagen deposition, and downregulates the expression of fibrotic proteins. Genetic deletion of c-kit significantly inhibits NF-κB phosphorylation and the expression of inflammatory cytokines IL-6 and IL-1β. In vitro, SCF provoked a fibrogenic phenotype in WT TECs that was abolished by either c-kit deletion or SC-75741. The SCF/c-kit signaling pathway in TECs promotes renal interstitial fibrosis in UUO mice via activation of the NF-κB pathway. Targeted inhibition of c-kit in TECs alleviates inflammatory responses and fibrosis, improves renal function, and may offer a novel therapeutic target for delaying the progression of CKD.

Patients with moderate-to-severe allergic rhinitis (AR) often experience a heavy clinical burden and require more medications to alleviate nasal symptoms. The aim of this study was to evaluate the efficacy and safety of GSP301, a fixed-dose combination nasal spray containing olopatadine hydrochloride and mometasone furoate, in patients with seasonal AR (SAR). In this multicenter, randomized, double-blind, parallel-group study, moderate-to-severe SAR patients were assigned at a 1:1:1 ratio to receive intranasal GSP301, olopatadine hydrochloride (OLO), or mometasone furoate (MF) for 14 days. The primary endpoint was the change from baseline in the average A.M. and P.M. 12-hour reflective total nasal symptom score (rTNSS). Secondary endpoints included changes in the instantaneous TNSS (iTNSS), individual nasal symptoms, reflective total ocular symptom score (rTOSS), instantaneous total ocular symptom score (iTOSS), individual ocular symptoms, and rhinoconjunctivitis quality-of-life questionnaire (RQLQ). Exploratory endpoints and adverse events were also analyzed. Among the 534 subjects, the GSP301 group demonstrated statistically significant improvements in the average rTNSS compared with the OLO group [posterior least square mean difference (LSMD) = -0.56; P < 0.0001] and the MF group (posterior LSMD = -0.43; P < 0.0001). Consistent benefits were observed across secondary endpoints, including iTNSS, rTOSS, RQLQ, and individual nasal and ocular symptoms (all P < 0.05). Additionally, GSP301 reduced the levels of interleukin (IL)-5 and eosinophilic cationic protein (ECP) in nasal secretions. Treatment-emergent adverse events (TEAEs) occurred in 11.2%, 13.5%, and 11.3% of patients in the GSP301, OLO, and MF groups, respectively. Compared with OLO and MF, GSP301 demonstrated superior efficacy, safety, and potential advantages in alleviating local inflammation in patients with moderate-to-severe SAR.

Abstract The question of whether islet neogenesis occurs in adult humans has been a subject of long-standing debate. To explore the characteristics of islet endocrine cells associated with pancreatic ducts, we employed imaging mass cytometry to examine pancreatic tissues from individuals across different age groups, including those with prediabetes or type 2 diabetes (T2D). Our analysis revealed the presence of all five pancreatic islet endocrine cell types, along with two types of non-hormone-expressing endocrine cells, located within or immediately adjacent to the ducts. These cells were most abundant in infancy, with a gradual decline observed through adulthood. Notably, ductal β cells predominated in infancy, whereas ductal α cells became more prevalent in adulthood, and significantly increased in the group aged over 60 years. Obesity further increased the ductal β cells in the subjects aged over 60 years. Under prediabetic and T2D conditions, an increase in all duct-related endocrine cells was observed. These findings indicate that ductal cells may serve as a reservoir for new pancreatic endocrine cells, offering potential insights into the promotion of endogenous β cell regeneration in diabetic patients. Highlights ◯ Characterization of various islet endocrine cell types related to ducts in human pancreas. ◯ The insulin-positive cells are the dominant cells among all duct-related islet endocrine cell types during the infancy period, however, the glucagon-positive cells become the dominant cells in adulthood. ◯ T2D, Obesity, and aging are involved in the increase in the number of duct-related endocrine cells.

Relative fat mass (RFM) is a novel indicator of central adiposity. Cognitive impairment (CI), obesity, and type 2 diabetes mellitus (T2DM) collectively pose substantial public health challenges, contributing to irreversible health consequences and imposing significant economic burdens on healthcare systems worldwide. This study aimed to evaluate the sex-specific association between RFM and CI in middle-aged and older hospitalized patients with T2DM. This cross-sectional study analyzed data from 1328 patients (aged ≥45 years) admitted to the Department of Endocrinology, Tianjin Union Medical Center, between July 2018 and July 2022. CI was defined as a Montreal Cognitive Assessment score < 26. Logistic regression models, restricted cubic spline analyses, and sensitivity analyses were used to assess the association between RFM and CI across sex-specific quartiles. The overall prevalence of CI was 45.6% (605/1,328). The mean age of the study population was 62.4 ± 7.3 years, and 49.3% were female. Among the female participants, we identified a nonlinear inverse J-shaped relationship between RFM and CI (p for nonlinearity = 0.013), characterized by an increasing risk of CI up to an inflection point at an RFM of approximately 43.7, after which the risk plateaued. The third RFM quartile (40.02–42.86) exhibited the highest prevalence of CI (adjusted odds ratio: 2.54, 95% confidence interval: 1.54–4.16). In contrast, no significant association was observed between RFM and CI in males in either unadjusted or fully adjusted models. These findings were consistent across stratified and sensitivity analyses. Among middle-aged and older patients with T2DM, RFM demonstrates a sex-specific, nonlinear association with CI in females. These results highlight the potential utility of RFM as a simple and practical indicator for identifying cognitive risk in female patients with T2DM, supplementing traditional adiposity measures such as body mass index. Not applicable.