Isorhamnetin Alleviates Mitochondrial Injury in Severe Acute Pancreatitis via Modulation of KDM5B/HtrA2 Signaling Pathway.

Severe acute pancreatitis (SAP), a widespread inflammatory condition impacting the abdomen with a high mortality rate, poses challenges due to its unclear pathogenesis and the absence of effective treatment options. Isorhamnetin (ISO), a naturally occurring flavonoid, demonstrates robust antioxidant and anti-inflammatory properties intricately linked to the modulation of mitochondrial function. However, the specific protective impact of ISO on SAP remains to be fully elucidated. In this study, we demonstrated that ISO treatment significantly alleviated pancreatic damage and reduced serum lipase and amylase levels in the mouse model of SAP induced by sodium taurocholate (STC) or L-arginine. Utilizing an in vitro SAP cell model, we found that ISO co-administration markedly prevented STC-induced pancreatic acinar cell necrosis, primarily by inhibiting mitochondrial ROS generation, preserving ATP production, maintaining mitochondrial membrane potential, and preventing the oxidative damage and release of mitochondrial DNA. Mechanistically, our investigation identified that high-temperature requirement A2 (HtrA2) may play a central regulatory role in mediating the protective effect of ISO on mitochondrial dysfunction in STC-injured acinar cells. Furthermore, through an integrated approach involving bioinformatics analysis, molecular docking analysis, and experimental validation, we uncovered that ISO may directly impede the histone demethylation activity of KDM5B, leading to the restoration of pancreatic HtrA2 expression and thereby preserving mitochondrial function in pancreatic acinar cells following STC treatment. In conclusion, this study not only sheds new light on the intricate molecular complexities associated with mitochondrial dysfunction during the progression of SAP but also underscores the promising value of ISO as a natural therapeutic option for SAP.

Qingkailing granule alleviates pulmonary fibrosis by inhibiting PI3K/AKT and SRC/STAT3 signaling pathways.

Pulmonary fibrosis (PF) poses a significant challenge with limited treatment options and a high mortality rate of approximately 45 %. Qingkailing Granule (QKL), derived from the Angong Niuhuang Pill, shows promise in addressing pulmonary conditions. Using a comprehensive approach, combining network pharmacology analysis with experimental validation, this study explores the therapeutic effects and mechanisms of QKL against PF for the first time. In vivo, QKL reduced collagen deposition and suppressed proinflammatory cytokines in a bleomycin-induced PF mouse model. In vitro studies demonstrated QKL's efficacy in protecting cells from bleomycin-induced injury and reducing collagen accumulation and cell migration in TGF-ß1-induced pulmonary fibrosis cell models. Network pharmacology analysis revealed potential mechanisms, confirmed by western blotting, involving the modulation of PI3K/AKT and SRC/STAT3 signaling pathways. Molecular docking simulations highlighted interactions between QKL's active compounds and key proteins, showing inhibitory effects on epithelial damage and fibrosis. Collectively, these findings underscore the therapeutic potential of QKL in alleviating pulmonary inflammation and fibrosis through the downregulation of PI3K/AKT and SRC/STAT3 signaling pathways, with a pivotal role attributed to its active compounds.

Elucidating the distinctive regulatory effects and mechanisms of active compounds in Salvia miltiorrhiza Bunge via network pharmacology: Unveiling their roles in the modulation of platelet activation and thrombus formation.

Salvia miltiorrhiza Bunge. (DS), as an important traditional Chinese medicine (TCM), has a long history of usage for promoting blood circulation and removing blood stasis. Modern studies have shown that the chemical components of DS have many biological activities such as cardiovascular protection, anti-arrhythmia, anti-atherosclerosis, improvement of microcirculation, protection of myocardium, inhibition and removal of platelet aggregation. Nevertheless, the action mechanism of DS as well its active compounds on platelet activation has not been fully uncovered. This study aimed to find out the potential targets and mechanisms of DS in the modulation of platelet activation and thrombosis, using network pharmacology and biological experimental. These compounds with anti-thrombotic activity in DS, cryptotanshinone (CPT), isoeugenol (ISO) and tanshinone IIA (TSA), together with the corresponding targets being Src, Akt and RhoA are screened by network pharmacology. We confirmed that ISO, CPT and TSA dose-dependently inhibited platelet activation in vitro, mainly by inhibiting agonist-induced clot retraction, aggregation and P-selectin and ATP release. The western blot findings indicated that ISO, CPT, and TSA led to reduced levels of p-Akt and p-ERK in activated platelets. Additionally, ISO and TSA were observed to decrease p-cSrc expression while increasing RhoA expression. ISO, CPT, and TSA demonstrated a potential to restrict the advancement of carotid arterial thrombosis in vivo. We confirm that ISO, CPT and TSA are the key anti-thrombotic active compounds in DS. These active compounds exhibit unique inhibitory effects on platelet activation and thrombus formation by modulating the Akt/ERK and cSrc/RhoA signaling pathways.

Inhibition of the C1s Protease and the Classical Complement Pathway by 6-(4-Phenylpiperazin-1-yl)Pyridine-3-Carboximidamide and Chemical Analogs.

The classical pathway (CP) is a potent mechanism for initiating complement activity and is a driver of pathology in many complement-mediated diseases. The CP is initiated via activation of complement component C1, which consists of the pattern recognition molecule C1q bound to a tetrameric assembly of proteases C1r and C1s. Enzymatically active C1s provides the catalytic basis for cleavage of the downstream CP components, C4 and C2, and is therefore an attractive target for therapeutic intervention in CP-driven diseases. Although an anti-C1s mAb has been Food and Drug Administration approved, identifying small-molecule C1s inhibitors remains a priority. In this study, we describe 6-(4-phenylpiperazin-1-yl)pyridine-3-carboximidamide (A1) as a selective, competitive inhibitor of C1s. A1 was identified through a virtual screen for small molecules that interact with the C1s substrate recognition site. Subsequent functional studies revealed that A1 dose-dependently inhibits CP activation by heparin-induced immune complexes, CP-driven lysis of Ab-sensitized sheep erythrocytes, CP activation in a pathway-specific ELISA, and cleavage of C2 by C1s. Biochemical experiments demonstrated that A1 binds directly to C1s with a Kd of ∼9.8 µM and competitively inhibits its activity with an inhibition constant (Ki) of ∼5.8 µM. A 1.8-Å-resolution crystal structure revealed the physical basis for C1s inhibition by A1 and provided information on the structure-activity relationship of the A1 scaffold, which was supported by evaluating a panel of A1 analogs. Taken together, our work identifies A1 as a new class of small-molecule C1s inhibitor and lays the foundation for development of increasingly potent and selective A1 analogs for both research and therapeutic purposes.

Zinc/carbon nanomaterials inhibit antibiotic resistance genes by affecting quorum sensing and microbial community in cattle manure production.

This study used metagenomic sequencing to examine the effects of carbon-based zinc oxide nanoparticles (CZnONPs) and graphene-based zinc oxide nanoparticles (GZnONPs) on quorum sensing (QS), antibiotic resistance genes (ARGs) and microbial community changes during cattle manure production. The manure zinc content was significantly reduced in GZnONPs group. In the QS pathway, the autoinducer gene increases significantly in Control group, while the transporter and repressor genes experience a substantial increase in CZnONPs group. These results contributed to the significantly decreased the abundance of ARGs in GZnONPs group. The co-occurrence network analysis revealed a correlation between core ARGs and QS-related KEGG Orthology or ARGs' hosts, indicating that the selective pressure of zinc influences microbial QS, forming a unique ARG pattern in in vivo anaerobic fermentation. These findings suggest that implementing nutritional regulation in farming practices can serve as a preventive measure to mitigate the potential transmission of ARGs resulting from livestock waste.

Nano-Selenium inhibited antibiotic resistance genes and virulence factors by suppressing bacterial selenocompound metabolism and chemotaxis pathways in animal manure.

Numerous antibiotic resistance genes (ARGs) and virulence factors (VFs) found in animal manure pose significant risks to human health. However, the effects of graphene sodium selenite (GSSe), a novel chemical nano-Selenium, and biological nano-Selenium (BNSSe), a new bioaugmentation nano-Se, on bacterial Se metabolism, chemotaxis, ARGs, and VFs in animal manure remain unknown. In this study, we investigated the effects of GSSe and BNSSe on ARGs and VFs expression in broiler manure using high-throughput sequencing. Results showed that BNSSe reduced Se pressure during anaerobic fermentation by inhibiting bacterial selenocompound metabolism pathways, thereby lowering manure Selenium pollution. Additionally, the expression levels of ARGs and VFs were lower in the BNSSe group compared to the Sodium Selenite and GSSe groups, as BNSSe inhibited bacterial chemotaxis pathways. Co-occurrence network analysis identified ARGs and VFs within the following phyla Bacteroidetes (genera Butyricimonas, Odoribacter, Paraprevotella, and Rikenella), Firmicutes (genera Lactobacillus, Candidatus_Borkfalkia, Merdimonas, Oscillibacter, Intestinimonas, and Megamonas), and Proteobacteria (genera Desulfovibrio). The expression and abundance of ARGs and VFs genes were found to be associated with ARGs-VFs coexistence. Moreover, BNSSe disruption of bacterial selenocompound metabolism and chemotaxis pathways resulted in less frequent transfer of ARGs and VFs. These findings indicate that BNSSe can reduce ARGs and VFs expression in animal manure by suppressing bacterial selenocompound metabolism and chemotaxis pathways.

Endogenous SIRT6 in platelets negatively regulates platelet activation and thrombosis.

Thromboembolism resulting from platelet dysfunction constitutes a significant contributor to the development of cardiovascular disease. Sirtuin 6 (SIRT6), an essential NAD+-dependent enzyme, has been linked to arterial thrombosis when absent in endothelial cells. In the present study, we have confirmed the presence of SIRT6 protein in anucleated platelets. However, the precise regulatory role of platelet endogenous SIRT6 in platelet activation and thrombotic processes has remained uncertain. Herein, we present compelling evidence demonstrating that platelets isolated from SIRT6-knockout mice (SIRT6-/-) exhibit a notable augmentation in thrombin-induced platelet activation, aggregation, and clot retraction. In contrast, activation of SIRT6 through specific agonist treatment (UBCS039) confers a pronounced protective effect on platelet activation and arterial thrombosis. Moreover, in platelet adoptive transfer experiments between wild-type (WT) and SIRT6-/- mice, the loss of SIRT6 in platelets significantly prolongs the mean thrombus occlusion time in a FeCl3-induced arterial thrombosis mouse model. Mechanistically, we have identified that SIRT6 deficiency in platelets leads to the enhanced expression and release of proprotein convertase subtilisin/kexin type 9 (PCSK9), subsequently activating the platelet activation-associated mitogen-activated protein kinase (MAPK) signaling pathway. These findings collectively unveil a novel protective role of platelet endogenous SIRT6 in platelet activation and thrombosis. This protective effect is, at least in part, attributed to the inhibition of platelet PCSK9 secretion and mitogen-activated protein kinase signaling transduction. Our study provides valuable insights into the intricate interplay between SIRT6 and platelet function, shedding light on potential therapeutic avenues for managing thrombotic disorders.

Design and characterization of PROTAC degraders specific to protein N-terminal methyltransferase 1.

Protein N-terminal methylation catalyzed by N-terminal methyltransferase 1 (NTMT1) is an emerging methylation present in eukaryotes, playing important regulatory roles in various biological and cellular processes. Although dysregulation of NTMT1 has been linked to many diseases such as colorectal cancer, their molecular and cellular mechanisms remain elusive due to inaccessibility to an effective cellular probe. Here we report the design, synthesis, and characterization of the first-in-class NTMT1 degraders based on proteolysis-targeting chimera (PROTAC) strategy. Through a brief structure-activity relationship (SAR) study of linker length, a cell permeable degrader 1 involving a von Hippel-Lindau (VHL) E3 ligase ligand was developed and demonstrated to reduce NTMT1 protein levels effectively and selectively in time- and dose-dependent manners in colorectal carcinoma cell lines HCT116 and HT29. Degrader 1 displayed DC50 = 7.53 µM and Dmax > 90% in HCT116 (cellular IC50 > 100 µM for its parent inhibitor DC541). While degrader 1 had marginal cytotoxicity, it displayed anti-proliferative activity in 2D and 3D culture environment, resulting from cell cycle arrested at G0/G1 phase in HCT116. Label-free global proteomic analysis revealed that degrader 1 induced overexpression of calreticulin (CALR), an immunogenic cell death (ICD) signal protein that is known to elicit antitumor immune response and clinically linked to a high survival rate of patients with colorectal cancer upon its upregulation. Collectively, degrader 1 offers the first selective cellular probe for NTMT1 exploration and a new drug discovery modality for NTMT1-related oncology and diseases.

Characteristics of lymphocyte subsets and cytokine profiles of patients with COVID-19.

BACKGROUND: Abnormalities of lymphocyte subsets and cytokine profiles have been observed in most patients with coronavirus disease (COVID-19). Here, we explore the role of lymphocyte subsets and cytokines on hospital admission in predicting the severity of COVID-19. METHODS: This study included 214 patients with COVID-19 who were treated at Chongqing University Three Gorges Hospital from January 19, 2020 to April 30, 2020. Any mutants were not detected in the studied patients. Patients were divided into non-intensive care unit (ICU) (mild/moderate) group and ICU (severe/critical) group, according to the severity of the disease. Clinical and laboratory data, including peripheral lymphocyte subsets and cytokines, were analyzed and compared. Logistic regression was used to analyze the predictive factors for ICU admission. Receiver operating characteristic (ROC) curves were drawn to evaluate the predictive value of selected indicators for the severity of COVID-19. RESULTS: Of the 214 patients enrolled, 161 were non-ICU patients and 53 were ICU patients. Lymphopenia was observed in nearly all of ICU patients (96.2%) and 84.5% of non-ICU patients on hospital admission. The absolute number of lymphocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and natural killer (NK) cells were lower in ICU group (659.00 × 106/L, 417.00 × 106/L, 261.00 × 106/L, 140.00 × 106/L, 109.00 × 106/L, 102.00 × 106/L, respectively) than in non-ICU group (1063.00 × 109/L, 717.00 × 106/L, 432.00 × 106/L, 271.00 × 106/L, 133.00 × 106/L, 143.00 × 106/L, respectively). Interleukin (IL)-6 was significantly higher in ICU patients than in non-ICU patients (18.08 pg/mL vs. 3.13 pg/mL, P < 0.001). Multivariate logistic regression analysis showed that age (odds ratio: 1.067 [1.034-1.101]), diabetes mellitus (odds ratio: 9.154 [2.710-30.926]), CD3+ T cells (odds ratio: 0.996 [0.994-0.997]), and IL-6 (odds ratio: 1.006 [1.000-1.013]) were independent predictors for the development of severe disease. ROC curve analysis showed that the area under the ROC curve (AUC) of CD3+ T cells and IL-6 was 0.806 (0.737-0.874) and 0.785 (0.705-0.864), respectively, and the cutoff values were 510.50 × 106/L (sensitivity, 71.7%; specificity, 79.5%) and 6.58 pg/mL (77.4%, 74.5%), respectively. There were no statistical differences among all tested indicators of lymphocyte subsets and cytokines between severe group (n = 38) and critical group (n = 15) on hospital admission or ICU admission, respectively. CONCLUSIONS: The levels of lymphocyte subsets decreased and the level of IL-6 increased significantly in ICU COVID-19 patients compared with non-ICU COVID-19 patients. Therefore, the number of CD3+ T cells and the level of IL-6 on hospital admission may serve as predictive factors for identifying patients with wild-type virus infection who will have severe disease.

Concise syntheses of eburnane indole alkaloids.

The asymmetric divergent syntheses of a group of C20 ethyl oxo-functionalized eburnane alkaloids, (-)-eburnaminol (5), (+)-larutenine (6), (-)-terengganensine B (7), (-)-strempeliopine (8), and (-)-terengganensine A (9), have been achieved. The key step in the assembly of the complex ring system of the target molecules is a photoredox catalytic nitrogen-centered radical cascade reaction, which allows the regioselective and stereoselective construction of the B, C, and D rings and the installation of the C21 chirality of the eburnane alkaloid skeleton in one pot.

Association between the MIF-173G/C Polymorphism and Serum MIF levels with Pulmonary Tuberculosis: A Meta-analysis.

Many studies have indicated that Macrophage migration inhibitory factor (MIF)-173G/C gene polymorphisms are associated with susceptibility to pulmonary tuberculosis (PTB). Additionally, some studies have suggested that there are higher levels of serum MIF in patients with PTB than the controls. However, the results of these studies were underpowered. The current study aimed to precisely evaluate the association between the MIF-173G/C polymorphism and serum MIF concentrations with PTB. Therefore, a systematic literature search was preformed to identify studies involving the indicated association. Eleven articles (1316 cases and 1272 controls) were included in the study. The results indicated that the MIF-173G/C polymorphism was significantly associated with PTB susceptibility, especially in Asians. Interestingly, the results further detected that circulating MIF levels were significantly higher in patients with PTB than in healthy controls, but this was only the case among Asians. Moreover, the statistical significance was also similar to that of the high quality group. The present study indicated that the MIF-173G/C polymorphism may contribute to the development of PTB. Furthermore, significantly higher serum MIF levels were observed in PTB patients than in controls, which further indicated that the MIF may play an important role in PTB progression, particularly in Asians.

Serum and tissue leptin in lung cancer: A meta-analysis.

Many studies have found that leptin is involved in tumorigenesis and the progression of lung cancer. However, these studies were inconsistent. Therefore, we performed a meta-analysis to investigate the role of leptin in the patients with lung cancer. A systematic literature search in the several databases and on commercial Internet search engines was carried out to identify studies published up to July 8, 2016. The standardized mean difference (SMD) and odds ratio (OR) with 95% confidence interval (CI) were used to investigate the effect sizes. Finally, 21 eligible articles were included in the current meta-analysis. Overall, there is no relationship between levels of serum leptin and lung cancer. However, a subgroup analysis in high-study quality group found a weak association between serum leptin concentrations and lung cancer in Chinese (SMD=0.77, P=0.035). Additionally, the meta-analysis indicates that the serum leptin levels were lower in the weight-losing group than in the sustained weight group (SMD=-0.80, P=0.001). Further, there was evidence of a significant association between expression levels of leptin protein in tissue and lung cancer (OR=7.35, P<0.001). The present meta-analysis suggests that the serum and tissue leptin may be involved in the pathogenesis of lung cancer and tumor metastasis, especially among Chinese. However, the leptin may not appear to play an important role in cancer cachexia development.

Formal Synthesis of Anticoagulant Drug Fondaparinux Sodium.

The practical formal synthesis of the anticoagulant drug fondaparinux sodium 1 was accomplished using an optimized modular synthetic strategy. The important pentasaccharide 2, a precursor for the synthesis of fondaparinux sodium, was synthesized on a 10 g scale in 14 collective steps with 3.5% overall yield from well-functionalized monosaccharide building blocks. The strategy involved a convergent [3 + 2] coupling approach, with excellent stereoselectivity in every step of glycosylation from the monosaccharide building blocks. Efficient routes to the syntheses of these fully functionalized building blocks were developed, minimizing oligosaccharide stage functional-group modifications. The syntheses of all building blocks avoided rigorous reaction conditions and the use of expensive reagents. In addition, common intermediates and a series of one-pot reactions were employed to enhance synthetic efficiency, improving the yield considerably. In the monosaccharide-to-oligosaccharide assembly reactions, cheaper activators (e.g., NIS/TfOH, TESOTf, and TfOH) were used to facilitate highly efficient glycosylations. Furthermore, crystallization of several monosaccharide and oligosaccharide intermediates significantly simplified purification procedures, which would be greatly beneficial to the scalable synthesis of fondaparinux sodium.

Total Synthesis of Lignan Lactone (-)-Hinokinin.

This research paper is aimed at studying the total synthesis of pharmacologically active lignan (-)-hinokinin. The synthesis features a three-step cascade reaction involving highly stereoselective Michael addition, anion-oxidative hydroxylation, and oxygen anion cyclization to construct the pivotal butyrolactonimidate intermediate.

One-pot synthesis of multisubstituted butyrolactonimidates: total synthesis of (-)-nephrosteranic Acid.

Multisubstituted chiral butyrolactonimidates have been synthesized via a one-pot, three-step cascade reaction in which (R)-N-tert-butanesulfinyl imidates and α,ß-unsaturated diesters undergo highly stereoselective Michael addition, anion-oxidative hydroxylation, and cyclization. The synthesized butyrolactonimidates are versatile intermediates for preparation of substituted butyrolactones and furans. The usefulness of this cascade reaction is demonstrated through the concise total synthesis of natural product (-)-nephrosteranic acid.

High solid content latex: preparation methods and application.

One of the major challenges in emulsion polymerization over the past two decades was how to increase the solid content of latex products. In contrast to the conventional latex, high solid content (HSC) latex has a large volume fraction of dispersed phase, even larger than 70% in weight. Conventional emulsion polymerization, miniemulsion polymerization, self-emulsification polymerization and concentrated emulsion polymerization were all used to prepare HSC latexes, and many good results have been reported in recent years. Meanwhile, many applications of HSC latexes have also been developed. The present review summarized the progresses in the past few years mainly on the preparation methods and application of HSC latexes. Finally, some research directions as well as prospects were also proposed.

Linear dislocation tunes chirality: STM study of chiral transition and amplification in a molecular assembly on an HOPG surface.

Molecular arrangement and transition in the domain boundary of a chiral two-dimensional assembly is clearly revealed by high-resolution STM images on an HOPG surface and a linear dislocation formed by molecular trimers and located at opposite chiral domains is found to directly reverse the chirality on DTCD self-assembly.