Adipokines, including C1q/tumor necrosis factor (TNF)-related proteins (CTRPs), adiponectin, TNF-α, and leptin, are crucial bioactive molecules that are secreted by adipose tissue and circulate in the bloodstream. To date, 15 members of the CTRP family, which are collectively classified as part of the C1q/TNF superfamily, have been identified. Among these, CTRP3 stands out as a unique adipokine because of its distinct structural and functional properties. Recent research has highlighted the significant role of CTRP3 in the pathogenesis of various diseases. This review aims to comprehensively summarize the involvement and mechanisms of CTRP3 in the development of numerous disorders, as well as its potential therapeutic implications.

Endolysosomes, considered the cellular recycling compartments, receive and degrade materials from multiple pathways. However, whether endolysosomes can acquire cargo through alternative mechanisms remains unclear. Here, we identify a previously unrecognized endolysosomal pathway for material uptake. In this process, endolysosomes extend two membrane protrusions that envelop and ultimately engulf autophagosomes, independently of autophagosome-endolysosome fusion and the endosomal sorting complex required for transport complex (ESCRT)-mediated microautophagy. The endolysosomes containing internalized autophagosomes, acquire additional autophagosomes through homotypic fusion. A subset of autophagosomes is marked by F-actin on their membranes and the majority of them contain the ER protein Sec61β and the peroxisomal protein Pex16 within their lumens, whereas mitochondria remain excluded. Our discovery of this endolysosomal process unveils a previously uncharacterized pathway for cargo acquisition by endolysosomes.

BACKGROUND:Acute pancreatitis in pregnancy (APIP) is a rare and serious condition, and severe APIP (SAPIP) can lead to pancreatic necrosis, abscess, multiple organ dysfunction, and other adverse maternal and infant outcomes. Therefore, early identification or prediction of SAPIP is important. AIM:To assess factors for early identification or prediction of SAPIP. METHODS:The clinical data of patients with APIP were retrospectively analyzed. Patients were classified with mild acute pancreatitis or severe acute pancreatitis, and the clinical characteristics and laboratory biochemical indexes were compared between the two groups. Logical regression and receiver operating characteristic curve analyses were performed to assess the efficacy of the factors for identification or prediction of SAPIP. RESULTS:A total of 45 APIP patients were enrolled. Compared with the mild acute pancreatitis group, the severe acute pancreatitis group had significantly increased (P < 0.01) heart rate (HR), hemoglobin, neutrophil ratio (NEUT%), and neutrophil-lymphocyte ratio (NLR), while lymphocytes were significantly decreased (P < 0.01). Logical regression analysis showed that HR, NEUT%, NLR, and lymphocyte count differed significantly (P < 0.01) between the groups. These may be factors for early identification or prediction of SAPIP. The area under the curve of HR, NEUT%, NLR, and lymphocyte count in the receiver operating characteristic curve analysis was 0.748, 0.732, 0.821, and 0.774, respectively. The combined analysis showed that the area under the curve, sensitivity, and specificity were 0.869, 90.5%, and 70.8%, respectively. CONCLUSION:HR, NEUT%, NLR, and lymphocyte count can be used for early identification or prediction of SAPIP, and the combination of the four factors is expected to improve identification or prediction of SAPIP.

The prevalence of calcific aortic valve disease (CAVD) remains substantial while there is currently no medical therapy available. Forkhead box O1 (FOXO1) is known to be involved in the pathogenesis of cardiovascular diseases, including vascular calcification and atherosclerosis; however, its specific role in calcific aortic valve disease remains to be elucidated. In this study, we identified FOXO1 significantly down-regulated in the aortic valve interstitial cells (VICs) of calcified aortic valves by investigating clinical specimens and GEO database analysis. FOXO1 silencing or inhibition promoted VICs osteogenic differentiation in vitro and aortic valve calcification in Apoe-/- mice, respectively. We identified that FOXO1 facilitated the ubiquitination and degradation of RUNX2, which process was mainly mediated by SMAD-specific E3 ubiquitin ligase 2 (SMURF2). Our discoveries unveil a heretofore unacknowledged mechanism involving the FOXO1/SMURF2/RUNX2 axis in CAVD, thereby proposing the potential therapeutic utility of FOXO1 or SMURF2 as viable strategies to impede the progression of CAVD.

The presence of bacteria in diabetic wounds not only leads to the formation of biofilms but also triggers oxidative stress and inflammatory responses, which hinder the wound-healing process. Therefore, it is imperative to formulate a comprehensive strategy that can proficiently eliminate bacteria and enhance the wound microenvironment. Herein, this work develops multifunctional metal-phenolic nanozymes (TA-Fe/Cu nanocapsules), wherein the one-pot coordination of tannic acid (TA)and Fe3+/Cu2+ using a self-sacrificial template afforded hollow nanoparticles (NPs) with exceptional photothermal and reactive oxygen species scavenging capabilities. After photothermal disruption of the biofilms, TA-Fe/Cu NPs autonomously capture bacteria through hydrogen bonding interactions with peptidoglycans (the bacterial cell wall component), ultimately bolstering the bactericidal efficacy. Furthermore, these NPs exhibit peroxidase-like enzymatic activity, efficiently eliminating surplus hydrogen peroxide in the vicinity of the wound and mitigating inflammatory responses. As the wound transitions into the remodeling phase, the presence of Cu2+ stimulates vascular migration and regeneration, expediting the wound-healing process. This study innovatively devises a minimalist approach to synthesize multifunctional metal-phenolic nanozymes integrating potent photothermal antibacterial activity, bacterial capture, anti-inflammatory, and angiogenesis properties, showcasing their great potential for diabetic wound treatment.

Autophagosome–lysosome fusion mediated by SNARE complexes is an essential step in autophagy. Two SNAP29-containing SNARE complexes have been extensively studied in starvation-induced bulk autophagy, while the relevant SNARE complexes in other types of autophagy occurring under non-starvation conditions have been overlooked. Here, we found that autophagosome–lysosome fusion in selective autophagy under non-starvation conditions does not require SNAP29-containing SNARE complexes, but requires the STX17-SNAP47-VAMP7/VAMP8 SNARE complex. Further, the STX17-SNAP47-VAMP7/VAMP8 SNARE complex also functions in starvation-induced autophagy. SNAP47 is recruited to autophagosomes following concurrent detection of ATG8s and PI(4,5)P 2 via its Pleckstrin homology domain. By contrast, SNAP29-containing SNAREs are excluded from selective autophagy due to inactivation by O-GlcNAcylation under non-starvation conditions. These findings depict a previously unknown, default SNARE complex responsible for autophagosome–lysosome fusion in both selective and bulk autophagy, which could guide research and therapeutic development in autophagy-related diseases.

Supplemental Material and Methods

Figure S3: IL-18 promotes PC cell proliferation.

目的 对比腹腔镜胆总管探查后,经胆道镜直视下顺行置入单猪尾胆道支架并行胆总管一期缝合术与T管引流术的疗效及安全性.方法 2019年6月～2022年6月我院行腹腔镜下胆总管探查术的病人98例.按手术方式不同分为胆道支架组(40例)及T管引流组(58例).比较两组病人术前一般情况、术中情况、术后恢复及并发症等指标.结果 胆道支架组手术耗时、胆总管操作耗时、出血量、术后VAS疼痛指数、Caprini评分均短于(少于)T管引流组,差异有统计学意义(P<0.05).两组无术后死亡及再次手术.两组术后首日总胆红素、γ-谷氨酰转肽酶、镇痛药使用次数比较差异无统计学意义(P>0.05),胆道支架组术后首日血清白蛋白、肛门排气时间、抗生素使用时间、白细胞恢复正常时间、腹腔引流管拔除时间、术后住院时间、胆道引流时间及总费用显著优于T管引流组,差异有统计学意义(P<0.05).两组术后并发症发生率分别为5.0％和6.9％,两组比较差异无统计学意义(P>0.05).结论 经胆道镜顺行置入单猪尾胆道支架并行胆总管一期缝合安全性好,术后恢复快,不长期带管.

Figure S1: IL-18 is higher in PC tissues and correlates with poorer survival. Immunohistochemical (IHC) staining of IL-18

Supplementary Figures S1-S7 - This file includes supplementary figures S1-S7: Figure S1. PPARD increased active β-catenin and its target gene (e.g. c-Myc and cyclin D1) expression levels in mouse IECs and human HCT116 colorectal cancer cells by western blot and qRT-PCR. Figure S2. PPARD and its ligand GW501516 promoted intestinal tumorigenesis in multiple APC mutant mouse models, shown by intestinal photographs and tumor number counts. Figure S3. Western blot and IHCs showing that PPARD increased BMP7/TAK1/active β-catenin expression levels in mouse IECs. Figure S4. IHC microphotographs and score results showing active β-catenin expression levels in 41 human paired colorectal adenomas (Adenoma), CRC tumor centers (Tumor center), and cancer invasive fronts (Invasive front). Figure S5. Western blot and IHC results showing that PPARD upregulated AKT1 but not AKT2 to increase p-rpS6 levels in mouse IECs and human HCT116 colorectal cancer cells. Figure S6. Immunofluorescence staining of rRNA, IHC microphotographs and IHC score results of CDK1 showing rRNA expression levels in mouse intestinal tissues from PD and ApcÎ"580-PD mice and their corresponding control littermates, and nuclear CDK1 expression levels in 41 human paired colorectal adenomas (Adenoma), CRC tumor centers (Tumor center), and cancer invasive fronts (Invasive front). Figure S7. Multiple human public database analyses showing PPARD and BMP7 genetic alterations in colon cancer patients, and comparison of the survival probability for the colon cancer patients with low and high expression of BMP7.

Figure S5: IL-18 promotes PC cell proliferation, invasion and metastasis.

AIMS:Dopamine D1 receptor (D1R) hypofunction is associated with negative and cognitive symptoms in schizophrenia; therefore, the mechanism of D1R function modulation needs further investigation. Gm527 is the rodent homologous of the schizophrenia-related gene C14orf28, encoding a predicated D1R-interacting protein. However, the role of Gm527-D1R interaction in schizophrenia needs to be clarified.METHODS:Gm527-floxed mice were generated and crossed with D1-Cre mice (D1:Gm527-/-) to knockout Gm527 in D1R-positive neurons. Then behavioral tests were performed to explore the schizophrenia-related phenotypes. Immunofluorescence, fluorescence in situ hybridization, electrophysiological recording, quantitative real-time PCR, and western blotting were conducted to investigate the mechanisms.RESULTS:Working memory, long-term memories, and adult neurogenesis in the DG were enhanced in D1:Gm527-/- mice. LTP was also increased in the DG in D1:Gm527-/- mice, resulting from the Gm527 knockout-induced D1R expression enhancement on the plasma membrane and subsequently cAMP signaling and NMDA receptor pathways activation. The requirement of Gm527 knockout in the DG was confirmed by reversing Gm527 expression or knockdown Gm527 in the DG D1R-positive neurons through AAV-CAG-FLEX-Gm527-GFP or AAV-CMV-FLEX-EGFP-Gm527-RNAi injection.CONCLUSIONS:The DG Gm527 knockout induces D1R hyperfunction in improving schizophrenia cognitive symptoms.

Microvascular dysfunction caused by hyperglycemia leads to slow healing of diabetic wounds and significantly increases the risk of bacterial infection. The misuse of antibiotics can also lead to bacterial resistance, making the management of diabetic wounds more challenging. Thus, developing new antibacterial agents or strategies to overcome antibiotic resistance is highly pursued. Herein, novel supramolecular photothermal nanoparticles (MCC/CS NPs), assembled from mono-carboxyl corrole (MCC) and chitosan via hydrogen bonding and π-π stacking, are developed and used for treating bacterial wound infection. The MCC molecules possess good photothermal performance and the chitosan with inherent bioactivity can exert moderate antibacterial effects. The aggregation of MCC in MCC/CS NPs induced by chitosan-templated self-assembly further quenches molecular fluorescence and realizes an extraordinary photothermal conversion efficiency of 66.4%. Moreover, the highly positively charged MCC/CS NPs can selectively target bacteria via electrostatic interactions. Under near-infrared laser irradiation, the MCC/CS NPs achieve potent photothermal and inherent antimicrobial synergistic effects against Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA) in vitro. Furthermore, the bacteria-infected diabetic wound model confirms that the MCC/CS NPs can effectively kill drug-resistant bacteria, accelerate wound healing and angiogenesis, and show good biocompatibility, representing a novel and efficient photothermal antibacterial nanoplatform.

Binding of a synthesized fluorescent probe to latent fingerprints results in the aggregation-induced emission of green light, which is better perceived by the human eye than other colors and provides up to three levels of minutiae characteristics of latent fingerprints.

目的 探讨辐照灭菌前后医用胶原蛋白海绵的三螺旋结构及变化.方法 使用热裂解气质联用仪(Py-GCMS)对γ-射线辐照前后的胶原蛋白海绵进行测试,通过分析裂解组分探讨其三螺旋结构及变化.使用拉曼光谱技术佐证辐照前后胶原蛋白海绵三螺旋结构的变化,进一步通过对样品的圆二色光谱数据进行计算来分析判断辐照前后三螺旋结构的完整性是否改变.结果 辐照后胶原蛋白海绵的局部肽链断裂导致交联度降低,但是其完整的三螺旋结构得以保持.结论 该工作可为胶原蛋白相关研究提供实验参考,为胶原蛋白海绵的生产企业提供技术支撑.

A growing body of evidence suggests that metabolic events play essential roles in the development of liver fibrosis. Immune response gene 1 (IRG1) catalyzes the generation of itaconate, which function as a metabolic checkpoint under several pathological circumstances. In the present study, the hepatic level of IRG1 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis. And then the pathological significance of IRG1 and the pharmacological potential of 4-octyl itaconate (4-OI), a cell-permeable derivate of itaconate, in liver fibrosis were investigated in mice. The results indicated that the hepatic level of IRG1 was upregulated in mice with liver fibrosis. CCl4-induced formation of fibrotic septa and deposition of collagen was aggravated in IRG1 KO mice. IRG1 deletion also resulted in increased expression of transforming growth factor beta 1 (TGF-β1), enhanced phosphorylation of Smad3, elevated level of alpha smooth muscle actin (α-SMA) and hydroxyproline, which were associated with compromised activation of nuclear erythroid 2-related factor 2 (Nrf2)-mediated antioxidant system and exacerbated oxidative stress. Interestingly, supplementation with 4-OI activated Nrf2 pathway, suppressed TGF-β1 signaling and attenuated fibrogenesis. Our data indicated that upregulation of IRG1 might function as a protective response during the development of liver fibrosis, and 4-OI might have potential value for the pharmacological intervention of liver fibrosis.

目的 将病例教学法(case-based learning,CBL)与钉钉教学平台相结合,尝试构建新型胆胰外科见习医生教学模式.方法 将2019年1—12月在华中科技大学同济医学院附属同济医院胆胰外科见习的本科生60名作为教学对象,随机(随机数字表法)分为试验组(n=30)和对照组(n=30).试验组采用CBL联合钉钉教学平台的教学模式,对照组采用单纯CBL模式.见习结束后进行感兴趣程度调查和临床试践能力测试及理论测试,比较两组之间的差异.结果 见习结束后与对照组学员相比,试验组学员对课程感兴趣程度更高.(P=0.02).临床试践能力测试考核,试验组见习医生得分为(93.5±4.9)分,对照组见习医生得分为(88.6±3.2)分(t=4.586,P<0.01).理论测试考核,试验组见习医生得分为(94.4±4.1)分,对照组见习医生得分为(90.3±2.8)分(t=4.523,P<0.01).结论 CBL联合钉钉教学平台的新型教学模式可以有效提高胆胰外科见习医生的感兴趣程度和教学成绩.

Autolysosomes contain components both from autophagosomes and lysosomes. The contents inside the autophagosomal lumen are degraded during autophagy, while the fate of autophagosomal components on autolysosomal membrane remains unknown. Here, we found the autophagosomal membrane and transmembrane proteins are not degraded, but recycled from autolysosomes. We named this process autophagosomal components recycling (ACR). We further identified a multiprotein complex composed of SNX4, SNX5 and SNX17 essential for ACR which we termed “recycler”. In this, SNX4 and SNX5 form a heterodimer that recognizes an autophagosomal cargo STX17 and is required for generating membrane curvature on autolysosomes both via their BAR domains, to mediate the cargo sorting process. SNX17 interacts with both the dynein-dynactin complex and the SNX4-SNX5 dimer to facilitate retrograde transport of STX17. Depletion of any subunit of recycler completely blocks ACR, and also inhibits autophagy. Our discovery of ACR and identification of recycler reveal an important retrieval and recycling pathway on autolysosomes.

Due to their high thermal conductivity, hexagonal boron nitride nanosheets (BNNS) have great promise for thermal management materials. However, the lack of efficient, low cost, and large-scale approach to prepare functionalized BNNS is still the main factor limiting this research so far. Here, an ionic liquid crystal (ILC)assisted method based on mechanical exfoliation is proposed to prepare functionalized BNNS. Importantly, free ILC can be recycled after exfoliation, thus reducing costs and expanding production. This method demonstrates that BNNS could still be prepared from ILC after nine times of recycling and reuse and the chemical structure of ILC was not destroyed. The reliable interaction between BNNS and ILC would achieve the noncovalent functionalization of BNNS. The resulting functionalized BNNS exhibited remarkable dispersion stability in water and organic liquids. Thanks to the excellent comprehensive properties of the functionalized BNNS, multifunctional flexible BNNS/aramid nanofibers (ANFs) composite papers is prepared. Compared to pure ANF papers, the BNNS/ANF composite papers have a significantly improved mechanical properties, thermal conductivity, flame retardance, and acid-base resistance. The ILC recycling approach has proved to be efficient, low cost, and green, providing a practical route to expedite its application for thermal management in modern electronic devices.