Salvianolic acid A attenuates Angiotensin II-induced cardiac fibrosis through regulating the Txnip signaling pathway.

ABSTRACT: Cardiac fibrosis, characterized by excessive collagen accumulation in heart tissues, poses a significant clinical challenge in various heart diseases and complications. Although salvianolic acid A (Sal A) from Danshen (Salvia miltiorrhiza) has shown promise in the treatment of ischemic heart disease, myocardial infarction, and atherosclerosis, its effects on cardiac fibrosis remain unexplored. Our study investigated the efficacy of Sal A in reducing cardiac fibrosis and elucidated its underlying molecular mechanisms. We observed that Sal A demonstrated significant cardioprotective effects against Angiotensin II (Ang II)-induced cardiac remodeling and fibrosis, showing a dose-dependent reduction in fibrosis in mice and suppression of cardiac fibroblast proliferation and fibrotic protein expression in vitro. RNA sequencing revealed that Sal A counteracted Ang II-induced upregulation of Txnip, and subsequent experiments indicated that it acts through the inflammasome and ROS pathways. These findings establish the anti-fibrotic effects of Sal A, notably attenuated by Txnip overexpression, and highlight its significant role in modulating inflammation and oxidative stress pathways. This underscores the importance of further research on Sal A and similar compounds, especially regarding their effects on inflammation and oxidative stress, which are key factors in various cardiovascular diseases.

Preventive and Therapeutic Potential of Streptococcus cristatus CA119 in Experimental Periodontitis in Rats.

Periodontitis is an inflammatory condition of the oral cavity caused by a mixed infection of various bacteria, which not only severely affects the alveolar bone and connective tissues but also displays potential correlations with distal intestinal inflammation. In this study, we aimed to elucidate the therapeutic effects of Streptococcus cristatus CA119 on experimental periodontitis in rats and its impact on intestinal morphology. The results demonstrate that CA119 is capable of colonizing the oral cavity and exerting antagonistic effects on Porphyromonas gingivalis and Fusobacterium nucleatum, thus leading to a significant reduction in the oral pathogen load. Following CA119 intervention, there was a significant alleviation of weight loss in rats induced by periodontitis (P < 0.001). CA119 also regulated the expression of IL-6 (P < 0.05), IL-1ß (P < 0.001), IL-18 (P < 0.001), COX-2 (P < 0.001), iNOS (P < 0.001), and MCP-1 (P < 0.01) in the gingival tissue. Additionally, CA119 reduced oxidative stress levels in rats and enhanced their antioxidant capacity. Microcomputed tomography (micro-CT) and histological analysis revealed that CA119 significantly reduced alveolar bone loss and reversed the downregulation of OPG/RANKL (P < 0.001). Furthermore, CA119 exhibited a significant protective effect against intestinal inflammation induced by periodontal disease and improved the colonic morphology in rats. In conclusion, this study demonstrates the role of CA119 as a potential oral probiotic in the prevention and treatment of experimental periodontitis, underscoring the potential of probiotics as a complementary approach to traditional periodontal care.

Bacillus halotolerans SW207 alleviates enterotoxigenic Escherichia coli-induced inflammatory responses in weaned piglets by modulating the intestinal epithelial barrier, the TLR4/MyD88/NF-κB pathway, and intestinal microbiota.

Enterotoxigenic Escherichia coli (ETEC) is one of the major pathogens contributing to piglet diarrhea, with significant implications for both piglet health and the economic aspects of the livestock industry. SW207 is an isolate of Bacillus halotolerans isolated from the cold- and disease-resistant Leixiang pigs in Northeastern China. We have discovered that SW207 can survive in the pig's gastrointestinal fluid and under conditions of high bile salt concentration, displaying potent antagonistic activity against ETEC. In this study, we established a weaned piglet diarrhea model infected with ETEC to investigate the role of SW207 in preventing diarrhea and improving intestinal health. Results indicate that SW207 upregulates the expression of tight junction proteins, including claudin-1, occludin, and zonula occludens-1, at both the transcriptional and translational levels. Furthermore, SW207 reduces serum endotoxin, D-lactic acid, and various oxidative stress markers while enhancing piglet mechanical barrier function. In terms of immune barrier, SW207 suppressed the activation of the TLR4/MyD88/NF-κB pathway, reducing the expression of various inflammatory factors and upregulating the expression of small intestine mucosal sIgA. Concerning the biological barrier, SW207 significantly reduces the content of E. coli in the intestines and promotes the abundance of beneficial bacteria, thereby mitigating the microbiota imbalance caused by ETEC. In summary, SW207 has the potential to prevent weaned piglet diarrhea caused by ETEC, alleviate intestinal inflammation and epithelial damage, and facilitate potential beneficial changes in the intestinal microbiota. This contributes to elucidating the potential mechanisms of host-microbe interactions in preventing pathogen infections.IMPORTANCEEnterotoxigenic Escherichia coli (ETEC) has consistently been one of the significant pathogens causing mortality in weaned piglets in pig farming. The industry has traditionally relied on antibiotic administration to control ETEC-induced diarrhea. However, the overuse of antibiotics has led to the emergence of drug-resistant zoonotic bacterial pathogens, posing a threat to public health. Therefore, there is an urgent need to identify alternatives to control pathogens and reduce antibiotic usage. In this study, we assessed the protective effect of a novel probiotic in a weaned piglet model infected with ETEC and analyzed its mechanisms both in vivo and in vitro. The study results provide theoretical support and reference for implementing interventions in the gut microbiota to alleviate early weaned piglet diarrhea and improve intestinal health.

Influence of protonic acid on the structure and properties of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) in oxidation polymerization.

Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is widely used because of its excellent performance. We report the synthesis of two PEDOT:PSS dispersions. The two dispersions differ by the addition of additional protonic acid in the oxidative polymerization system. Although there are examples of the introduction of acids into the polymerization system, the effects of acid on the structure and properties of these materials, in particular their mechanisms of action, have not been elucidated. We describe the chemical structure and molecular weight of two PEDOT polymers using Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, UV-vis-NIR spectroscopy, and density functional theory calculations. The carrier concentration, carrier mobility, and surface morphology of the composites are characterized by UV-vis-NIR spectroscopy, electron spin resonance, Raman spectra, Hall effect measurements, and atomic force microscopy. The crystallinity of PEDOT:PSS was measured by X-ray diffraction patterns. We show that the addition of a proper amount of protonic acid to the oxidative polymerization system can effectively reduce the formation of the terminal carbonyl group of PEDOT chains, which is conducive to the growth of polymer chains, and further improve the carrier concentration, which leads to an improvement of conductivity. Our results highlight the optimization of the chemical structure of PEDOT in order to increase its molecular weight and ultimately its conductivity.

Sesamin-mediated high expression of BECN2 ameliorates cartilage endplate degeneration by reducing autophagy and inflammation.

Lumbar disc degeneration (LDD) is a prevalent clinical spinal disease characterized by the calcification and degeneration of the cartilage endplate (CEP), which significantly reduces nutrient supply to the intervertebral disc. Traditional Chinese medicine offers a conservative and effective approach for treating LDD. We aimed to investigate the molecular mechanisms underlying the therapeutic effects of Sesamin in LDD treatment. Transcriptome sequencing was used to analyze the effect of Sesamin on LPS-induced ATDC5. We explored the role of BECN2, a target gene of Sesamin, in attenuating LPS-induced degeneration of ATDC5 cells. Our results revealed the identification of 117 differentially expressed genes (DEGs), with 54 up-regulated and 63 down-regulated genes. Notably, Sesamin significantly increased the expression of BECN2 in LPS-induced ATDC5 cell degeneration. Overexpressed BECN2 enhanced cell viability and inhibited cell apoptosis in LPS-induced ATDC5 cells, while BECN2 knockdown reduced cell viability and increased apoptosis. Furthermore, BECN2 played a crucial role in attenuating chondrocyte degeneration by modulating autophagy and inflammation. Specifically, BECN2 suppressed autophagy by reducing the expression of ATG14, VPS34, and GASP1, and alleviated the inflammatory response by decreasing the expression of inflammasome proteins NLRP3, NLRC4, NLRP1, and AIM2. In vivo experiments further supported the beneficial effects of Sesamin in mitigating LDD. This study provides novel insights into the potential molecular mechanism of Sesamin in treating LDD, highlighting its ability to mediate autophagy and inflammation inhibition via targeting the BECN2. This study provides a new therapeutic strategy for the treatment of LDD, as well as a potential molecular target for LDD.

Cytological and transcriptomic analyses provide insights into the pollen fertility of synthetic allodiploid Brassica juncea hybrids.

KEY MESSAGE: Imbalanced chromosomes and cell cycle arrest, along with down-regulated genes in DNA damage repair and sperm cell differentiation, caused pollen abortion in synthetic allodiploid Brassica juncea hybrids. Interspecific hybridization is considered to be a major pathway for species formation and evolution in angiosperms, but the occurrence of pollen abortion in the hybrids is common, prompting us to recheck male gamete development in allodiploid hybrids after the initial combination of different genomes. Here, we investigated the several key meiotic and mitotic events during pollen development using the newly synthesised allodiploid B. juncea hybrids (AB, 2n = 2× = 18) as a model system. Our results demonstrated the partial synapsis and pairing of non-homologous chromosomes concurrent with chaotic spindle assembly, affected chromosome assortment and distribution during meiosis, which finally caused difference in genetic constitution amongst the final tetrads. The mitotic cell cycle arrest during microspore development resulted in the production of anucleate pollen cells. Transcription analysis showed that sets of key genes regulating cyclin (CYCA1;2 and CYCA2;3), DNA damage repair (DMC1, NBS1 and MMD1), and ubiquitin-proteasome pathway (SINAT4 and UBC) were largely downregulated at the early pollen meiosis stages, and those genes involved in sperm cell differentiation (DUO1, PIRL1, PIRL9 and LBD27) and pollen wall synthesis (PME48, VGDH11 and COBL10) were mostly repressed at the late pollen mitosis stages in the synthetic allodiploid B. juncea hybrids (AB). In conclusion, this study elucidated the related mechanisms affecting pollen fertility during male gametophyte development at the cytological and transcriptomic levels in the synthetic allodiploid B. juncea hybrids.

Early Progression of Abdominal Aortic Aneurysm is Decelerated by Improved Endothelial Barrier Function via ALDH2-LIN28B-ELK3 Signaling.

The involvement of endothelial barrier function in abdominal aortic aneurysm (AAA) and its upstream regulators remains unknown. Single-cell RNA sequencing shows that disrupted endothelial focal junction is an early (3 days) and persistent (28 days) event during Angiotensin II (Ang II)-induced AAA progression. Consistently, mRNA sequencing on human aortic dissection tissues confirmed downregulated expression of endothelial barrier-related genes. Aldehyde dehydrogenase 2 (ALDH2), a negative regulator of AAA, is found to be upregulated in the intimal media of AAA samples, leading to testing its role in early-stage AAA. ALDH2 knockdown/knockout specifically in endothelial cells (ECs) significantly increases expression of EC barrier markers related to focal adhesion and tight junction, restores endothelial barrier integrity, and suppresses early aortic dilation of AAA (7 and 14 days post-Ang II). Mechanically, ELK3 acts as an ALDH2 downstream regulator for endothelial barrier function preservation. At the molecular level, ALDH2 directly binds to LIN28B, a regulator of ELK3 mRNA stability, hindering LIN28B binding to ELK3 mRNA, thereby depressing ELK3 expression and impairing endothelial barrier function. Therefore, preserving vascular endothelial barrier integrity via ALDH2-specific knockdown in ECs holds therapeutic potential in the early management of AAAs.

The mechanism by which Naru 3 pill protects against intervertebral disc cartilage endplate degeneration based on network pharmacology and experimental verification.

CONTEXT: Naru 3 pill is a traditional Mongolian medicine for the treatment of intervertebral disc degeneration (IDD), but the mechanism is not yet clear. OBJECTIVE: This study investigated the mechanism of Naru 3 pill in the treatment of IDD. MATERIALS AND METHODS: Active ingredients and related targets of Naru 3 pill, as well as IDD-related genes, were collected from public databases. The analysis was performed by protein‒protein interaction network analysis, gene ontology and Kyoto Gene and Genome Encyclopedia (KEGG) functional enrichment analysis, molecular docking and molecular dynamics simulations. Finally, the network pharmacology results were validated by in vitro experiments. RESULTS: Network analysis showed that sesamin, piperine and ellagic acid were potential key components and CASP3, BAX and BCL2 were key targets. KEGG analysis indicated the apoptotic pathway as a potential pathway. Molecular docking showed that sesamin interacted better with the targets than the other components. The results of molecular dynamics simulations indicated that the three systems BAX-sesamin, BCL2-sesamin and CASP3-sesamin were stable and reasonable during the simulation. In vitro experiments showed that sesamin had the least effect on cell growth and the most pronounced proliferation-promoting effect, and so sesamin was considered the key component. The experiments confirmed that sesamin had antiapoptotic effects and reversed the expression of CASP3, BAX and BCL2 in degeneration models, which was consistent with the network pharmacology results. Furthermore, sesamin alleviated extracellular matrix (ECM) degeneration and promoted cell proliferation in the IDD model. CONCLUSION: The present study suggested that Naru 3 pill might exert its therapeutic and antiapoptotic effects on IDD by delaying ECM degradation and promoting cell proliferation, which provides a new strategy for the treatment of IDD.

Visible-light-driven Oxygen Vacancy and Carbon Doping of C@TiO2-x Photocatalyst for Enhanced Pollutants Degradation Performance.

Oxygen Vacancy (OVs) and carbon doping of the photocatalyst body will significantly enhance the photocatalytic efficiency. However, synchronous regulation of these two aspects is challenging. In this paper, a novel C@TiO2-x photocatalyst was designed by coupling the surface defect and doping engineering of titania, which can effectively remove rhodamine B (RhB) and has a relatively high performance with wide pH range, high photocatalytic activity and good stability. Within 90 minutes, the photocatalytic degradation rate of RhB by C@TiO2-x (94.1 % at 20 mg/L) is 28 times higher than that of pure TiO2 . Free radical trapping experiments and electron spin resonance techniques reveal that superoxide radicals (⋅O2- ) and photogenerated holes (h+ ) play key roles in the photocatalytic degradation of RhB. This study demonstrates the possibility of regulating photocatalysts to degrade pollutants in wastewater based on an integrated strategy.

Metabolome and transcriptome analyses of anthocyanin biosynthesis reveal key metabolites and candidate genes in purple wheat (Triticum aestivum L.).

Wheat (Triticum aestivum L.) is continuously subjected to genetic improvement to optimize grain quality. Purple wheat has recently gained attention because of its high anthocyanin and nutrient content. In this study, we performed an integrated transcriptome and metabolome analysis of the inbred wheat lines ZM152 (white wheat line) and ZM163 (purple wheat line) to elucidate molecular networks and identify potential genes regulating anthocyanin synthesis. A total of 564 metabolites were detected, of which 47 metabolite contents differed significantly between the two lines. Twenty-five flavonoids, including four anthocyanins, were significantly higher in purple wheat. High contents of cyanidin 3-rutinoside and malvidin 3-glucoside might contribute to the purple coloration of the wheat grains. Consistently, gene ontology and pathway enrichment analyses revealed that flavonoid and anthocyanin biosynthesis were mostly enriched, and the expression of anthocyanin structural genes was specifically upregulated in purple wheat lines, while transcription factors (TFs) were mostly downregulated in purple wheat lines. Especially, the correlation analysis showed the anthocyanin synthesis-related genes CHS (TraesCS2B02G048400) and UFGT (TraesCS7A02G155400) were likely regulated negatively by the TFs MYB4 (TraesCS1A02G268800, TraesCS1B02G279400), TT8 (TraesCS1D02G094200, TraesCS1B02G113100, and TraesCS1A02G102400), which thus could be considered important regulatory genes in the anthocyanin biosynthesis pathway of purple wheat lines. In summary, these results offer new insights into anthocyanin biosynthesis and accumulation of purple wheat, and provide very useful candidate genes for future colored wheat breeding.

Unveiling different antibiotic degradation mechanisms on dual reaction center catalysts with nitrogen vacancies via peroxymonosulfate activation.

Metal-nitrogen-site catalysts are widely recognized as effective heterogeneous catalysts in peroxymonosulfate (PMS)-based advanced oxidation processes. However, the selective oxidation mechanism for organic pollutants is still contradictory. In this work, manganese-nitrogen active centers and tunable nitrogen vacancies were synchronously constructed on graphitic carbon nitride (LMCN) through l-cysteine-assisted thermal polymerization to reveal different antibiotic degradation mechanisms. Benefiting from the synergism of manganese-nitrogen bond and nitrogen vacancies, the LMCN catalyst exhibited excellent catalytic activity for the degradation of tetracycline (TC) and sulfamethoxazole (SMX) antibiotics with first-order kinetic rate constants of 0.136 min-1 and 0.047 min-1, which were higher than those of other catalysts. Electron transfer dominated TC degradation at low redox potentials, while electron transfer and high-valent manganese (Mn (V)) were responsible for SMX degradation at high redox potentials. Further experimental studies unveiled that the pivotal role of nitrogen vacancies is to promote electron transfer pathway and Mn(V) generation, while nitrogen-coordinated manganese as the primary catalytic active site determines Mn(V) generation. In addition, the antibiotic degradation pathways were proposed and the toxicity of byproducts was analyzed. This work provides an inspiring idea for the controlled generation of reactive oxygen species by targeted activation of PMS.

Artificial Neural Network Modeling to Predict Neonatal Metabolic Bone Disease in the Prenatal and Postnatal Periods.

Importance: Early recognition of metabolic bone disease (MBD) in infants is necessary but difficult; an appropriate tool to screen infants at risk of developing MBD is needed. Objectives: To develop a predictive model for neonates at risk for MBD in the prenatal and postnatal periods and detect the pivotal exposed factors in each period. Design, Setting, and Participants: A diagnostic study was conducted from January 1, 2012, to December 31, 2021, in Shanghai, China. A total of 10 801 pregnant women (singleton pregnancy, followed up until 1 month after parturition) and their infants (n = 10 801) were included. An artificial neural network (ANN) framework was used to build 5 predictive models with different exposures from prenatal to postnatal periods. The receiver operating characteristic curve was used to evaluate the model performance. The importance of each feature was examined and ranked. Results: Of the 10 801 Chinese women who participated in the study (mean [SD] age, 29.7 [3.9] years), 7104 (65.8%) were local residents, 1001 (9.3%) had uterine scarring, and 138 (1.3%) gave birth to an infant with MBD. Among the 5 ANN models, model 1 (significant prenatal and postnatal factors) showed the highest AUC of 0.981 (95% CI, 0.970-0.992), followed by model 5 (postnatal factors; AUC, 0.977; 95% CI, 0.966-0.988), model 4 (all prenatal factors; AUC, 0.850; 95% CI, 0.785-0.915), model 3 (gestational complications or comorbidities and medication use; AUC, 0.808; 95% CI, 0.726-0.891), and model 2 (maternal nutritional conditions; AUC, 0.647; 95% CI, 0.571-0.723). Birth weight, maternal age at pregnancy, and neonatal disorders (anemia, respiratory distress syndrome, and septicemia) were the most important model 1 characteristics for predicting infants at risk of MBD; among these characteristics, extremely low birth weight (importance, 50.5%) was the most powerful factor. The use of magnesium sulfate during pregnancy (model 4: importance, 21.2%) was the most significant predictor of MBD risk in the prenatal period. Conclusions and Relevance: In this diagnostic study, ANN appeared to be a simple and efficient tool for identifying neonates at risk for MBD. Combining prenatal and postnatal factors or using postnatal exposures alone provided the most precise prediction. Extremely low birth weight was the most significant predictive factor, whereas magnesium sulfate use during pregnancy could be an important bellwether for MBD before delivery.

Detection of various microplastics in placentas, meconium, infant feces, breastmilk and infant formula: A pilot prospective study.

Pregnancy and infancy are sensitive windows for environmental exposures. However, no study has investigated the presence of microplastics (MPs) in mother-infant pairs, and the exposure sources. Therefore, we aim to assess MPs exposure in placenta, meconium, infant feces, breast milk and infant formula samples, and assess the potential sources of pregnancy and lactational exposure to MPs. A total of 18 mother-infant pairs were recruited, and placentas and meconium samples were collected. Infant feces, breast milk and infant formula samples were collected at 6 months of age. We also collected data on plastic use and feeding habits through two questionnaires to determine the source of exposure. We used an Agilent 8700 laser infrared imaging spectrometer to analyze samples. Sixteen types of MPs were identified, and polyamide (PA) and polyurethane (PU) were dominant. >74 % of the MPs found were 20-50 µm in size. The water intake and usage of scrub cleanser or toothpaste may be exposure sources of pregnant women. The breastfeeding and usage of feeding bottles and plastic toys may be exposure sources for infants. Given the lack of relevant studies, our results highlight the need of investigating the contribution of plastic products to the MPs exposure during the lactational period.

Acetylation Enhances the Anticancer Activity and Oral Bioavailability of 5-Demethyltangeretin.

A kind of hydroxylated polymethoxyflavone (PMFs) existing in the citrus genus, 5-Demethyltangeretin (5-DTAN), has been reported to possess several bioactivities in vitro and in vivo. The aim of this study was to investigate whether acetylation could enhance the anticancer activity and oral bioavailability of 5-DTAN. PC-3 human prostate cancer cells were treated with tangeretin (TAN), 5-DTAN, and 5-acetylated TAN (5-ATAN), and the results showed that the cytotoxic effect 5-ATAN (IC50 value of 5.1 µM) on the cell viability of PC-3 cells was stronger than that of TAN (IC50 value of 17.2 µM) and 5-DTAN (IC50 value of 11.8 µM). Compared to 5-DTAN, 5-ATAN treatment caused a more pronounced DNA ladder, increased the sub-G1 phase population, and induced G2/M phase arrest in the cell cycle of PC-3 cells. We also found that 5-ATAN triggered the activation of caspase-3 and the progression of the intrinsic mitochondrial pathway in PC-3 cells, suggesting the induction of apoptosis. In a cell wound healing test, 5-ATAN dose-dependently reduced the cell migration, and the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) was decreased after 48 h of 5-ATAN treatment. Moreover, oral administration of 5-ATAN showed a significantly stronger inhibitory effect on tumor size and tumor weight in tumor-bearing nude mice than those of vehicle or the 5-DTAN group (p < 0.05). Furthermore, pharmacokinetic results showed that single-dose oral administration of 5-ATAN exhibited a higher maximum concentration (Cmax) and area under the curve (AUC) of 5-DTAN in plasma than that of 5-DTAN. More extensive distribution of 5-DTAN to most tissues of mice was also observed in mice treated with 5-ATAN for 7 days. In conclusion, acetylation strongly enhances the anticancer activity and oral bioavailability of 5-DTAN and could be a promising strategy to promote the potential bioactivities of natural products.

The Association Between Microplastics and Microbiota in Placentas and Meconium: The First Evidence in Humans.

Pregnancy and infancy are vulnerable times for detrimental environmental exposures. However, the exposure situation of microplastics (MPs) for mother-infant pairs and the adverse health effect of MPs are largely unknown. Therefore, we explored MP exposure in placentas and meconium samples, and the potential correlation of MP exposure with microbiota in placentas and meconium. A total of 18 mother-infant pairs were effectively recruited from Shanghai, China. The study required pregnant women to provide placentas and meconium samples. An Agilent 8700 laser infrared imaging spectrometer (LDIR) was applied to identify MPs. Microbiota detection was identified by 16S rRNA sequencing. Sixteen types of MPs were found in all matrices, and polyamide (PA) and polyurethane (PU) were the major types we identified. MPs detected in samples with a size of 20-50 µm were more than 76.46%. At the phylum level, both placenta and meconium microbiota were mainly composed of Proteobacteria, Bacteroidota, and Firmicutes. We also found some significant differences between placenta and meconium microbiota in ß-diversity and gut composition. Additionally, we found polystyrene was inversely related with the Chao index of meconium microbiota. Polyethylene was consistently inversely correlated with several genera of placenta microbiota. The total MPs, PA, and PU consistently impacted several genera of meconium microbiota. In conclusion, MPs are ubiquitous in placentas and meconium samples, indicating the wide exposure of pregnant women and infants. Moreover, our findings may support a link between high concentration of MPs and microbiota genera in placentas and meconium. Additionally, there were several significant associations between the particle size of MPs in 50-100 µm and meconium microbiota.

Bifidobacterium spp. and their metabolite lactate protect against acute pancreatitis via inhibition of pancreatic and systemic inflammatory responses.

Severe acute pancreatitis (SAP) is a critical illness characterized by a severe systemic inflammatory response resulting in persistent multiple organ failure and sepsis. The intestinal microbiome is increasingly appreciated to play a crucial role in modulation of AP disease outcome, but limited information is available about the identity and mechanism of action for specific commensal bacteria involved in AP-associated inflammation. Here we show that Bifidobacteria, particularly B. animalis, can protect against AP by regulating pancreatic and systemic inflammation in germ-free (GF) and oral antibiotic-treated (Abx) mouse models. Colonization by B. animalis and administration of its metabolite lactate protected Abx and GF mice from AP by reducing serum amylase concentration, ameliorating pancreatic lesions and improving survival rate after retrograde injection of sodium taurocholate. B. animalis relieved macrophage-associated local and systemic inflammation of AP in a TLR4/MyD88- and NLRP3/Caspase1-dependent manner through its metabolite lactate. Supporting our findings from the mouse study, clinical AP patients exhibited a decreased fecal abundance of Bifidobacteria that was inversely correlated with the severity of systemic inflammatory responses. These results may shed light on the heterogeneity of clinical outcomes and drive the development of more efficacious therapeutic interventions for AP, and potentially for other inflammatory disorders.

Polyphenols, flavonoids and inflammasomes: the role of cigarette smoke in COPD.

COPD is predicted to become the third leading cause of morbidity and mortality worldwide by 2030. Cigarette smoking (active or passive) is one of its chief causes, with about 20% of cigarette smokers developing COPD from cigarette smoke (CS)-induced irreversible damage and sustained inflammation of the airway epithelium. Inflammasome activation leads to the cleavage of pro-interleukin (IL)-1ß and pro-IL-18, along with the release of pro-inflammatory cytokines via gasdermin D N-terminal fragment membrane pores, which further triggers acute phase pro-inflammatory responses and concurrent pyroptosis. There is currently intense interest in the role of nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein-3 inflammasomes in chronic inflammatory lung diseases such as COPD and their potential for therapeutic targeting. Phytochemicals including polyphenols and flavonoids have phyto-medicinal benefits in CS-COPD. Here, we review published articles from the last decade regarding the known associations between inflammasome-mediated responses and ameliorations in pre-clinical manifestations of CS-COPD via polyphenol and flavonoid treatment, with a focus on the underlying mechanistic insights. This article will potentially assist the development of drugs for the prevention and therapy of COPD, particularly in cigarette smokers.

Whole-body PET tracking of a d-dodecapeptide and its radiotheranostic potential for PD-L1 overexpressing tumors.

Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d-peptides is limited. This highlights the need for whole-body, quantitative tracking of d-peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d-dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d-peptides, but also underscore the utility of d-peptides as radiopharmaceuticals.

Design, Synthesis, Bioactivity Evaluation, Crystal Structures, and In Silico Studies of New α-Amino Amide Derivatives as Potential Histone Deacetylase 6 Inhibitors.

Hydroxamate, as a zinc-binding group (ZBG), prevails in the design of histone deacetylase 6(HDAC6) inhibitors due to its remarkable zinc-chelating capability. However, hydroxamate-associated genotoxicity and mutagenicity have limited the widespread application of corresponding HDAC6 inhibitors in the treatment of human diseases. To avoid such side effects, researchers are searching for novel ZBGs that may be used for the synthesis of HDAC6 inhibitors. In this study, a series of stereoisomeric compounds were designed and synthesized to discover non-hydroxamate HDAC6 inhibitors using α-amino amide as zinc-ion-chelating groups, along with a pair of enantiomeric isomers with inverted L-shaped vertical structure as cap structures. The anti-proliferative activities were determined against HL-60, Hela, and RPMI 8226 cells, and 7a and its stereoisomer 13a exhibited excellent activities against Hela cells with IC50 = 0.31 µM and IC50 = 5.19 µM, respectively. Interestingly, there is a significant difference between the two stereoisomers. Moreover, an evaluation of cytotoxicity toward human normal liver cells HL-7702 indicated its safety for normal cells. X-ray single crystal diffraction was employed to increase insights into molecule structure and activities. It was found that the carbonyl of the amide bond is on the different side from the amino and pyridine nitrogen atoms. To identify possible protein targets to clarify the mechanism of action and biological activity of 7a, a small-scale virtual screen using reverse docking for HDAC isoforms (1-10) was performed and the results showed that HDAC6 was the best receptor for 7a, suggesting that HDAC6 may be a potential target for 7a. The interaction pattern analysis showed that the α-amino amide moiety of 7a coordinated with the zinc ion of HDAC6 in a bidentate chelate manner, which is similar to the chelation pattern of hydroxamic acid. Finally, the molecular dynamics simulation approaches were used to assess the docked complex's conformational stability. In this work, we identified 7a as a potential HDAC6 inhibitor and provide some references for the discovery of non-hydroxamic acid HDAC6 inhibitors.

Hydrogen therapy after resuscitation improves myocardial injury involving inhibition of autophagy in an asphyxial rat model of cardiac arrest.

Hydrogen (H2) therapy is a therapeutic strategy using molecular H2. Due to its ability to regulate cell homeostasis, H2 therapy has exhibited marked therapeutic effects on a number of oxidative stress-associated diseases. The present study investigated the effectiveness of H2 therapy in protecting against myocardial injury in a rat model of asphyxial cardiac arrest and cardiopulmonary resuscitation. Rats underwent 10-min asphyxia-induced cardiac arrest (CA) and cardiopulmonary resuscitation (CPR), and were randomly divided into control and H2 therapy groups. After resuscitation, the H2 therapy group was administered room air mixed with 2% H2 gas for respiration. During CA/CPR, the arterial pressure and heart rate were measured every minute. Survival rate, cardiac function, myocardial injury biomarkers creatine kinase-MB and cardiac troponin-T, and histopathological changes were evaluated to determine the protective effects of H2 therapy in CA/CPR. Immunohistochemistry and western blot analysis were used to determine the expression levels of autophagy-associated proteins. In vitro, H9C2 cells were subjected to hypoxia/reoxygenation and H2-rich medium was used in H2 treatment groups. Western blotting and immunofluorescence were used to observe the expression levels of autophagy-associated proteins. Moreover, an adenovirus-monomeric red fluorescent protein-green fluorescent protein-LC3 construct was used to explore the dynamics of autophagy in the H9C2 cells. The results showed that H2 therapy significantly improved post-resuscitation survival and cardiac function. H2 therapy also improved mitochondrial mass and decreased autophagosome numbers in cardiomyocytes after resuscitation. The treatment inhibited autophagy activation, with lower expression levels of autophagy-associated proteins and decreased autophagosome formation in vivo and vitro. In conclusion, H2 gas inhalation after return of spontaneous circulation improved cardiac function via the inhibition of autophagy.