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Renal tubulointerstitial fibrosis was a crucial pathological feature of diabetic nephropathy (DN), and renal tubular injury might associate with abnormal mitophagy. In this study, we investigated the effects and molecular mechanisms of AMPK agonist metformin on mitophagy and cellular injury in renal tubular cell under diabetic condition. The high fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice model and HK-2 cells were used in this study. Metformin was administered in the drinking water (200 mg/kg/d) for 24 weeks. Renal tubulointerstitial lesions, oxidative stress and some indicators of mitophagy (e.g., LC3II, Pink1, and Parkin) were examined both in renal tissue and HK-2 cells. Additionally, compound C (an AMPK inhibitor) and Pink1 siRNA were applied to explore the molecular regulation mechanism of metformin on mitophagy. We found that the expression of p-AMPK, Pink1, Parkin, LC3II, and Atg5 in renal tissue of diabetic mice was decreased obviously. Metformin reduced the levels of serum creatinine, urine protein, and attenuated renal oxidative injury and fibrosis in HFD/STZ induced diabetic mice. In addition, Metformin reversed mitophagy dysfunction and the over-expression of NLRP3. In vitro pretreatment of HK-2 cells with AMPK inhibitor compound C or Pink1 siRNA negated the beneficial effects of metformin. Furthermore, we noted that metformin activated p-AMPK and promoted the translocation of Pink1 from the cytoplasm to mitochondria, then promoted the occurrence of mitophagy in HK-2 cells under HG/HFA ambience. Our results suggested for the first time that AMPK agonist metformin ameliorated renal oxidative stress and tubulointerstitial fibrosis in HFD/STZ-induced diabetic mice via activating mitophagy through a p-AMPK-Pink1-Parkin pathway.

The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp-microbiome-immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.

Objective: Taohong Siwu decoction (THSWD) is one of the classic prescriptions for promoting blood circulation and removing blood stasis, and it has a good therapeutic effect on ischemic stroke. We sought to explore the therapeutic effects of THSWD on pyroptosis in rats with middle cerebral artery occlusion-reperfusion (MCAO/R). Methods: MCAO/R model of rats were established by suture-occluded method. MCAO/R rats were randomly divided into five groups, which were model group, nimodipine group, THSWD high, medium and low dose group (18, 9, and 4.5 g/kg, respectively), rats of sham group without thread embolus. All rats were treated by intragastric administration for 7 days. We detected the level of inflammatory factors. NLRP3 and Caspase-1 were detected by immunofluorescence. Western blot was used to detect NLRP3, Caspase-1, ASC, and GSDMD in penumbra. Also, the expression of TXNIP, HMGB1, toll-like receptors (TLR4), NF-κB, and MAPK were detected. Results: THSWD treatment improved the behavioral function and brain pathological damage. These results showed that the levels of TNF-α, TGF-β, IL-2, IL-6, IL-1β, and IL-18 were significantly reduced in THSWD treatment groups. THSWD could significantly decrease the expression levels of NLRP3, Caspase-1, Caspase-1 p10, ASC, TXNIP, GSDMD, HMGB1, TLR4/NFκB, p38 MAPK, and JNK in penumbra. Conclusion: Our results showed that THSWD could reduce the activation level of NLRP3 inflammatory corpuscle, down-regulate GSDMD, and inhibit pyroptosis in MCAO/R rats. These may be affected by inhibiting HMGB1/TLR4/NFκB, MAPK signaling pathways.

Oxidative stress-induced mitochondrial dysfunction and neuronal cell death have important roles in the development of neurodegenerative diseases. Dynamin related protein 1 (Drp1) is a critical factor in regulating mitochondrial dynamics. A variety of posttranslational modifications of Drp1 have been reported, including phosphorylation, ubiquitination, sumoylation and S -nitrosylation. In this study, we found that c-Abl phosphorylated Drp1 at tyrosine 266, 368 and 449 in vitro and in vivo , which augmented the GTPase activity of Drp1 and promoted Drp1-mediated mitochondrial fragmentation. Consistently, c-Abl-mediated phosphorylation is important for GTPase activity of Drp1 and mitochondrial fragmentation. Furthermore, we found that Drp1 phosphorylation mediated by c-Abl is required for oxidative stress-induced cell death in primary cortical neurons. Taken together, our findings reveal that c-Abl-Drp1 signaling pathway regulates oxidative stress-induced mitochondrial fragmentation and cell death, which might be a potential target for the treatment of neurodegenerative diseases.

Stretchable electronics are in high demand for next-generation wearable devices, but their fabrication is still challenging. Stretchable conductors, flexible pressure sensors, and foldable light-emitting diodes （LEDs） have been reported; however, the fabrication of stable stretchable batteries, as power suppliers for wearable devices, is significantly behind the development of other stretchable electronics. Several stretchable lithium-ion batteries and primary batteries have been fabricated, but their low capacities and complicated manufacturing processes are obstacles for practical applications. Herein, we report a stretchable zinc/manganese-oxide （Zn-MnO2） full battery based on a silver-nanowire- coated sponge prepared via a facile dip-coating process. The spongy electrode, with a three-dimensional （3D） binary network structure, provided not only high conductivity and stretchability, but also enabled a high mass loading of electrochemically active materials （Zn and MnO2 particles）. The fabricated Zn-MnO2 battery exhibited an areal capacity as high as 3.6 mAh·cm^-2 and could accommodate tensile strains of up to 100% while retaining 89% of its original capacity. The facile solution-based strategy of dip-coating active materials onto a cheap sponge-based stretchable current collector opens up a new avenue for fabricating stretchable batteries.

Most existing small object detection methods rely on residual blocks to process deep feature maps. However, these residual blocks, composed of multiple large-kernel convolution layers, incur high computational costs and contain redundant information, which makes it difficult to improve detection performance for small objects. To address this, we designed an improved feature pyramid network called L Feature Pyramid Network (L-FPN), which optimizes the allocation of computational resources for small object detection by reconstructing the original FPN structure. Based on L-FPN, we further proposed a small object detector named BPD-YOLO. We introduce a Dual-phase Asymptotic Feature Fusion mechanism (DAFF), where the shallow and deep semantic features extracted from the backbone network are initially fused in parallel to mitigate the semantic gap. Subsequently, the intermediate semantic layers are progressively integrated, enabling effective fusion of both shallow and deep feature representations. Additionally, we designed the Deep Spatial Pyramid Fusion module (DSPF), which generates multi-scale feature representations as an alternative to conventional residual block stacking, thereby reducing computational overhead. In the shallow feature extraction stage, DSPF focuses on semantic integration and enhances the extraction of small object features. This strategy, which adaptively selects different modules based on the resolution of the feature maps, is referred to as the Decoupled feature Extraction-semantic Integration mechanism (DEI). Finally, we conducted extensive experiments and thorough evaluations on both the VisDrone and TinyPerson datasets. The results demonstrate that, on the VisDrone dataset, compared to the baseline model YOLOv8n + p2, our BPD-YOLO model with L-FPN achieves a 2.8% improvement in mAP50 and a 1.4% increase in mAP50-95. On the TinyPerson dataset, BPD-YOLO further demonstrates its superiority in high-resolution feature extraction, effectively enhancing detection accuracy while significantly reducing computational costs.

COVID-19 caused by SARS-CoV-2 has spread around the world. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 is a critical component that directly interacts with host ACE2. Here, we simulate the ACE2 recognition processes of RBD of the WT, Delta, and OmicronBA.2 variants using our recently developed supervised Gaussian accelerated molecular dynamics (Su-GaMD) approach. We show that RBD recognizes ACE2 through three contact regions (regions I, II, and III), which aligns well with the anchor–locker mechanism. The higher binding free energy in State d of the RBDOmicronBA.2-ACE2 system correlates well with the increased infectivity of OmicronBA.2 in comparison with other variants. For RBDDelta, the T478K mutation affects the first step of recognition, while the L452R mutation, through its nearby Y449, affects the RBDDelta-ACE2 binding in the last step of recognition. For RBDOmicronBA.2, the E484A mutation affects the first step of recognition, the Q493R, N501Y, and Y505H mutations affect the binding free energy in the last step of recognition, mutations in the contact regions affect the recognition directly, and other mutations indirectly affect recognition through dynamic correlations with the contact regions. These results provide theoretical insights for RBD-ACE2 recognition and may facilitate drug design against SARS-CoV-2.

Background MRI-based tumor shrinkage patterns (TSP) after neoadjuvant therapy (NAT) have been associated with pathological response. However, the understanding of TSP after early NAT remains limited. We aimed to analyze the relationship between TSP after early NAT and pathological response after therapy in different molecular subtypes. Methods We prospectively enrolled participants with invasive ductal breast cancers who received NAT and performed pretreatment DCE-MRI from September 2020 to August 2022. Early-stage MRIs were performed after the first (1st-MRI) and/or second (2nd-MRI) cycle of NAT. Tumor shrinkage patterns were categorized into four groups: concentric shrinkage, diffuse decrease (DD), decrease of intensity only (DIO), and stable disease (SD). Logistic regression analysis was performed to identify independent variables associated with pathologic complete response (pCR), and stratified analysis according to tumor hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) disease subtype. Results 344 participants (mean age: 50 years, 113/345 [33%] pCR) with 345 tumors (1 bilateral) had evaluable 1st-MRI or 2nd-MRI to comprise the primary analysis cohort, of which 244 participants with 245 tumors had evaluable 1st-MRI (82/245 [33%] pCR) and 206 participants with 207 tumors had evaluable 2nd-MRI (69/207 [33%] pCR) to comprise the 1st- and 2nd-timepoint subgroup analysis cohorts, respectively. In the primary analysis, multivariate analysis showed that early DD pattern (OR = 12.08; 95% CI 3.34–43.75; p  < 0.001) predicted pCR independently of the change in tumor size (OR = 1.37; 95% CI 0.94–2.01; p  = 0.106) in HR + /HER2 − subtype, and the change in tumor size was a strong pCR predictor in HER2 + (OR = 1.61; 95% CI 1.22–2.13; p  = 0.001) and triple-negative breast cancer (TNBC, OR = 1.61; 95% CI 1.22–2.11; p  = 0.001). Compared with the change in tumor size, the SD pattern achieved a higher negative predictive value in HER2 + and TNBC. The statistical significance of complete 1st-timepoint subgroup analysis was consistent with the primary analysis. Conclusion The diffuse decrease pattern in HR + /HER2 − subtype and stable disease in HER2 + and TNBC after early NAT could serve as additional straightforward and comprehensible indicators of treatment response. Trial registration : Trial registration at https://www.chictr.org.cn/ . Registration number: ChiCTR2000038578, registered September 24, 2020.

A bstract In this work, we proceed to study the CP asymmetry in the angular distributions of τ → K S πν τ decays within a general effective field theory framework including four-fermion operators up to dimension-six. It is found that, besides the commonly considered scalar-vector interference, the tensor-scalar interference can also produce a non-zero CP asymmetry in the angular distributions, in the presence of complex couplings. Using the dispersive representations of the Kπ form factors as inputs, and taking into account the detector efficiencies of the Belle measurement, we firstly update our previous SM predictions for the CP asymmetries in the same four Kπ invariant-mass bins as set by the Belle collaboration. Bounds on the effective couplings of the non-standard scalar and tensor interactions are then obtained under the combined constraints from the CP asymmetries measured in the four bins and the branching ratio of τ − → K S π − ν τ decay, with the numerical results given respectively by Im ϵ ̂ S = − 0 . 008 ± 0 . 027 and Im ϵ ̂ T = 0 . 03 ± 0 . 12, at the renormalization scale μ τ = 2 GeV in the MS ¯ scheme. Using the best-fit values, we also find that the distributions of the CP asymmetries can deviate significantly from the SM expectation in almost the whole Kπ invariant-mass region. Nevertheless, the current bounds on Im ϵ ̂ S and Im ϵ ̂ T are still plagued by large experimental uncertainties, but will be improved with more precise measurements from the Belle II experiment as well as the proposed Tera-Z and STCF facilities. Assuming further that the non-standard scalar and tensor interactions originate from a weakly-coupled heavy new physics well above the electroweak scale, the SU(2) L invariance of the resulting SMEFT Lagrangian would indicate that very strong limits on Im ϵ ̂ S and Im ϵ ̂ T could also be obtained from the neutron electric dipole moment and the D 0 − D ¯ 0 mixing. With the bounds from these processes taken into account, it is then found that, unless there exist extraordinary cancellations between the new physics contributions, neither the scalar nor the tensor interaction can produce any significant effects on the CP asymmetries (relative to the SM predictions) in the processes considered, especially under the “single coefficient dominance” assumption.

Background Hesperidin is a citrus flavonoid with anti-inflammatory and antioxidant potential. However, its protective effects on bovine mammary epithelial cells (bMECs) exposed to oxidative stress have not been elucidated. Results In this study, we investigated the effects of hesperidin on H 2 O 2 -induced oxidative stress in bMECs and the underlying molecular mechanism. We found that hesperidin attenuated H 2 O 2 -induced cell damage by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, increasing catalase (CAT) activity, and improving cell proliferation and mitochondrial membrane potential. Moreover, hesperidin activated the Keap1/Nrf2/ARE signaling pathway by inducing the nuclear translocation of Nrf2 and the expression of its downstream genes NQO1 and HO-1 , which are antioxidant enzymes involved in ROS scavenging and cellular redox balance. The protective effects of hesperidin were blocked by the Nrf2 inhibitor ML385, indicating that they were Nrf2 dependent. Conclusions Our results suggest that hesperidin could protect bMECs from oxidative stress injury by activating the Nrf2 signaling pathway, suggesting that hesperidin as a natural antioxidant has positive potential as a feed additive or plant drug to promote the health benefits of bovine mammary. Graphical Abstract