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BackgroundThe escalation of global population aging has accentuated the prominence of senile diabetes mellitus (SDM) as a consequential public health concern. Oxidative stress and chronic inflammatory cascades prevalent in individuals with senile diabetes significantly amplify disease progression and complication rates. Traditional Chinese Medicine (TCM) emerges as a pivotal player in enhancing blood sugar homeostasis and retarding complication onset in the clinical management of senile diabetes. Nonetheless, an evident research gap persists regarding the integration of TCM’s renal tonification pharmacological mechanisms with experimental validation within the realm of senile diabetes therapeutics.AimsThe objective of this study was to investigate the mechanisms of action of New Shenqi Pills (SQP) in the treatment of SDM and make an experimental assessment.MethodsNetwork analysis is used to evaluate target pathways related to SQP and SDM. Mitochondrial-related genes were obtained from the MitoCarta3.0 database and intersected with the common target genes of the disease and drugs, then constructing a protein-protein interaction (PPI) network making use of the GeneMANIA database. Representative compounds in the SQP were quantitatively measured using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to ensure quality control and quantitative analysis of the compounds. A type 2 diabetes mice (C57BL/6) model was used to investigate the pharmacodynamics of SQP. The glucose lowering efficacy of SQP was assessed through various metrics including body weight and fasting blood glucose (FBG). To elucidate the modulatory effects of SQP on pancreatic beta cell function, we measured oral glucose tolerance test (OGTT), insulin histochemical staining and tunel apoptosis detection, then assessed the insulin-mediated phosphoinositide 3-kinase (PI3K)/protein kinase A (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway in diabetic mice via Western blotting. Additionally, we observe the structural changes of the nucleus, cytoplasmic granules and mitochondria of pancreatic islet β cells.ResultsIn this investigation, we identified a total of 1876 genes associated with senile diabetes, 278 targets of SQP, and 166 overlapping target genes, primarily enriched in pathways pertinent to oxidative stress response, peptide response, and oxygen level modulation. Moreover, an intersection analysis involving 1,136 human mitochondrial genes and comorbidity targets yielded 15 mitochondria-related therapeutic targets. Quality control assessments and quantitative analyses of SQP revealed the predominant presence of five compounds with elevated concentrations: Catalpol, Cinnamon Aldehyde, Rehmanthin D, Trigonelline, and Paeonol Phenol. Vivo experiments demonstrated notable findings. Relative to the control group, mice in the model group exhibited significant increases in body weight and fasting blood glucose levels, alongside decreased insulin secretion and heightened islet cell apoptosis. Moreover, β-cells nuclear condensation and mitochondrial cristae disappearance were observed, accompanied by reduced expression levels of p-GSK-3β protein in islet cells (p < 0.05 or p < 0.01). Conversely, treatment groups administered SQP and Rg displayed augmented expressions of the aforementioned protein markers (p < 0.05 or p < 0.01), alongside preserved mitochondrial cristae structure in islet β cells.ConclusionOur findings suggest that SQP can ameliorate diabetes by reducing islet cell apoptosis and resist oxidative stress. These insulin-mediated PI3K/AKT/GSK-3β pathway plays an important regulatory role in this process.

This review provides a comprehensive analysis of the critical role played by macrophages and their underlying mechanisms in the progression of diabetic cardiomyopathy (DCM). It begins by discussing the origins and diverse subtypes of macrophages, elucidating their spatial distribution and modes of intercellular communication, thereby emphasizing their significance in the pathogenesis of DCM. The review then delves into the intricate relationship between macrophages and the onset of DCM, particularly focusing on the epigenetic regulatory mechanisms employed by macrophages in the context of DCM condition. Additionally, the review discusses various therapeutic strategies aimed at targeting macrophages to manage DCM. It specifically highlights the potential of natural food components in alleviating diabetic microvascular complications and examines the modulatory effects of existing hypoglycemic drugs on macrophage activity. These findings, summarized in this review, not only provide fresh insights into the role of macrophages in diabetic microvascular complications but also offer valuable guidance for future therapeutic research and interventions in this field.

BackgroundDespite advancements, breast cancer outcomes remain stagnant, highlighting the need for precise biomarkers in precision medicine. Traditional TNM staging is insufficient for identifying patients who will respond well to treatment.MethodsOur study involved over 6,900 breast cancer patients from 14 datasets, including in-house clinical data and single-cell data from 8 patients (37,451 cells). We integrated 10 machine learning algorithms in 55 combinations and analyzed 100 existing breast cancer signatures. IHC assays were conducted for validation, and potential immunotherapies and chemotherapies were explored.ResultsWe pinpointed six stable Panoptosis-related genes from multi-center cohorts, leading to a robust Panoptosis-model. This model outperformed existing clinical and molecular features in predicting recurrence and mortality risks, with high-risk patients showing worse outcomes. IHC validation from 30 patients confirmed our findings, indicating the model’s broader applicability. Additionally, the model suggested that low-risk patients benefit more from immunotherapy, while high-risk patients are sensitive to specific chemotherapies like BI-2536 and ispinesib.ConclusionThe Panoptosis-model represents a major advancement in breast cancer prognosis and treatment personalization, offering significant insights for effectively managing a wide range of breast cancer patients.

Cognitive dysfunction is increasingly recognized as a complication and comorbidity of diabetes, supported by evidence of abnormal brain structure and function. Although few mechanistic metabolic studies have shown clear pathophysiological links between diabetes and cognitive dysfunction, there are several plausible ways in which this connection may occur. Since, brain functions require a constant supply of glucose as an energy source, the brain may be more susceptible to abnormalities in glucose metabolism. Glucose metabolic abnormalities under diabetic conditions may play an important role in cognitive dysfunction by affecting glucose transport and reducing glucose metabolism. These changes, along with oxidative stress, inflammation, mitochondrial dysfunction, and other factors, can affect synaptic transmission, neural plasticity, and ultimately lead to impaired neuronal and cognitive function. Insulin signal triggers intracellular signal transduction that regulates glucose transport and metabolism. Insulin resistance, one hallmark of diabetes, has also been linked with impaired cerebral glucose metabolism in the brain. In this review, we conclude that glucose metabolic abnormalities play a critical role in the pathophysiological alterations underlying diabetic cognitive dysfunction (DCD), which is associated with multiple pathogenic factors such as oxidative stress, mitochondrial dysfunction, inflammation, and others. Brain insulin resistance is highly emphasized and characterized as an important pathogenic mechanism in the DCD.

Colorectal cancer (CRC) is a major health burden, accounting for approximately 10% of all new cancer cases worldwide. Accumulating evidence suggests that the crosstalk between the host mucins and gut microbiota is associated with the occurrence and development of CRC. Mucins secreted by goblet cells not only protect the intestinal epithelium from microorganisms and invading pathogens but also provide a habitat for commensal bacteria. Conversely, gut dysbiosis results in the dysfunction of mucins, allowing other commensals and their metabolites to pass through the intestinal epithelium, potentially triggering host responses and the subsequent progression of CRC. In this review, we summarize how gut microbiota and bacterial metabolites regulate the function and expression of mucin in CRC and novel treatment strategies for CRC.

Psychological disorders are associated with increased risk of severe inflammatory bowel disease (IBD) by causing gut microbiota dysbiosis and colonic mucosal barrier damage. However, the interaction between chronic restraint stress (CRS), gut microbiota composition, and colonic mucus remains unclear. We demonstrated that mice under CRS conditions exhibited alterations in microbiota composition, disruption of colonic mucus, and aggravation of colitis. In addition, the abundance of Akkermansia muciniphila was significantly decreased in mice under CRS and UC patients with depression, and positively associated with the expression of MUC2. After antibiotic treatment, the recipient mice colonized with CRS microbiota showed barrier defects and severe colitis. Administration of Akkermansia muciniphila was found to restore colonic mucus and modify the gut microbiota. We confirm that CRS-mediated gut microbiota dysbiosis results in colonic mucosal barrier damage and aggravation of colitis. Our results suggest that A. muciniphila is expected to be a potential probiotic to protect and treat colonic mucus that is involved in IBD with psychological disorders.

Stanniocalcin-1 (STC1) is a glycoprotein hormone whose abnormal expression has been reported to be associated with a variety of tumors, but its function in breast cancer is not well understood. Through modulation of STC1 expression in different breast cancer cell lines, our study found that STC1 could promote the proliferation and growth of breast cancer cells and promote metastasis. Furthermore, STC1 reduced apoptosis induction by irradiation. We also found that STC1 could promote a homologous recombination-mediated DNA damage repair by recruiting BRCA1 to sites of damage. Moreover, STC1 silencing sensitized breast cancer cells to treatment with irradiation (IR), olaparib, or cisplatin in vitro. In clinical settings, the serum concentration of STC1 was higher in breast cancer patients than in healthy women, as detected by enzyme-linked immunosorbent assay (ELISA). In addition, immunohistochemical staining of breast cancer specimens showed that a high expression of STC1 was negatively correlated with recurrence-free survival in breast cancer, indicating that STC1 expression could be used as a predictive marker for a poor prognosis in breast cancer. All these findings indicate that STC1 promotes breast cancer tumorigenesis and that breast cancers with a high level of STC1 are more resistant to treatment, probably through homologous recombination (HR) promotion. Furthermore, combining STC1 inhibition and DNA damage-inducing drugs may be a novel approach to improve the survival of patients with STC1-expressing breast cancer.

Background: Diabetic retinopathy (DR) is one of the most common and severe microvascular complications of diabetes mellitus (DM), which results in blindness among adults worldwide. Presently, the efficacy of drug treatments for diabetic retinopathy (DR) is not satisfactory, thus urgently necessitating effective drug treatment measures. TangWang prescription (TWP) has been found to have retinal protection effects in previous clinical and basic research. However, there is a lack of rigorous, randomized, and controlled studies. This study aims to evaluate the efficacy and safety of TWP in delaying the development of DR.Methods: This study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical trial, consisting of 384 participants to be randomized in a 1:1 ratio in the treatment and control groups. Furthermore, the treatment and control groups will be administered the TangWang prescription and the placebo, respectively, each at a dose of one bag twice a day. The study period will last for 48 weeks. The primary outcome measure will be the changes in the degree of retinal microvascular lesions before and after treatment. The secondary outcome will be changes in the degree of hemangioma, microvascular bleeding, microvascular leakage, macular edema, and vision. All statistical tests will be two-sided, and a p < 0.05 will be considered statistically significant.Discussion: We hypothesize that the patients with DR will benefit from TangWang prescription, and in addition to the central random system and platform of dynamic information collection, the patients’ conditions will be monitored, and the data collected for analysis. If successful, this study will provide evidence that the TWP formulation delays in the progression of DR.Trial registration: The design of this trial has been registered with the ClinicalTrials.gov (NCT03025399).

Aim: Diabetic retinopathy (DR) is a serious complication of diabetes (DM). Luo Tong formula (LTF) exerts protective effects against DR in rats, but its underlying mechanism remains unknown. Methods: Sprague-Dawley rats injected with streptozotocin (STZ) were used as an experimental diabetes model. LTF or calcium dobesilate (CaD) was administered to diabetic rats via gastric gavage. After the 12 weeks of treatment, blood and tissue samples were collected to determine serum glucose and retinal structure. Blood samples were collected for blood glucose and hemorheology analysis. Gene or protein expression levels were evaluated by immunohistochemistry, western blotting and/or quantitative real-time polymerase chain reaction (PCR). Results: DM rats exhibits significantly increased blood retinal-barrier (BRB) breakdown and VEGF/VEGFR expression in the retina, and decreased miR-200b and tight junction ZO-1/Occludin/ Claudin-5 genes expression, as well as Ang-1/Tie-2 expressions in the retina compared to normal control group. LTF treatment significantly moderated histological abnormalities in diabetic rats, independent of blood glucose level; improved some hemorrheological parameters; decreased the expressions of VEGF/VEGFR and BRB breakdown, significantly increased PEDF and tight junction proteins ZO-1/Occludin, as well as increased retinal miR-200b expression compared to non-treatment diabetic rats. Moreover, LTF prevented the reduction in Ang-1/Tie-2 expression. Conclusions: LTF treatment ameliorated DR through its repair vascular and attenuate vascular leakage. A mechanism involving miR-200b may contribute to benefit effects.

Background: The gut microbiota plays important roles in the occurrence and development of obesity and diabetes through participating in nutrient absorption and metabolism. Microecological regulation is likely to be key to understanding the effects of Chinese medicine. The Linggui Zhugan (LGZG) formula is a well-known Chinese medicine for controlling obesity in the clinic. However, its pharmacological effects and mechanism of action in diabetes require further exploration.Objective: To evaluate the effects of LGZG on body weight, glycemic control, lipid levels, and gut microbiota in high-fat diet-induced diabetic mice.Methods: High-fat diet-induced diabetic mice were subjected to an 8-week protocol of LGZG administration. We then evaluated the pharmacological effects of LGZG and its influence on gut microbes in fecal samples using the 16S rRNA-based microbiome profiling technique.Results: LGZG administration significantly reduced body weight and body fat mass in diabetic mice. Compared with the high-fat diet control group, LGZG favorably influenced blood glucose control, decreased blood glucose levels, and increased glucose tolerance, accompanied by an improvement in lipid metabolism. Furthermore, the global community composition and relative abundance of many taxa differed between mice fed chow or a high-fat diet. As expected, LGZG supplementation altered the general community structure of gut microbiota, the Firmicutes/Bacteroidetes ratio, and the relative abundance of certain bacteria, such as Bacteroides, Lactobacillus, Oscillospira, and Helicobacter.Conclusion: LGZG effectively controlled obesity and relieved insulin resistance, which may be closely related to its impact on gut microbiota.

BackgroundEndometriosis, a prevalent gynecological disease, has an unclear pathogenesis. Micronutrients play a crucial role in disease development, which has led to an investigation of their association with endometriosis.MethodsIn this study, we analyzed the relationship between 15 micronutrients and endometriosis using both univariate and multivariate Mendelian randomization (MR) to assess the correlation. The results were validated using high-performance liquid chromatography (HPLC).ResultsThe univariate MR analysis indicated that vitamin B6 (OR = 1.7060, 95% CI: 1.1796–2.4672, p = 0.0045) and calcium (OR = 1.4834, 95% CI: 1.0747–2.0475, p = 0.0165) are associated with an increased risk of endometriosis. Higher intakes of vitamin B6 and calcium are associated with a greater likelihood of developing endometriosis. The MR Egger regression’s intercept term demonstrated no evidence of pleiotropy (p > 0.05) or heterogeneity (p > 0.05) in the SNPs for calcium and vitamin B6. In multivariate MR analysis, vitamin B6 (OR = 2.397, 95% CI: 1.231–4.669, p = 0.01) was linked to an increased risk of endometriosis, independently of other exposure factors. No significant heterogeneity (p = 0.831) or pleiotropy (p = 0.369) was observed in the genetic variation of endometriosis, affirming the reliability of the multivariate MR analysis. HPLC confirmed a significant increase in serum levels of vitamin B6 and calcium, aligning with the MR analysis findings.ConclusionVitamin B6 and calcium may be associated with this disease, with vitamin B6 potentially acting as an independent risk factor. Further research is essential to elucidate the role of micronutrients in disease, offering novel insights for prevention and treatment strategies.

ObjectiveHow to conduct objective and accurate individualized assessments of patients with disorders of consciousness (DOC) and carry out precision rehabilitation treatment technology is a major rehabilitation problem that needs to be solved urgently.MethodsIn this study, a multi-layer brain network was constructed based on functional magnetic resonance imaging (fMRI) to analyze the structural and functional brain networks of patients with DOC at different levels and to find regulatory targets (imaging markers) with recovery potential for DOC. Then repeated transcranial magnetic stimulation (rTMS) was performed in DOC patients to clinically validate.ResultsThe brain network connectivity of DOC patients with different consciousness states is different, and the most obvious brain regions appeared in the olfactory cortex and precuneus. rTMS stimulation could effectively improve the consciousness level of DOC patients and stimulate the occipital lobe (specific regions found in this study) and the dorsolateral prefrontal cortex (DLPFC), and both parts had a good consciousness recovery effect.ConclusionIn clinical work, personalized stimulation regimen treatment combined with the brain network characteristics of DOC patients can improve the treatment effect.

IntroductionThe incorporation of Staphylococcus xylosus in sausage production is hypothesized to affect various physicochemical properties and flavor profiles of sausages. This study aimed to evaluate the simulation of these features in a sausage model and establish its applicability for in vitro studies.MethodsBoth a control and an experimental model, inclusive of Staphylococcus xylosus, were assessed for changes in physicochemical indexes (pH and water activity, Aw) and the concentration of flavoring components (esters and aldehydes). Thiobarbituric acid reactive substances (TBARS) values were also measured to evaluate lipid oxidation.ResultsThe introduction of Staphylococcus xylosus resulted in no significant changes in pH and Aw between the sausage and the model. However, there was a considerable increase in the content of volatile flavor compounds, specifically esters and aldehydes, in the experimental groups compared to the control. Additionally, the TBARS values in experimental groups were significantly lower than those in the control group at the end of the testing period.DiscussionThe findings indicate that Staphylococcus xylosus plays a critical role in enhancing the flavor profile of sausages through the increased synthesis of volatile compounds and inhibiting fat oxidation. The sausage model effectively simulated the physicochemical and flavor index responses, demonstrating its potential utility for further in vitro research on sausage fermentation and preservation techniques.

IntroductionPullorum disease is one of the common bacterial infectious diseases caused by Salmonella pullorum (S. pullorum), which can result in a decrease in the reproductive performance of laying hens, thus causing considerable economic losses. However, studies about the characteristics of intestinal microbiota with pullorum and their potential association with reproductive performance in hens are still limited. This study was to identify the gut microbiota associated with S. pullorum in poultry.MethodsA total of 30 hens with S. pullorum-negative (PN) and 30 hens with S. pullorum-positive (PP) were analyzed for hatching eggs laid in 2 weeks (HEL), fertilization eggs (FE), chick number (CN), and microbial structure.ResultsThere were significant differences in HEL (p < 0.01), FE (p < 0.01), and CN (p < 0.01) between PP and PN. Histomorphological observations showed abnormal morphology of the ovaries and fallopian tubes and low integrity of epithelial tissue in the ileum and cecum in PP. 16S rRNA gene sequencing revealed that beneficial cecal microbes, such as Bacteroides, Desulfovibrio, and Megamonas, were positively correlated with reproductive performance and had lower abundance in PP (p = 0.001). Furthermore, diminished phosphotransferase system (PTS) and pentose phosphate pathway, butanoate metabolism and oxidative phosphorylation were also found in PP.DiscussionTaken together, this study clarified the morphological characteristics of the reproductive tract and intestines of chickens infected with S. pullorum and preliminarily explored the potential association between cecal microbiota and reproductive performance in hens. Our data may provide a reference for revealing the intestinal microbial characteristics of hens in resisting pullorum and exploring novel approaches to infection control in future studies.

IntroductionRheumatoid arthritis (RA), which affects nearly 1% of the world’s population, is a debilitating autoimmune disease. Bone erosion caused by periarticular osteopenia and synovial pannus formation is the most destructive pathological changes of RA, also leads to joint deformity and loss of function,and ultimately affects the quality of life of patients. Osteoclasts (OCs) are the only known bone resorption cells and their abnormal differentiation and production play an important role in the occurrence and development of RA bone destruction; this remains the main culprit behind RA.MethodBased on the latest published literature and research progress at home and abroad, this paper reviews the abnormal regulation mechanism of OC generation and differentiation in RA and the possible targeted therapy.ResultOC-mediated bone destruction is achieved through the regulation of a variety of cytokines and cell-to-cell interactions, including gene transcription, epigenetics and environmental factors. At present, most methods for the treatment of RA are based on the regulation of inflammation, the inhibition of bone injury and joint deformities remains unexplored.DiscussionThis article will review the mechanism of abnormal differentiation of OC in RA, and summarise the current treatment oftargeting cytokines in the process of OC generation and differentiation to reduce bone destruction in patients with RA, which isexpected to become a valuable treatment choice to inhibit bone destruction in RA.

Gastric cancer, a common malignant disease, seriously endangers human health and life. The high mortality rate due to gastric cancer can be attributed to a lack of effective therapeutic drugs. Cancer cells utilize the glycolytic pathway to produce energy even under aerobic conditions, commonly referred to as the Warburg effect, which is a characteristic of gastric cancer. The identification of new targets based on the glycolytic pathway for the treatment of gastric cancer is a viable option, and accumulating evidence has shown that phytochemicals have extensive anti-glycolytic properties. We reviewed the effects and mechanisms of action of phytochemicals on aerobic glycolysis in gastric cancer cells. Phytochemicals can effectively inhibit aerobic glycolysis in gastric cancer cells, suppress cell proliferation and migration, and promote apoptosis, via the PI3K/Akt, c-Myc, p53, and other signaling pathways. These pathways affect the expressions of HIF-1α, HK2, LDH, and other glycolysis-related proteins. This review further assesses the potential of using plant-derived compounds for the treatment of gastric cancer and sheds insight into the development of new drugs.

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease that can lead to joint deformity and loss of function. Recent studies have shown great progress in the research of mesenchymal stem cells (MSCs) in RA. However, thus far, there have been no bibliometric or visualization analyses in this field. This bibliometric analysis provides a comprehensive overview of the general information and research hotspots of MSCs and RA.MethodsArticles relevant to MSCs and RA, published between 2012 and 2021, were searched using the Web of Science Core Collection database. Irrelevant publications were excluded from the analysis. Bibliometric and visualization analyses were conducted using VOSviewer, CiteSpace, and Scimago Graphica.ResultsA total of 577 articles were analyzed. The annual number of publications increased from 2012 to 2017 and plateaued from 2017 to 2021. China and the USA had the largest number of publications. Collaboration among different organizations mainly occurs between institutes of the same country. Stem Cell Research and Therapy and Frontiers in Immunology were the most popular journals in this field. All the top 20 co-cited authors had a positive co-citation relationship. The top references indicate that MSCs can contribute to RA research and treatment mainly via immunomodulation. From 2012 to 2021, “collagen-induced arthritis,” “immunomodulation,” and “therapy” were some of the keywords associated with MSCs and RA, while “extracellular vesicles” showed a strong keyword burst from 2019 to 2021.ConclusionMSCs and RA have been widely studied in different countries and institutions and by different authors over the last ten years. China and the USA had the largest number of publications. Different types of journals provide admirable sources for researchers. Some keywords, including immunomodulation and extracellular vesicles, may be hot spots in the near future. There will be more basic research and clinical translation of MSCs and RA, and substantial new treatments for RA will soon be developed.

IntroductionThere is an urgent need to address vaccine hesitancy to achieve booster vaccination. This study aimed to reveal the factors associated with vaccine hesitancy (including COVID-19 vaccine) among Chinese residents, address modifications of the factors since the previous year, and propose vaccination rate improvement measures.Materials and methodsThis qualitative return visit study was performed between January and mid-February 2022, following the last interview conducted between February and March 2021. According to an outline designed in advance, 60 Chinese residents from 12 provinces participated in semi-structured interviews.ResultsVaccine safety was the biggest concern raised by respondents, followed by self-immunity and vaccine effectiveness, eliciting concern since the interview last year. Notably, online media accounted for a more significant portion of suggestion sources than before, and fear of pain was a novel factor affecting vaccine hesitancy. Moreover, unlike other areas, those from provinces with a per capita gross domestic product of 3–5 (RMB 10,000) reported less concern about vaccine price and effectiveness. They tended to seek advice via online media less and were greatly influenced by vaccination policies.ConclusionsInfluential factors of vaccine hesitancy among Chinese residents are changing dynamically. Monitoring these trends is essential for public health measures and higher vaccination levels.

Gout renal injury has an insidious onset, no obvious symptoms, and laboratory abnormalities in the early stages of the disease. The injury is not easily detected, and in many cases, the patients have entered the renal failure stage at the time of diagnosis. Therefore, the detection of gout renal injury–related risk factors and early diagnostic biomarkers of gout renal injury is essential for the prevention and early diagnosis of the disease. This article reviews the research progress in risk factors and early diagnostic biomarkers of gout renal injury.

Cell–cell interactions (CCI) play significant roles in manipulating biological functions of cells. Analyzing the differences in CCI between healthy and diseased conditions of a biological system yields greater insight than analyzing either conditions alone. There has been a recent and rapid growth of methods to infer CCI from single-cell RNA-sequencing (scRNA-seq), revealing complex CCI networks at a previously inaccessible scale. However, the majority of current CCI analyses from scRNA-seq data focus on direct comparisons between individual CCI networks of individual samples from patients, rather than “group-level” comparisons between sample groups of patients comprising different conditions. To illustrate new biological features among different disease statuses, we investigated the diversity of key network features on groups of CCI networks, as defined by different disease statuses. We considered three levels of network features: node level, as defined by cell type; node-to-node level; and network level. By applying these analysis to a large-scale single-cell RNA-sequencing dataset of coronavirus disease 2019 (COVID-19), we observe biologically meaningful patterns aligned with the progression and subsequent convalescence of COVID-19.

BackgroundAutoimmune diseases (AIDs) are a class of chronic disabling diseases characterized by inflammation and damage to muscles, joints, bones, and internal organs. Recent studies have shown that much progress has been made in the research of exosomes in AIDs. However, there is no bibliometric analysis in this research field. This study aims to provide a comprehensive overview of the knowledge structure and research hotspots of exosomes in AIDs through bibliometrics.MethodPublications related to exosomes in AIDs from 2002 to 2021 were searched on the web of science core collection (WoSCC) database. VOSviewers, CiteSpace and R package “bibliometrix” were used to conduct this bibliometric analysis.Results312 articles from 48 countries led by China and the United States were included. The number of publications related to exosomes in AIDs is increasing year by year. Central South University, Sun Yat Sen University, Tianjin Medical University and University of Pennsylvania are the main research institutions. Frontiers in immunology is the most popular journal in this field, and Journal of Immunology is the most co-cited journal. These publications come from 473 authors among which Ilias Alevizos, Qianjin Lu, Wei Wei, Jim Xiang and Ming Zhao had published the most papers and Clotilde Théry was co-cited most often. Studying the mechanism of endogenous exosomes in the occurrence and development of AIDs and the therapeutic strategy of exogenous exosomes in AIDs are the main topics in this research field. “Mesenchymal stem cells”, “microRNA”, “biomarkers”, “immunomodulation”, and “therapy” are the primary keywords of emerging research hotspots.ConclusionThis is the first bibliometric study that comprehensively summarizes the research trends and developments of exosomes in AIDs. This information identifies recent research frontiers and hot directions, which will provide a reference for scholars studying exosomes.

Immune checkpoint therapies such as PD-1 blockade have vastly improved the treatment of numerous cancers, including basal cell carcinoma (BCC). However, patients afflicted with pancreatic ductal carcinoma (PDAC), one of the deadliest malignancies, overwhelmingly exhibit negative responses to checkpoint therapy. We sought to combine data analysis and machine learning to differentiate the putative mechanisms of BCC and PDAC non-response. We discover that increased MHC-I expression in malignant cells and suppression of MHC and PD-1/PD-L expression in CD8+ T cells is associated with nonresponse to treatment. Furthermore, we leverage machine learning to predict response to PD-1 blockade on a cellular level. We confirm divergent resistance mechanisms between BCC, PDAC, and melanoma and highlight the potential for rapid and affordable testing of gene expression in BCC patients to accurately predict response to checkpoint therapies. Our findings present an optimistic outlook for the use of quantitative cross-cancer analyses in characterizing immune responses and predicting immunotherapy outcomes.

Kidney disease encompasses a complex set of diseases that can aggravate or start systemic pathophysiological processes through their complex metabolic mechanisms and effects on body homoeostasis. The prevalence of kidney disease has increased dramatically over the last two decades. CD4+CD25+ regulatory T (Treg) cells that express the transcription factor forkhead box protein 3 (Foxp3) are critical for maintaining immune homeostasis and preventing autoimmune disease and tissue damage caused by excessive or unnecessary immune activation, including autoimmune kidney diseases. Recent studies have highlighted the critical role of metabolic reprogramming in controlling the plasticity, stability, and function of Treg cells. They are also likely to play a vital role in limiting kidney transplant rejection and potentially promoting transplant tolerance. Metabolic pathways, such as mitochondrial function, glycolysis, lipid synthesis, glutaminolysis, and mammalian target of rapamycin (mTOR) activation, are involved in the development of renal diseases by modulating the function and proliferation of Treg cells. Targeting metabolic pathways to alter Treg cells can offer a promising method for renal disease therapy. In this review, we provide a new perspective on the role of Treg cell metabolism in renal diseases by presenting the renal microenvironment、relevant metabolites of Treg cell metabolism, and the role of Treg cell metabolism in various kidney diseases.

Vitiligo is the most common depigmenting disorder characterized by white patches in the skin. The pathogenetic origin of vitiligo revolves around autoimmune destruction of melanocytes in which, for instance, oxidative stress is responsible for melanocyte molecular, organelle dysfunction and melanocyte specific antigen exposure as well as melanocyte cell death and thus serves as an important contributor for vitiligo progression. In recent years, natural products have shown a wide range of pharmacological bioactivities against many skin diseases, and this review focuses on the effects and mechanisms of natural compounds against vitiligo models. It is showed that some natural compounds such as flavonoids, phenols, glycosides and coumarins have a protective role in melanocytes and thereby arrest the depigmentation, and, additionally, Nrf2/HO-1, MAPK, JAK/STAT, cAMP/PKA, and Wnt/β-catenin signaling pathways were reported to be implicated in these protective effects. This review discusses the great potential of plant derived natural products as anti-vitiligo agents, as well as the future directions to explore.

Making full use of high fiber and low-cost crop coproducts is helpful to alleviate the situation of people and livestock competing for crops. Digestion of dietary fibers in pigs is mainly through microbial fermentation in the large intestine. To reveal microbiota related to fiber digestion in pigs, fecal samples have been collected from 274 healthy female Suhuai pigs at 160 days of age under the same feeding conditions and have measured apparent neutral detergent fiber (NDF) and acid detergent fiber (ADF) digestibility. Samples from Suhuai pigs with extreme high and low apparent NDF digestibility and extreme high and low apparent ADF digestibility were subjected to shotgun metagenomic sequencing. At the species level, 62 microbial species in H_NDF group and 54 microbial species in H_ADF group were related to high fiber digestibility. Among them, Lachnospiraceae bacterium 3-1 and Alistipes sp. CAG:514 may be new types of microorganisms associated with fiber digestion. In addition, we found that more abundant GH5 and GH48 family (contribute to cellulose degradation) genes, GH39 and GH53 family (contribute to hemicellulose degradation) genes in microorganisms may contribute to the higher apparent NDF digestibility of pigs, and more abundant GH3 and GH9 family (contribute to cellulose degradation) genes in microorganisms may contribute to the higher apparent ADF digestibility of pigs. The abundance of AA4 family (helps in lignin degradation) genes in H_NDF and H_ADF groups was significantly higher than that in L_NDF and L_ADF groups, respectively (P < 0.05). Three pathways in H_NDF group and four pathways in H_ADF group are important pathways associated with degradation of non-starch polysaccharides, and their relative abundance is significantly higher than that in L_NDF and L_ADF groups, respectively. Gut microbiota of Suhuai pigs with high apparent fiber digestibility had higher abundance of genes and microbiota related to fiber digestion and may have stronger fiber digestion potential compared with low apparent fiber digestibility group. This study revealed that the characteristics of gut microbiota and microbial gene functions of pigs with high fiber apparent digestibility, which provided a theoretical basis and reference for further understanding the impact of gut microbiota on fiber digestibility of pigs.

Rheumatoid arthritis (RA) is a common, chronic, systemic autoimmune disease, and its clinical features are the proliferation of joint synovial tissue, the formation of pannus and the destruction of cartilage. The global incidence of RA is about 1%, and it is more common in women. The basic feature of RA is the body’s immune system disorders, in which autoreactive CD4+T cells, pathogenic B cells, M1 macrophages, inflammatory cytokines, chemokines and autoantibodies abnormally increase in the body of RA patients B cell depletion therapy has well proved the important role of B cells in the pathogenesis of RA, and the treatment of RA with B cells as a target has also been paid more and more attention. Although the inflammatory indicators in RA patients receiving B-cell depletion therapy have been significantly improved, the risk of infection and cancer has also increased, which suggests that we need to deplete pathogenic B cells instead of all B cells. However, at present we cannot distinguish between pathogenic B cells and protective B cells in RA patients. In this review, we explore fresh perspectives upon the roles of B cells in the occurrence, development and treatment of RA.

Single-cell RNA sequencing (scRNA-seq) data provides unprecedented information on cell fate decisions; however, the spatial arrangement of cells is often lost. Several recent computational methods have been developed to impute spatial information onto a scRNA-seq dataset through analyzing known spatial expression patterns of a small subset of genes known as a reference atlas. However, there is a lack of comprehensive analysis of the accuracy, precision, and robustness of the mappings, along with the generalizability of these methods, which are often designed for specific systems. We present a system-adaptive deep learning-based method (DEEPsc) to impute spatial information onto a scRNA-seq dataset from a given spatial reference atlas. By introducing a comprehensive set of metrics that evaluate the spatial mapping methods, we compare DEEPsc with four existing methods on four biological systems. We find that while DEEPsc has comparable accuracy to other methods, an improved balance between precision and robustness is achieved. DEEPsc provides a data-adaptive tool to connect scRNA-seq datasets and spatial imaging datasets to analyze cell fate decisions. Our implementation with a uniform API can serve as a portal with access to all the methods investigated in this work for spatial exploration of cell fate decisions in scRNA-seq data. All methods evaluated in this work are implemented as an open-source software with a uniform interface.

Epithelial-to-mesenchymal transition (EMT) plays an important role in many biological processes during development and cancer. The advent of single-cell transcriptome sequencing techniques allows the dissection of dynamical details underlying EMT with unprecedented resolution. Despite several single-cell data analysis on EMT, how cell communicates and regulates dynamics along the EMT trajectory remains elusive. Using single-cell transcriptomic datasets, here we infer the cell–cell communications and the multilayer gene–gene regulation networks to analyze and visualize the complex cellular crosstalk and the underlying gene regulatory dynamics along EMT. Combining with trajectory analysis, our approach reveals the existence of multiple intermediate cell states (ICSs) with hybrid epithelial and mesenchymal features. Analyses on the time-series datasets from cancer cell lines with different inducing factors show that the induced EMTs are context-specific: the EMT induced by transforming growth factor B1 (TGFB1) is synchronous, whereas the EMTs induced by epidermal growth factor and tumor necrosis factor are asynchronous, and the responses of TGF-β pathway in terms of gene expression regulations are heterogeneous under different treatments or among various cell states. Meanwhile, network topology analysis suggests that the ICSs during EMT serve as the signaling in cellular communication under different conditions. Interestingly, our analysis of a mouse skin squamous cell carcinoma dataset also suggests regardless of the significant discrepancy in concrete genes between in vitro and in vivo EMT systems, the ICSs play dominant role in the TGF-β signaling crosstalk. Overall, our approach reveals the multiscale mechanisms coupling cell–cell communications and gene–gene regulations responsible for complex cell-state transitions.

Snail2 has an important role in the epithelial-mesenchymal transition (EMT) and tumor metastasis. Here, we report that Snail2 is highly expressed during TGF-β induced EMT in HL-7702 cells. Additionally, overexpression of Snail2 successfully promotes the migration and invasion of these cells, both in vitro and in a mouse model. Furthermore, our results show that HDAC1 and HDAC3 could suppress the Snail2 gene promoter. Moreover, we find that the acetylation of H3K4 and H3K56 are significantly reduced during the EMT process of liver HL-7702 cells. Thus, our results indicate that HDAC1 and HDAC3 epigenetically suppress the expression of Snail2 during the EMT of liver cells, revealing an opposing function of HDACs during the migration of malignant tumors.

The digestion ability of pigs to dietary fiber is derived from their intestinal microbiota, especially hindgut microbiota. However, tolerance of pigs to high dietary fiber and the changes of microbiota profile with fiber levels are still unclear. To investigate the changes of gut microbiota with dietary fiber and its relationship with fiber digestibility, we conducted comparative analyses of growth rate, apparent fiber digestibility, gut microbiota and volatile fatty acid (VFA) profiles in Chinese Suhuai pigs feeding diets with different defatted rice bran (DFRB) fiber levels. We found that dietary fiber level had no effect on the growth rate of Suhuai pigs. Although the apparent digestibility of Cellulose, insoluble dietary fiber (IDF) and total dietary fiber (TDF) decreased with dietary fiber level, we found that the apparent digestibility of Cellulose, IDF and TDF of Suhuai pigs was not changed when provided with diet containing 19.10% TDF (as feed basis). The pigs provided with diet containing 19.10% TDF had higher microbial richness, proportions of several fiber-degrading bacteria taxa at genus level and predicted microbial functions (such as carbohydrate metabolism, energy metabolism) in cecum compared to those fed with basal diet. In addition, the fiber-induced increasing of fiber-degrading bacteria promoted the VFAs metabolism, which potentially helped Suhuai pigs to maintain growth rate. However, as TDF reached to 24.11% (as feed basis), the apparent digestibility of fiber decreased and the positive effect on intestine microbiota in caecum were absent. Together, our data suggest that appropriate fiber level could increase the diversity and metabolic capacity of distal gut microbiota to improve the utilization efficiency of fiber resources without altering the growth rate of pigs.

Cell fate decisions play a pivotal role in development, but technologies for dissecting them are limited. We developed a multifunction new method, Topographer, to construct a “quantitative” Waddington’s landscape of single-cell transcriptomic data. This method is able to identify complex cell-state transition trajectories and to estimate complex cell-type dynamics characterized by fate and transition probabilities. It also infers both marker gene networks and their dynamic changes as well as dynamic characteristics of transcriptional bursting along the cell-state transition trajectories. Applying this method to single-cell RNA-seq data on the differentiation of primary human myoblasts, we not only identified three known cell types, but also estimated both their fate probabilities and transition probabilities among them. We found that the percent of genes expressed in a bursty manner is significantly higher at (or near) the branch point (~97%) than before or after branch (below 80%), and that both gene-gene and cell-cell correlation degrees are apparently lower near the branch point than away from the branching. Topographer allows revealing of cell fate mechanisms in a coherent way at three scales: cell lineage (macroscopic), gene network (mesoscopic), and gene expression (microscopic).

Improving the relative abundance of bacteria and their activity is still the basis for the efficient operation of anammox process. Here, biomagnetic effect was used to promote anammox granules. Batch test results show that the application of an electromagnetic field (EMF) with a strength of 0.09 μT increased the nitrogen removal performance of anammox by 32.44% while higher strength EMF of 0.20 and 0.25 μT inhibited the activity of anammox bacteria. Long-term experiment indicated that the addition of EMF with a strength of 0.09 μT greatly improved nitrogen removal performance of the granular sludge, especially the total nitrogen removal performance increased by 15.3%. After 120 days of reactor operation, the nitrogen loading rate was increased to 6.4 kg N/m3/d, and the total nitrogen removal rate of the reactors with and without EMF addition reached 4.92 kg N/m3/d and 4.25 kg N/m3/d, respectively. Throughout the experiment, the removal rate of NH4+-N and NO2−-N of anammox reactor with 0.09 μT EMT addition was always higher than that without EMF addition. The high-throughput sequencing analysis showed that the proportion of Candidatus Brocadia in reactors with and without EMF addition were 21.3% and 15.8%, respectively. The application of EMF with an intensity of 0.09 μT increased the relative abundance of the main anammox bacteria. 70 kos were enriched under EMF conditions, including ko00780 (Biotin metabolism), ko00540 (Lipopolysaccharide biosynthesis), ko00590 (Arachidonic acid metabolism). 51 kos like ko03030 (DNA replication) decreased after EMF addition. This study demonstrates the feasibility of EMF to promote anammox and expands the application of EMF in wastewater treatment.

Bayesian uncertainty quantification has a pivotal role in structural identification, yet the posterior distribution estimation of unknown parameters and system responses is still a challenging task. This study explores a novel method, named manifold-constrained Gaussian processes (GPs), for the probabilistic identification of multi-DOF structural dynamical systems, taking shear-type frames subjected to ground motion as a demonstrative paradigm. The key idea of the method is to restrict the GPs (priorly defined over system responses) on a manifold that satisfies the equation of motion of the structural system. In contrast to widely used Bayesian probabilistic model updating methods, the manifold-constrained GPs avoid the numerical integration when formulating the joint probability density function of unknown parameters and system responses, hence achieving an accurate and computationally efficient inference for the posterior distributions. An eight-storey shear-type frame is analyzed as a case study to demonstrate the effectiveness of the manifold-constrained GPs. The results indicate the posterior distributions of system responses, and unknown parameters can be successfully identified, and reliable probabilistic model updating can be achieved.

Aging-related neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are gradually becoming the primary burden of society and cause significant health-care concerns. Aging is a critical independent risk factor for neurodegenerative diseases. The pathological alterations of neurodegenerative diseases are tightly associated with mitochondrial dysfunction, inflammation, and oxidative stress, which in turn stimulates the further progression of neurodegenerative diseases. Given the potential research value, lncRNAs have attracted considerable attention. LncRNAs play complex and dynamic roles in multiple signal transduction axis of neurodegeneration. Emerging evidence indicates that lncRNAs exert crucial regulatory effects in the initiation and development of aging-related neurodegenerative diseases. This review compiles the underlying pathological mechanisms of aging and related neurodegenerative diseases. Besides, we discuss the roles of lncRNAs in aging. In addition, the crosstalk and network of lncRNAs in neurodegenerative diseases are also explored.

Practical application of the partial nitritation–anaerobic ammonium oxidation (anammox) process has attracted increasing attention because of its low operational costs. However, the nitritation process, as a promising way to supply nitrite for anammox, is sensitive to the variations in substrate concentration and dissolved oxygen (DO) concentration. Therefore, a stable supply of nitrite becomes a real bottleneck in partial nitritation–anammox process, limiting their potential for application in mainstream wastewater treatment. In this study, five 18-L sequencing batch reactors were operated in parallel at room temperature (22°C ± 4°C) to explore the nitritation performance with different carrier materials, including sepiolite-nonwoven carrier (R1), zeolite-nonwoven carrier (R2), brucite-nonwoven carrier (R3), polyurethane carrier (R4), and nonwoven carrier (R5). The ammonia oxidation rate (AOR) in R1 reached the highest level of 0.174 g-N L−1 d−1 in phase II, which was 1.4-fold higher than the control reactor (R4). To guarantee a stable supply of nitrite for anammox process, the nitrite accumulation efficiency (NAE) was always higher than 77%, even though the free ammonia (FA) decreases to 0.08 mg-N/L, and the pH decreases to 6.8 ± 0.3. In phase V, the AOR in R1 reached 0.206 g-N L−1 d−1 after the DO content increase from 0.7 ± 0.3 mg/L to 1.7 ± 0.3 mg/L. The NAE in R1 was consistently higher than 68.6%, which was much higher than the other reactor systems (R2: 43.8%, R3: 46.6%, R4: 23.7%, R5: 22.7%). Analysis of 16S rRNA gene sequencing revealed that the relative abundance of Nitrobacter and Nitrospira in R1 was significantly lower than other reactors, indicating that the sepiolite carrier plays an important role in the inhibition of nitrite-oxidizing bacteria. These results indicate that the sepiolite nonwoven composite carrier can effectively improve the nitritation process, which is highly beneficial for the application of partial nitritation–anammox for mainstream wastewater treatment.

This study assessed the activity and community structure in different types of sludge to reveal the partition mechanism of anammox and nitrifiers in a full-scale partial nitrification–anammox plant. Batch experiments confirmed that suspended sludge had higher partial nitrification capacity, and biofilm sludge had higher anammox activity, 16.9 times higher than suspended sludge. qPCR analysis confirmed that the amoA gene was mainly present in suspended sludge, and the highest abundance of the Amx gene was observed in biofilm sludge, reaching 1.01 × 107 copies/ng DNA. High-throughput results revealed that Nitrosomonas was the main ammonia-oxidizing bacteria with high activity in suspended sludge, and Candidatus Brocadia had the highest abundance of 13.4% in biofilm sludge. This is the exploration of the microbial community of three different sludge types in the full-scale sidestream PN/A system for the first time, which can guide the construction and replication of full-scale PN/A plants.

Atherosclerosis, a complex chronic inflammatory disease, involves multiple alterations of diverse cells, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), monocytes, macrophages, dendritic cells (DCs), platelets, and even mesenchymal stem cells (MSCs). Globally, it is a common cause of morbidity as well as mortality. It leads to myocardial infarctions, stroke and disabling peripheral artery disease. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that secreted by multiple cell types and play a central role in cell-to-cell communication by delivering various bioactive cargos, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence demonstrated that miRNAs and lncRNAs in EVs are tightly associated with the initiation and development of atherosclerosis. In this review, we will outline and compile the cumulative roles of miRNAs and lncRNAs encapsulated in EVs derived from diverse cells in the progression of atherosclerosis. We also discuss intercellular communications via EVs. In addition, we focused on clinical applications and evaluation of miRNAs and lncRNAs in EVs as potential diagnostic biomarkers and therapeutic targets for atherosclerosis.