ABSTRACT
The immune system is a major regulatory system of the body, that is composed of immune cells, immune organs, and related signaling factors. As an organism ages, observable age-related changes in the function of the immune system accumulate in a process described as 'immune aging. Research has shown that the impact of aging on immunity is detrimental, with various dysregulated responses that affect the function of immune cells at the cellular level. For example, increased aging has been shown to result in the abnormal chemotaxis of neutrophils and decreased phagocytosis of macrophages. Age-related diminished functionality of immune cell types has direct effects on host fitness, leading to poorer responses to vaccination, more inflammation and tissue damage, as well as autoimmune disorders and the inability to control infections. Similarly, age impacts the function of the immune system at the organ level, resulting in decreased hematopoietic function in the bone marrow, a gradual deficiency of catalase in the thymus, and thymic atrophy, resulting in reduced production of related immune cells such as B cells and T cells, further increasing the risk of autoimmune disorders in the elderly. As the immune function of the body weakens, aging cells and inflammatory factors cannot be cleared, resulting in a cycle of increased inflammation that accumulates over time. Cumulatively, the consequences of immune aging increase the likelihood of developing age-related diseases, such as Alzheimer's disease, atherosclerosis, and osteoporosis, among others. Therefore, targeting the age-related changes that occur within cells of the immune system might be an effective anti-aging strategy. In this article, we summarize the relevant literature on immune aging research, focusing on its impact on aging, in hopes of providing new directions for anti-aging research.
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BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. NAFLD leads to liver fibrosis and hepatocellular carcinoma, and it also has systemic effects associated with metabolic diseases, cardiovascular diseases, chronic kidney disease, and malignant tumors. Therefore, it is important to diagnose NAFLD early to prevent these adverse effects. METHODS: The GSE89632 dataset was downloaded from the Gene Expression Omnibus database, and then the optimal genes were screened from the data cohort using lasso and Support Vector Machine Recursive Feature Elimination (SVM-RFE). The ROC values of the optimal genes for the diagnosis of NAFLD were calculated. The relationship between optimal genes and immune cells was determined using the DECONVOLUTION algorithm CIBERSORT. Finally, the specificity and sensitivity of the diagnostic genes were verified by detecting the expression of the diagnostic genes in blood samples from 320 NAFLD patients and liver samples from 12 mice. RESULTS: Through machine learning we identified FOSB, GPAT3, RGCC and RNF43 were the key diagnostic genes for NAFLD, and they were further demonstrated by a receiver operating characteristic curve analysis. We found that the combined diagnosis of the four genes identified NAFLD samples well from normal samples (AUC = 0.997). FOSB, GPAT3, RGCC and RNF43 were strongly associated with immune cell infiltration. We also experimentally examined the expression of these genes in NAFLD patients and NAFLD mice, and the results showed that these genes are highly specific and sensitive. CONCLUSIONS: Data from both clinical and animal studies demonstrate the high sensitivity, specificity and safety of FOSB, GPAT3, RGCC and RNF43 for the diagnosis of NAFLD. The relationship between diagnostic key genes and immune cell infiltration may help to understand the development of NAFLD. The study was reviewed and approved by Ethics Committee of Tianjin Second People's Hospital in 2021 (ChiCTR1900024415).
Subject(s)
Non-alcoholic Fatty Liver Disease , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/diagnosis , Humans , China , Animals , ROC Curve , Reproducibility of Results , Mice , Mice, Inbred C57BL , Male , Databases, Genetic , Gene Expression Profiling , Support Vector Machine , Gene Expression RegulationABSTRACT
The modification of RNA through the N6-methyladenosine (m6A) has emerged as a growing area of research due to its regulatory role in gene expression and various biological processes regulating the expression of genes. m6A RNA methylation is a post-transcriptional modification that is dynamic and reversible and found in mRNA, tRNA, rRNA, and other non-coding RNA of most eukaryotic cells. It is executed by special proteins known as "writers," which initiate methylation; "erasers," which remove methylation; and "readers," which recognize it and regulate the expression of the gene. Modification by m6A regulates gene expression by affecting the splicing, translation, stability, and localization of mRNA. Aging causes molecular and cellular damage, which forms the basis of most age-related diseases. The decline in skeletal muscle mass and functionality because of aging leads to metabolic disorders and morbidities. The inability of aged muscles to regenerate and repair after injury poses a great challenge to the geriatric populace. This review seeks to explore the m6A epigenetic regulation in the myogenesis and regeneration processes in skeletal muscle as well as the progress made on the m6A epigenetic regulation of aging skeletal muscles.
Subject(s)
Adenosine , Aging , Epigenesis, Genetic , Muscle, Skeletal , Humans , Aging/genetics , Aging/metabolism , Adenosine/analogs & derivatives , Adenosine/metabolism , Animals , Muscle, Skeletal/metabolism , Transcriptome , Muscle Development/genetics , MethylationABSTRACT
Currently, there are increasingly diverse treatment modalities for chronic functional constipation (CFC). This study aims to compare the relative efficacy and safety of chemical drugs, fecal microbiota transplantation (FMT), probiotics, dietary fiber, and acupuncture in the treatment of patients with CFC. We searched relevant randomized controlled trials (RCTs) published in five databases up to November 2023. Network meta-analysis (NMA) was carried out using R Studio 4.2.1. Cumulative ranking probability plots, assessed through the surface under the cumulative ranking (SUCRA), were employed to rank the included drugs for various outcome measures. We included a total of 45 RCT studies with 17â 118 patients with CFC. From the SUCRA values and NMA results FMT showed the best utility in terms of clinical efficacy, Bristol stool form scale scores, patient assessment of constipation quality of life scores, and the treatment modality with the lowest ranked incidence of adverse effects was electroacupuncture. Subgroup analysis of the chemotherapy group showed that sodium A subgroup analysis of the chemical group showed that sodium picosulfate 10â mg had the highest clinical efficacy. FMT is more promising in the treatment of CFC and may be more effective in combination with the relatively safe treatment of acupuncture.
Subject(s)
Acupuncture Therapy , Constipation , Dietary Fiber , Fecal Microbiota Transplantation , Probiotics , Constipation/therapy , Constipation/microbiology , Humans , Fecal Microbiota Transplantation/adverse effects , Dietary Fiber/therapeutic use , Probiotics/therapeutic use , Probiotics/adverse effects , Chronic Disease , Acupuncture Therapy/methods , Treatment Outcome , Network Meta-Analysis , Randomized Controlled Trials as Topic , Quality of Life , Laxatives/therapeutic useABSTRACT
Multiple epigenetic factors play a regulatory role in maintaining the homeostasis of cutaneous components and are implicated in the aging process of the skin. They have been associated with the activation of the senescence program, which is the primary contributor to age-related decline in the skin. Senescent species drive a series of interconnected processes that impact the immediate surroundings, leading to structural changes, diminished functionality, and heightened vulnerability to infections. Geroprotective medicines that may restore the epigenetic balance represent valid therapeutic alliances against skin aging. Most of them are well-known Western medications such as metformin, nicotinamide adenine dinucleotide (NAD+), rapamycin, and histone deacetylase inhibitors, while others belong to Traditional Chinese Medicine (TCM) remedies for which the scientific literature provides limited information. With the help of the Geroprotectors.org database and a comprehensive analysis of the referenced literature, we have compiled data on compounds and formulae that have shown potential in preventing skin aging and have been identified as epigenetic modulators.
Subject(s)
Epigenesis, Genetic , Skin Aging , Humans , Epigenesis, Genetic/drug effects , Skin Aging/drug effects , Skin Aging/genetics , Animals , Skin/metabolism , Skin/drug effects , Medicine, Chinese Traditional/methods , Protective Agents/pharmacologyABSTRACT
Tumor immunotherapy can be a suitable cancer treatment option in certain instances. Here we investigated the potential immunomodulatory effect of oral glycyrrhiza polysaccharides (GCP) on the antitumor function of γδT cells in intestinal epithelial cells in mice. We found that GCP can inhibit tumor growth and was involved in the regulation of systemic immunosuppression. GCP administration also promoted the differentiation of gut epithelia γδT cells into IFN-γ-producing subtype through regulation of local cytokines in gut mucosa. GCP administration increased local cytokine levels through gut microbiota and the gut mucosa Toll-like receptors / nuclear factor kappa-B pathway. Taken together, our results suggest that GCP might be a suitable candidate for tumor immunotherapy, although further clinical research, including clinical trials, are required to validate these results.
Subject(s)
Gastrointestinal Microbiome , Glycyrrhiza , NF-kappa B , Polysaccharides , Animals , Gastrointestinal Microbiome/drug effects , Mice , NF-kappa B/metabolism , Polysaccharides/pharmacology , Glycyrrhiza/chemistry , Toll-Like Receptors/metabolism , Signal Transduction/drug effects , Mice, Inbred C57BL , Intestinal Mucosa/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/microbiology , Antineoplastic Agents/pharmacologyABSTRACT
Neurodegenerative diseases (NDDs) remain a global health challenge. Previous studies have reported potential links between environmental factors and NDDs, however, findings remain controversial across studies and elusive to be interpreted as evidence of robust causal associations. In this study, we comprehensively explored the causal associations of the common environmental factors with major NDDs including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), based on updated large-scale genome-wide association study data through two-sample Mendelian randomization (MR) approach. Our results indicated that, overall, 28 significant sets of exposure-outcome causal association evidence were detected, 12 of which were previously underestimated and newly identified, including average weekly beer plus cider intake, strenuous sports or other exercises, diastolic blood pressure, and body fat percentage with AD, alcohol intake frequency with PD, apolipoprotein B, systolic blood pressure, and forced expiratory volume in 1â¯s (FEV1) with ALS, and alcohol intake frequency, hip circumference, forced vital capacity, and FEV1 with MS. Moreover, the causal effects of several environmental factors on NDDs were found to overlap. From a triangulation perspective, our investigation provided insights into understanding the associations of environmental factors with NDDs, providing causality-oriented evidence to establish the risk profile of NDDs.
Subject(s)
Alzheimer Disease , Amyotrophic Lateral Sclerosis , Exposome , Multiple Sclerosis , Parkinson Disease , Humans , Amyotrophic Lateral Sclerosis/genetics , Genome-Wide Association Study , Mendelian Randomization Analysis , Alzheimer Disease/genetics , Multiple Sclerosis/geneticsABSTRACT
Bergamot essential oil (BEO) is an extract of the bergamot fruit with significant neuroprotective effect. This study was to investigate the effects and the underlying mechanism of BEO in mitigating depression. GC-MS were used to identify its constituents. Antidepressive properties of BEO were evaluated by sucrose preference test (SPT), force swimming test (FST) and open field test (OFT). Nissl staining was used to determine the number of Nissl bodies in hippocampus (HIPP) of rats. Changes in HIPP dendritic length and dendritic spine density were detected by Golgi-Cox staining. Immunohistochemistry and Western blot were used to detect the postsynaptic density protein-95 (PSD-95) and synaptophysin (SYP) in the HIPP of rats. The enzyme-linked immunosorbent assay was used to determine the 5-hydroxytryptamine (5-HT), insulin-like growth factor 1 (IGF-1) and interleukin-1ß (IL-1ß) in the HIPP, serum and cerebrospinal fluid (CSF) of rats. Inhaled BEO significantly improved depressive behaviour in chronic unpredictable mild stress (CUMS) rats. BEO increased Nissl bodies, dendritic length and spine density, PSD-95 and SYP protein in the HIPP. Additionally, BEO upregulated serum 5-HT, serum and CSF IGF-1, while downregulating serum IL-1ß. Collectively, inhaled BEO mitigates depression by protecting the plasticity of hippocampal neurons, hence, providing novel insights into treatment of depression.
Subject(s)
Depression , Oils, Volatile , Rats , Animals , Depression/drug therapy , Depression/etiology , Depression/metabolism , Oils, Volatile/pharmacology , Oils, Volatile/metabolism , Insulin-Like Growth Factor I/metabolism , Serotonin/metabolism , Hippocampus/metabolism , Disks Large Homolog 4 Protein/metabolism , Neurons/metabolism , Stress, Psychological/complications , Stress, Psychological/drug therapy , Disease Models, Animal , Behavior, AnimalABSTRACT
Human umbilical cord mesenchymal stem cells (hUMSCs) belong to a multipotent stem cell population. Transplantation of icariin (ICA)-treated hUMSCs have better tissue repairing function in chronic liver injury. This study was to investigate whether the tissue-repairing effects and migration of hUMSCs after ICA treatment were regulated by circular RNAs (circRNAs). ICA was used to treat hUMSCs in vitro for 1 week and the expression profiles of circRNAs were generated using RNA sequencing. Differentially expressed circRNAs in hUMSCs after ICA intervention were screened. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were carried out to predict the potential function of dysregulated circRNAs. There were 52 differentially expressed circRNAs (32 circRNAs up-regulated and 20 circRNAs down-regulated) with fold changeâ ≥2.0 before and after ICA treatment. ADP-ribosylation factors were associated with the dysregulated circRNAs among Gene Ontology analysis. Kyoto Encyclopedia of Genes and Genomes analysis showed that only endocytosis pathway was associated with up-regulated circRNAs, whereas 4 pathways including homologous recombination, RNA transport, axon guidance, and proteoglycans in cancer were related to down-regulated circRNAs. Fifty-two differentially expressed circRNAs and 238 predicted microRNAs were included in circRNAs-microRNAs network. The mechanism of ICA inducing hUMSCs migration may be through regulating circRNAs expression which affects ADP-ribosylation factors protein signal pathways.
Subject(s)
Flavonoids , Mesenchymal Stem Cells , MicroRNAs , Humans , RNA, Circular/genetics , MicroRNAs/genetics , Umbilical Cord , ADP-Ribosylation Factors/genetics , Gene Expression ProfilingABSTRACT
BACKGROUND: Chronic intestinal inflammatory diseases play a crucial role in the onset of colorectal cancer (CRC). Effectively impeding the progression of colitis-associated colorectal cancer (CAC) can be instrumental in hindering CRC development. Wu-Mei-Pill (WMP), a formulation comprising various herbal extracts, is clinically employed for CAC treatment, yet the underlying mechanism of WMP's efficacy in CAC remains unclear. Our study firstly demonstrated the effects and mechanisms of WMP on transcriptional and metabolic levels based on integrated transcriptomics and untargeted metabolomics and relative experimental validations. MATERIALS AND METHODS: A CAC mouse model was established through a single injection of azoxymethane (AOM) followed by intermittent dextran sodium sulfate (DSS) intervention, with subsequent WMP administration. Initially, the therapeutic impact of WMP on the CAC model was assessed by observing survival rate, body weight change, colon length, tumor number, tumor load, and pathological changes in the colon tissue of CAC mice post-WMP intervention. Subsequently, differential genes and metabolites in the colorectal tissue of CAC mice following WMP intervention were identified through transcriptomics and non-targeted metabolomics. Finally, the influence of WMP on the peroxisome proliferator activated receptor (PPAR) pathway, Wnt pathway, and CC motif chemokine ligand 3 (CCL3)/ CC motif chemokine receptor 1 (CCR1) axis in CAC mice was verified through western blot, immunofluorescence, and ELISA based on the results of transcriptomics and non-targeted metabolomics. RESULTS: WMP intervention enhanced survival, alleviated body weight loss, shortened colon length, tumor occurrence, and pathological changes in the colorectal tissue of CAC mice, such as glandular damage, tumourigenesis, and inflammatory cell infiltration. Transcriptomic and non-targeted metabolomic results revealed that WMP intervention up-regulated the expression of key regulatory mechanisms of fatty acid oxidation PPAR pathway-related genes (Pparg, Ppara, Cpt1a, and Acadm) and metabolites (L-carnitine and L-palmitoylcarnitine). Additionally, it down-regulated Wnt pathway-related genes (Wnt3, Axin2, Tcf7, Mmp7, Lgr5, Wnt5a, Fzd6, Wnt7b, Lef1, and Fzd10 etc.) and pro-inflammatory related genes (Il1b, Il6, Il17a, Ccl3, and Ccr1 etc.). Experimental validation demonstrated that WMP up-regulated PPAR pathway-related proteins [PPARγ, PPARα, carnitine palmitoyltransferase 1A (CPT1A), and acyl-CoA dehydrogenase medium chain (ACADM)] in the colorectal tissue of CAC mice. It also down-regulated Wnt pathway-related proteins [ß-catenin, T-cell factor (TCF), lymphoid enhancer-binding factor (LEF), and matrix metallopeptidase 7 (MMP7)], inhibited the nuclear translocation of the key transcription factor ß-catenin in the Wnt pathway, and suppressed epithelial-to-mesenchymal transition (EMT) activation induced by the Wnt pathway (up-regulated E-cadherin and down-regulated Vimentin). Furthermore, WMP intervention reduced pro-inflammatory factors [interleukin (IL)-6, IL-1ß, and IL-17A] and decreased CCL3/CCR1 axis factors, including CCL3 protein levels and diminished F4/80+CCR1+ positive expressed cells. CONCLUSION: WMP significantly inhibits CAC tumorigenesis by up-regulating PPARα-mediated fatty acid oxidation, inhibiting the Wnt signaling pathway-mediated EMT, and suppressing CCL3/CCR1-mediated inflammatory responses.
Subject(s)
Azoxymethane , Colitis-Associated Neoplasms , Dextran Sulfate , Disease Models, Animal , Drugs, Chinese Herbal , Metabolomics , Transcriptome , Animals , Drugs, Chinese Herbal/pharmacology , Mice , Male , Colorectal Neoplasms , Mice, Inbred C57BL , Colon/drug effects , Colon/pathology , Colon/metabolism , Colitis/chemically inducedABSTRACT
One of the difficulties in the treatment of hepatocellular carcinoma is that it is impossible to eliminate the inhibitory effect of the tumor microenvironment on immune response. Therefore, it is particularly important to understand the formation process of the tumor microenvironment. Chronic inflammation is the core factor of cancer occurrence and the leading stage of inflammation-cancer transformation, and the natural killer cell subsets play an important role in it. Our study confirmed that in the stage of chronic liver injury, the local immunosuppressive microenvironment of the liver (i.e. the damaged microenvironment) has been formed, but this inhibitory effect is only for peripheral natural killer cells and has no effect on tissue-resident natural killer subsets. The markers of damage microenvironment are the same as those of tumor microenvironment.
Subject(s)
Inflammation , Killer Cells, Natural , Killer Cells, Natural/immunology , Animals , Inflammation/immunology , Inflammation/pathology , Liver/pathology , Liver/immunology , Male , Humans , Tumor Microenvironment/immunology , Chronic DiseaseABSTRACT
The changes in T regulatory cell (Treg) and T helper cell (Th) 17 ratios holds paramount importance in ensuring internal homeostasis and disease progression. Recently, novel subsets of Treg and Th17, namely IL-17-producing Treg and IL-10-producing Th17 have been identified. IL-17-producing Treg and IL-10-producing Th17 are widely considered as the intermediates during Treg/Th17 transformation. These "bi-functional" cells exhibit plasticity and have been demonstrated with important roles in multiple physiological functions and disease processes. Yin and Yang represent opposing aspects of phenomena according to the ancient Chinese philosophy "Yin-Yang" theory. Furthermore, Yin can transform into Yang, and vice versa, under specific conditions. This theory has been widely used to describe the contrasting functions of immune cells and molecules. Therefore, immune-activating populations (Th17, M1 macrophage, etc.) and immune overreaction (inflammation, autoimmunity) can be considered Yang, while immunosuppressive populations (Treg, M2 macrophage, etc.) and immunosuppression (tumor, immunodeficiency) can be considered Yin. However, another important connotation of "Yin-Yang" theory, the conversion between Yin and Yang, has been rarely documented in immune studies. The discovery of IL-17-producing Treg and IL-10-producing Th17 enriches the meaning of "Yin-Yang" theory and further promotes the relationship between ancient "Yin-Yang" theory and modern immunology. Besides, illustrating the functions of IL-17-producing Treg and IL-10-producing Th17 and mechanisms governing their differentiation provides valuable insights into the mechanisms underlying the dynamically changing statement of immune statement in health and diseases.
Subject(s)
Interleukin-17 , T-Lymphocytes, Regulatory , Humans , Interleukin-10 , Th17 Cells , InflammationABSTRACT
Nutritional supplements have been used to improve immune function. Condensed fuzheng extract (CFE) is a well-known traditional Chinese medicine (TCM) formula that is predominantly made from sheep placenta, Astragalus mongholicus Bunge, and Polygonatum kingianum Collett & Hemsl. However, the toxicological profile of CFE has not been determined. In this study, we investigated the acute (14 days) and sub-chronic (90 days) oral toxicities of CFE in mice and rats and the phytochemical composition of CFE. Materials and methods: For the assessment of acute toxicity, 80 ICR mice of both sexes were randomly divided into four groups. Three groups were treated with 4500, 2250 and 1125 mg/kg/d bw CFE daily (n = 10/group per sex) for 14 days; a separate group was used as control. To test the sub-chronic toxicity, male and female Sprague Dawley rats were orally administered 8150, 4075 or 2037 mg/kg bw of CFE for 90 days; a control group was included. Hematological, biochemical, and histopathological markers were tested at the end of the experiment. The chemical composition of CFE was determined by UPLC-HRMS method. Results: In both acute and sub-chronic toxicity studies, no mortalities, indications of abnormality, or treatment-related adverse effects were observed. The LD50 of CFE was higher than 4500 mg/kg. There were no significant changes in the hematological and biochemical data in the treatment group compared with the control group (p > 0.05). Histopathological analyses of the heart, liver, spleen, lungs, kidneys, thymus, testes (male rats) and ovaries (female rats) revealed no anatomical changes of each organ. Phytochemical analysis of CFE revealed the presence of flavonoids (highest abundance), phenols and alkaloids. In conclusion, our results showed that CFE is a safe and non-toxic formula. We also reported phytochemicals in CFE that may possess important pharmacological effects.
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Stress-mediated depression is one of the common psychiatric disorders with a high prevalence and suicide rate, there is a lack of effective treatment. Accordingly, effective treatments with few adverse effects are urgently needed. Pro-inflammatory cytokines (PICs) may play a key role in stress-mediated depression. Thereupon, both preclinical and clinical studies have found higher levels of IL-1ß, TNF-α and IL-6 in peripheral blood and brain tissue of patients with depression. Recent studies have found PICs cause depression by affecting neuroinflammation, monoamine neurotransmitters, hypothalamic pituitary adrenal axis and neuroplasticity. Moreover, they play an important role in the symptom, development and progression of depression, maybe a potential diagnostic and therapeutic marker of depression. In addition, well-established antidepressant therapies have some relief on high levels of PICs. Importantly, anti-inflammatory drugs relieve depressive symptoms by reducing levels of PICs. Collectively, reducing PICs may represent a promising therapeutic strategy for depression.
Subject(s)
Cytokines , Mental Disorders , Humans , Cytokines/metabolism , Depression/drug therapy , Depression/etiology , Hypothalamo-Hypophyseal System/metabolism , Pituitary-Adrenal System/metabolismABSTRACT
Background: Immunosenescence, an age-related deficit in immunity, associated with multiple disorders and making the successful aging a challenge. Although nearly 4000 articles have been published, only few review articles have summarized the research status. In order to better understand the most recent advances, hotspots and development trends in immunosenescence, it is very necessary to conduct a comprehensive bibliometric analysis. Hence, commonly used bibliometric analysis software CiteSpace and VOSviewer were employed to conduct a quantitative analysis and critical evaluation of publications in this study. Methods: Immunosenescence publications were screened from the Web of Science Core Collection (WoSCC). Microsoft Excel 2021, CiteSpace 5.8.R3, and VOSviewer 1.6.17 were used for bibliometric study. Results: A total of 3875 publications were retrieved from WoSCC. After screening by document type (article or review) (352 publications were excluded) and language of English (85 were excluded), 3438 studies were finally used for bibliometric analysis. The literature on immunosenescence had been continuously growing since 1991, and by 2020 it has skyrocketed 312 publications from 240 in 2019. USA (1111 publications, 35.01%) was the leading country of publications, followed by ITALY (379, 11.94%) and ENGLAND (366, 11.53%). Of the authors, Pawelec G from the Tubingen University of GERMANY contributed the greatest articles (93 publications). All the keywords could be divided into five clusters, and additional potent visualization bursts revealed that "gut microbiota," "health," "dysfunction," and "nivolumab" were the active hotspots presently. Conclusion: Based on the current data, we firstly concluded that there will be a dramatically rising publications on immunosenescence, and research teams from USA or GERMANY might be the best chooses for collaboration. Moreover, We particularly emphasized the development potential of mechanism and intervening strateges like "gut microbiota" and "nivolumab" in immunosenescence. We hope to provide new ideas for promoting the basic research and clinical application of immunosenescence.
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Bazi Bushen, a Chinese-patented drug with the function of relieving fatigue and delaying ageing, has been proven effective for extenuating skin senescence. To investigate the potential mechanism, senescence-accelerated mouse prone 6 (SAMP6) was intragastrically administered with Bazi Bushen for 9 weeks to induce skin homeostasis. Skin homeostasis is important in mitigating skin senescence, and it is related to many factors such as oxidative stress, SASP, apoptosis, autophagy and stem cell. In our study, skin damage in SAMP6 mice was observed using HE, Masson and SA-ß-gal staining. The content of hydroxyproline and the activities of SOD, MDA, GSH-PX and T-AOC in the skin were measured using commercial assay kits. The level of SASP factors (IL-6, IL-1ß, TNF-α, MMP2 and MMP9) in skin were measured using ELISA kits. The protein expressions of p16, p21, p53, Bax, Bcl-2, Cleaved caspase-3, LC3, p62, Beclin1, OCT4, SOX2 and NANOG were measured by western blotting. The expression of ITGA6 and COL17A1 was measured by immunofluorescence staining and western blotting. Our findings demonstrated that Bazi Bushen alleviated skin senescence by orchestrating skin homeostasis, reducing the level of oxidative stress and the expression of SASP, regulating the balance of apoptosis and autophagy and enhancing the protein expressions of ITGA6 and COL17A1 to improve skin structure in SAMP6 mice. This study indicated that Bazi Bushen could serve as a potential therapy for alleviating skin senescence.
Subject(s)
Aging , Skin , Animals , Mice , Apoptosis , Autophagy , Beclin-1ABSTRACT
OBJECTIVE: Infections and death have been a part of our daily lives since the COVID-2019 pandemic outbreak in 2019, and the societal and economic consequences have lingered for an unanticipated duration. Novel and effective treatments are still desperately needed around the world to combat the infection. Here, we discovered a novel traditional Chinese medicine formula (TCMF) to potentially combat COVID-19 through reverse systematic pharmacology (disease â targets â TCMF â disease). METHODS: Combining Integrative network pharmacology and the traditional Chinese medicine (TCM) theory, a TCMF for COVID-19 was identified. In silico physiological interactions between herbs and disease hub targets were validated by molecular docking and dynamics simulation. RESULTS: Based on disease-related gene/pathway targets and a combination of reverse pharmacology and TCM meridian tropism theory, a COVID-19-associated herb database was constructed. A new TCMF, including Gancao, Baitouweng, Congbai, and Diyu (GBCD), was discovered for anti-COVID-19 therapy. The KEGG and GO analyses of 49 intersecting genes suggested that GBCD could combat COVID-19 through antiviral, antiinflammation, immunoregulation, and cytoprotection activities. Moreover, these possible effects were validated through docking and MD simulation. CONCLUSIONS: To the best of our knowledge, this study is the first to combine reverse pharmacology and meridian tropism theories for TCMF development, and a novel herbal combination, GBCD, was discovered for anti-COVID-19 therapy.
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BACKGROUND: Bazi Bushen is a Chinese patented medicine with multiple health benefits and geroprotective effects, yet, no research has explored its effects on intestinal homeostasis. In this study, we aimed to investigate the effect of Bazi Bushen on intestinal inflammation and the potential mechanism of gut microbiota dysbiosis and intestinal homeostasis in senescence-accelerated mouse prone 6 (SAMP6). The hematoxylin and eosin (H&E) staining and immunohistochemistry were performed to assess the function of the intestinal mucosal barrier. The enzyme-linked immunosorbent assay (ELISA) and Western blotting were used to determine the level of intestinal inflammation. The aging-related ß-galactosidase (SA-ß-gal) staining and Western blotting were used to measure the extent of intestinal aging. The 16S ribosomal RNA (16S rRNA) was performed to analyze the change in gut microbiota composition and distribution. RESULTS: Bazi Bushen exerted remarkable protective effects in SAMP6, showing a regulated mucosal barrier and increased barrier integrity. It also suppressed intestinal inflammation through down-regulating pro-inflammatory cytokines (IL-6, IL-1ß, and TNF-α) and inhibiting TLR4/NFκB signaling pathway (MYD88, p-p65, and TLR4). Bazi Bushen improved intestinal aging by reducing the area of SA-ß-gal-positive cells and the expression of senescence markers p16, p21, and p53. In addition, Bazi Bushen effectively rebuilt the gut microbiota ecosystem by decreasing the abundance of Bacteroides and Klebsiella, whiles increasing the ratio of Lactobacillus/Bacteroides and the abundance of Akkermansia. CONCLUSION: Our study shows that Bazi Bushen could serve as a potential therapy for maintaining intestinal homeostasis. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.
Subject(s)
Gastrointestinal Microbiome , Toll-Like Receptor 4 , Animals , Mice , Toll-Like Receptor 4/genetics , Ecosystem , RNA, Ribosomal, 16S , NF-kappa B/genetics , Homeostasis , Signal Transduction , InflammationABSTRACT
PURPOSE: This study aims to elucidate the mechanism underlying temozolomide resistance in patients with MGMT promoter hypomethylated glioblastoma, which is correlated with poor prognosis. The objective is to identify therapeutic targets and drugs suitable for temozolomide-resistant glioblastoma patients using big data analysis. METHODS: In this retrospective study, transcriptome sequencing data from 457 glioblastoma patients, multi-omics data, and single-cell sequencing data were employed to assess the expression pattern, prognostic value, and biological functions of AHR in glioblastoma. The HERB database was utilized to screen for AHR-targeted drugs for glioblastoma treatment. Validation of our findings was conducted using multiplex immunofluorescence staining of clinical samples and T cells and tumor cells co-culture models. RESULTS: Our findings demonstrated that patients with MGMT promoter unmethylation did not benefit from postoperative temozolomide chemotherapy due to resistance arising from DNA repair function and tumor immune response. AHR was found to be expressed in immune cells and exhibited an immunomodulatory role in glioblastoma with MGMT promoter unmethylation. AHR was identified as a potential novel inhibitory immune checkpoint receptor, serving as a therapeutic target for temozolomide-resistant glioblastoma. Furthermore, targeting AHR with Semen aesculi markedly enhanced the cytotoxic effect of T cells on glioma cells. CONCLUSIONS: In addition to DNA repair function, the tumor immune response plays a pivotal role in temozolomide resistance of glioblastoma. Herbal compounds targeting AHR may offer an effective treatment for temozolomide-resistant glioblastoma.
Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/drug therapy , Glioblastoma/genetics , Glioblastoma/pathology , Temozolomide , Antineoplastic Agents, Alkylating , Retrospective Studies , Tumor Suppressor Proteins/metabolism , DNA Repair Enzymes/genetics , DNA Repair Enzymes/metabolism , DNA Modification Methylases/genetics , DNA Modification Methylases/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/genetics , Brain Neoplasms/pathology , DNA MethylationABSTRACT
Introduction: Kidney stone disease (KS) is a complicated disease with an increasing global incidence. It was shown that Bushen Huashi decoction (BSHS) is a classic Chinese medicine formula that has therapeutic benefits for patients with KS. However, its pharmacological profile and mechanism of action are yet to be elucidated. Methods: The present study used a network pharmacology approach to characterize the mechanism by which BSHS affects KS. Compounds were retrieved from corresponding databases, and active compounds were selected based on their oral bioavailability (≥30) and drug-likeness index (≥0.18). BSHS potential proteins were obtained from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, whereas KS potential genes were obtained from GeneCards and OMIM, TTD, and DisGeNET. Gene ontology and pathway enrichment analysis were used to determine potential pathways associated with genes. The ingredients of BSHS extract were identified by the ultra-high-performance liquid chromatography coupled with quadrupole orbitrap mass spectrometry (UHPLC-Q/Orbitrap MS). The network pharmacology analyses predicted the potential underlying action mechanisms of BSHS on KS, which were further validated experimentally in the rat model of calcium oxalate kidney stones. Results: Our study found that BSHS reduced renal crystal deposition and improved renal function in ethylene glycol(EG)+ammonium chloride(AC)-induced rats, and also reversed oxidative stress levels and inhibited renal tubular epithelial cell apoptosis in rats. BSHS upregulated protein and mRNA expression of E2, ESR1, ESR2, BCL2, NRF2, and HO-1 in EG+AC-induced rat kidney while downregulating BAX protein and mRNA expression, consistent with the network pharmacology results. Discussion: This study provides evidence that BSHS plays a critical role in anti-KS via regulation of E2/ESR1/2, NRF2/HO-1, and BCL2/BAX signaling pathways, indicating that BSHS is a candidate herbal drug for further investigation in treating KS.