Cardiac fibrosis, a major pathological hallmark of aging that leads to heart failure, is characterized by excessive collagen deposition. Our knowledge of what sustains collagen synthesis in the aging heart is still very preliminary. Here, we uncover a central role for chaperone-mediated autophagy (CMA), a selective lysosomal degradation pathway, in this process. We demonstrate that CMA is suppressed in the aging heart, which promotes collagen overproduction in fibroblasts, whereas enhancing CMA activity ameliorates fibrosis and diastolic dysfunction. Mechanistically, we identify SHMT2 (serine hydroxymethyltransferase 2) as a CMA substrate whose accumulation with aging drives collagen synthesis by increasing glycine availability. Integrative omics revealed a systemic downregulation of the ketone body β-hydroxybutyrate (BHB) in aged mice. BHB supplementation - via a cyclic ketogenic diet - restored CMA, attenuated fibrosis, and improved cardiac function. This recovery was mediated through BHB-induced activation of the HCAR2 receptor and subsequent phosphorylation of HSPA8/HSC70, which systemically reactivates the CMA machinery. Furthermore, we show that Lycium barbarum polysaccharide (LBP) rejuvenates hepatic ketogenesis and mimics the benefits of BHB. Our findings establish a BHB-HCAR2-CMA-SHMT2 regulatory axis as a critical mechanism driving aging-related cardiac fibrosis and highlight nutritional strategies that target CMA as promising therapies against cardiac aging.Abbreviations AcAc: acetoacetic acid; BHB: β-hydroxybutyrate; CMA: chaperone-mediated autophagy; COL1: collagen type I; COL3: collagen type III; ECM: extracellular matrix; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HCAR2: hydroxycarboxylic acid receptor 2; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; HF: heart failure; HK2: hexokinase 2; IVRT: isovolumic relaxation time; KD: ketogenic diet; LAMP2A: lysosome associated membrane protein 2A; LBP:Lycium barbarumpolysaccharide; PKM/PKM2: pyruvate kinase M1/2; SHMT2: serine hydroxymethyltransferase 2; VIM: vimentin.

BACKGROUND & AIMS:Emerging evidence supports a crucial role for tumor-associated macrophages in shaping the immunosuppressive tumor microenvironment. Furthermore, research has identified that the triggering receptor expressed on myeloid cells 2 has immunomodulatory functions. The present investigated the potential effect of triggering receptor expressed on myeloid cells 2 expression in tumor-associated macrophages on facilitating immune evasion in colorectal cancer. METHODS:Immunohistochemical analysis of clinical specimens, complemented by extensive data mining from The Cancer Genome Atlas, revealed a significant upregulation of triggering receptor expressed on myeloid cells 2 in colorectal cancer-associated tumor-associated macrophages, with this upregulation exhibiting a correlation with poor patient prognosis. RESULTS:Mechanistically, triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages were found to drive fibroblast activation through transforming growth factor-β signaling, inducing fibroblast-activated protein-positive cancer-associated fibroblasts that secrete collagen I/III to establish dense peritumoral barriers. Spatial profiling revealed that these fibrous structures physically impede CD8+ T-cell infiltration, restricting cytotoxic lymphocytes to stromal compartments. Intriguingly, triggering receptor expressed on myeloid cells 2 deficiency enhanced the secretion of matrix metalloproteinase 13 by macrophages, thereby promoting extracellular matrix degradation and improving T-cell penetration. In vivo, Trem2-knockout mice showed a reduction in tumor growth with enhanced intratumoral CD8+ T-cell infiltration compared with wild-type controls. CONCLUSIONS:Our findings establish triggering receptor expressed on myeloid cells 2+ tumor-associated macrophages as central regulators of stromal remodeling and suggest that therapeutic targeting of the triggering receptor expressed on myeloid cells 2/transforming growth factor-β/fibroblast-activated protein pathway may overcome immune resistance in patients with colorectal cancer.

Objective To explore the role of succinate in age-related cardiac fibrosis and its mechanisms. Methods In this study, we established three experimental models: naturally aged mice, young mice administered succinate by drinking water, and cultured NIH/3T3 fibroblasts exposed to succinate. Determine the concentration of succinate in serum and myocardial tissue from these samples. Protein levels of GPR91, HIF-1α, and fibrosis-related markers were measured along with TGF-β1 secretion and Smad2/3 phosphorylation. Overexpression and inhibition experiments were conducted to verify the signal axis. Results Aged mice and those that received succinate in their drinking water both showed significantly higher levels of succinate in the serum and heart tissue, with increased expression of the succinate receptor GPR91. After oral administration of succinate to young mice, myocardial fibrosis occurred that was similar to the changes in old age. In cultured NIH/3T3 cells, succinate exposure promoted a fibrotic phenotype. Further investigation found that succinate first increased the expression of GPR91, then promoted HIF-1α expression, leading to an increase in TGF-β1 secretion and Smad2/3 phosphorylation. Blocking either GPR91 or HIF-1α can prevent these fibrotic changes; However, when TGF-β1 is added, the phenotype in cells that have been inhibited for GPR91 will return. Notably, a Smad pathway inhibitor completely abolished the succinate-induced fibrosis. Conclusion In conclusion, succinate induces cardiac fibrosis through the GPR91-HIF-1α-TGF-β1-Smad signaling pathway.”

Ulcerative colitis (UC) is a chronic inflammatory disorder characterized by an impaired intestinal epithelial barrier. The complex etiology of UC includes genetic, environmental, immune and microbial factors. It has recently been proposed that dysregulated ketogenesis may play a role in the development of UC; however, the precise mechanism by which this occurs remains unclear. In this study, mice were treated with dextran sulfate sodium to induce UC. UC mice exhibited intestinal epithelial barrier dysfunction characterized by loss of tight junctions in intestinal epithelial cells (IECs) and an imbalance in the Th17/Treg ratio in the peripheral blood. A significant decrease in the ketogenic rate-limiting enzyme HMGCS2 was observed in the IECs of UC mice, which was responsible for the decrease of β-hydroxybutyric acid production. Notably, UC mice treated with artesunate (ART) showed increased HMGCS2 and ketogenesis, as well as restored Th17/Treg and recovered tight junction protein expression. These factors contributed to intestinal epithelial barrier repair and alleviated colitis. The addition of an AMPK inhibitor or mTOR activator effectively reversed the effects of ART on ketogenesis, thereby preventing subsequent restoration of the intestinal barrier. These findings were confirmed in vitro in DSS-treated colonocytes. In conclusion, ART facilitated intestinal epithelial barrier repair in UC by stimulating HMGCS2-dependent ketogenesis in IECs through the AMPK/mTOR signaling pathway.

Purpose:The aetiology of colorectal cancer (CRC) is attributed to the intrinsic malignant cell transformation and the extrinsic tumor microenvironment (TME). Within the TME, M2-like tumor-associated macrophages (TAMs) play a pivotal role in promoting CRC malignancy. Although the interaction between tumor cells and TAMs has been studied, the mechanism underlying the polarization of M2-like TAMs directed by CRC cells remains unclear. Materials and Methods:Macrophage polarization was analyzed by flow cytometry. Cytokine production was quantified by qPCR. EVs were identified by transmission electron microscopy and western blotting. CRC cell apoptosis and viability were measured by flow cytometry and CCK8 assay, respectively. Results:The results showed that CRC cells have high expression of HMGCS1, the enzyme responsible for catalyzing the synthesis of HMG-CoA during cholesterol biosynthesis. The increased expression of HMGCS1 resulted in an excess of cholesterol in CRC patients. The excess cholesterol derived from CRC cells was released via extracellular vesicles (EVs) and taken up by surrounding macrophages via the CD36 receptor. Macrophages that took up CRC cell-derived cholesterol showed a preferential polarization towards M2-like TAMs, which produced large amounts of pro-tumor cytokines. The production of these cytokines further accelerated the progression of the surrounding CRC. Conclusion:Our findings revealed a mutual stimulatory effect between CRC cells and M2-like TAMs. CRC cells with hyper-expressed HMGCS1 facilitated M2-like TAM polarization by releasing cholesterol-rich EVs, and M2-like TAMs in turn promoted CRC malignancy. These findings suggest that inhibiting excessive cholesterol production may be a promising strategy for the treatment of advanced CRC.

Age-related cardiac fibrosis is a key driver of heart failure and hallmark of aging whose mechanisms remain incompletely understood. Here we show elevated succinate levels in aged mice and humans drive cardiac fibrosis by enhancing fibroblast activation and collagen production. This process is mediated through succinate-dependent succinylation of PKM2 at lysine 125, promoting its transition from tetrameric to dimeric states. Using SUCNR1–/– mice, we establish that succinate signaling through SUCNR1/GPR91 promotes PKM2 succinylation and dimerization, creating a profibrotic network associated with aging-related diastolic dysfunction. Nuclear translocation of dimeric PKM2 enables fibroblast activation through HIF-1α binding, enhancing DNA-binding affinity and upregulating fibrogenic genes. Metformin treatment suppresses fibroblast activation by reducing succinate accumulation, revealing therapeutic potential for mitigating age-related cardiac fibrosis and diastolic dysfunction. Our findings identify metabolic dysregulation as a critical target and characterize a succinate-PKM2 signaling axis whose interruption may attenuate cardiac aging. Elevated succinate in aging drives cardiac fibrosis by inducing PKM2 succinylation, dimerization, and nuclear translocation, activating fibroblasts. Targeting this axis may slow cardiac aging

PurposeThis study examined the protective effects and mechanism of Lycium barbarum polysaccharides (LBP) in the context of intestinal barrier function and intestinal microbiota in mice with dextran sulfate sodium (DSS)-induced chronic ulcerative colitis (UC).MethodsC57BL/6J male mice were assigned to a standard normal diet without DSS (control group), a normal diet with DSS (DSS group, 2% DSS given discontinuously for 3 weeks) or a normal diet supplemented with LBP (1% dry feed weight, LBP group, 2% DSS given discontinuously for 3 weeks) for a total of 8 weeks, at which point colonic tissues and caecal contents were collected.ResultsLBP exerted a significant effect against colitis by increasing body weight, colon length, DAI and histopathological scores. LBP inhibited proinflammatory cytokines (IL-1 beta, IL-6, iNOS and TNF-alpha) expression, improved anti-inflammatory cytokine (IL-10) expression, promoted the expression of tight junction proteins (Occludin and ZO-1) via nuclear factor erythroid 2-related factor 2 (Nrf2) activation and decreased Claudin-2 expression to maintain the intestinal mucosal barrier. In addition, the abundances of some probiotics (Ruminococcaceae, Lactobacillus, Butyricicoccus, and Akkermansia) were decreased with DSS treatment but increased obviously with LBP treatment. And LBP reduced the abundance of conditional pathogens associated with UC (Mucispirillum and Sutterella). Furthermore, LBP improved the production of short-chain fatty acids (SCFAs), including acetic acid, propionic acid, butyric acid and isobutyric acid.ConclusionLBP can alleviate DSS-induced UC by regulating inflammatory cytokines and tight junction proteins. Moreover, LBP promotes probiotics, suppresses conditional pathogens and increases SCFAs production, showing a strong prebiotic effect.

Abstract Background and Aims Disruption of the intestinal barrier of the digestive tract is a common pathophysiological change in the elderly, which may partly contribute to gut dysfunction and inflammatory bowel disease [IBD]. This study aimed to discover new interactive epigenetic regulation patterns involved in intestinal barrier dysfunction and colitis in elderly populations. Methods Intestinal barrier function and structure were evaluated in naturally ageing mice and elderly people. High-throughput analysis was performed on colonic tissues from humans and mice. The synergistic roles of miR-1-3p and miR-124-3p were identified using microRNA mimic/agomirs. Related genes were examined in biopsies of old IBD patients. Results A defective mucus barrier was observed before mucosal microstructural damage during ageing. Elevated miR-1-3p expression in the colons of older individuals impaired the mucus barrier by directly targeting T-synthase, similarly to the mechanism of miR-124-3p, which we reported previously. Importantly, the synergistic effect of a half dose of each microRNA supplement on T-synthase and CDK4/6 was stronger than that of a full dose of miR-1-3p or miR-124-3p alone, and mice co-treated with two microRNAs showed greater susceptibility to chemical-induced colitis than mice treated with either microRNA alone. These two microRNAs were up-expressed in old IBD patients. Conclusions The slight increases in miR-1-3p and miR-124-3p expression with ageing may be important contributors to the breakdown of intestinal homeostasis by targeting divergent genes in different cells. These data reveal the potential ability of multiple microRNAs to exert synergistic effects to damage the intestinal barrier and promote inflammatory bowel disease development in elderly populations.

Abstract Purpose Colorectal cancer (CRC) ranks 2nd in morbidity and 3rd in mortality among all cancers worldwide. 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1) is ubiquitously expressed in humans. Remarkably, the mevalonate pathway is often dysregulated in many cancers, suggesting tumor dependency on this classic metabolic pathway. In addition to altered substrates in the mevalonate pathway, it was recently found that HMGCS1 was highly expressed in prostate, melanoma and breast cancers. The transmembrane glycoprotein KIT is critical for the survival and development of various cells through activating downstream pathways and targets. Our previous research has proved that KIT is hyper-expressed in CRC and promotes CRC progression. However, whether HMGCS1 mediates the tumor-promoting effect of KIT signaling has not been unclosed. Material and Methods We investigated the regulatory mechanism of KIT signaling on HMGCS1 expression and the role of increased HMGCS1 in CRC development by the use of gene over-expression and knock-down techniques in CRC cells, biological function tests, protein-DNA binding detection, bioinformatics, database analysis and c-kit loss-of-function mutant mice (Wadsm/m). Results HMGCS1 was up-regulated by KIT-JNK-c-Jun signaling in CRC cells and could be a biomarker for CRC. Highly expressed HMCGS1 promoted CRC cell proliferation and invasion while inhibiting apoptosis. Our results provided evidence for the role of HMGCS1 in CRC progression and suggested that blocking KIT-JNK-c-Jun-HMGCS1 might be a new strategy for treating CRC patients. Conclusion Our results indicated that KIT signaling could up-regulate HMGCS1 in CRC mediated by Ap-1/c-Jun. Hyper-expressed HMGCS1 promotes CRC cell proliferation and invasion while inhibiting apoptosis.

The impairment of the intestinal epithelial barrier and subsequent bacterial translocation are common in aging individuals, contributory to several local and systematic disorders. However, the underlying mechanism of the age-related degeneration has not been fully understood. In this study, we demonstrated that the intestinal KIT signaling declined and de-activated with aging, parallel with epithelial barrier dysfunction. Endoplasmic reticulum stress (ERS)/unfolded protein response (UPR) was obviously increased during aging. The ERS and its downstream IRE1α were highly activated in the aging colonic epithelium. Furthermore, by the use of Tunicamycin (Tm)-induced ERS mouse and cell models, we uncovered that the activity of the ERS/IRE1α accelerated the protein degradation of KIT via ubiquitin-proteasome pathway. The deficiency of KIT signaling further reduced the transcription of the tight junction protein Claudin-3. Of significance, Artesunate (ART) could be capable of ameliorating the detrimental effect of ERS/IRE1α, indicated by the re-gained KIT and Claudin-3 expressions and the restoration of the intestinal epithelial barrier. In conclusion, our present study provided novel evidence elucidating the ERS/IRE1α-induced loss of KIT and Claudin-3 in the aging colonic epithelium and also shed light on the protective effect of Artesunate on the intestinal epithelial barrier by blocking ERS/IRE1α activity during aging.

文章探索混合式教学在正常人体形态学微观实验教学中的应用.混合教学班采用线上线下混合式教学,对照班采用传统方法教学.教师采用期末理论和实验考试成绩、混合教学班学生问卷调查结果评估教学效果.理论考试成绩显示混合教学班优的比例高于对照班,不合格的比例低于对照班.实验考试成绩混合教学班优的比例高于对照班,中的比例低于对照班.问卷调查结果显示,大多数学生认可混合式教学,认为课堂教学环节设计比较合理,利用网络资源和自主学习的能力、对知识的归纳总结能力都得以提高.

Attenuated Oxaliplatin efficacy is a challenge in treating colorectal cancer (CRC) patients, contributory to the failure in chemotherapy and the risks in relapse and metastasis. However, the mechanism of Oxaliplatin de-efficacy during CRC treatment has not been completely elucidated. Microarray screening, western blot and qPCR on clinic CRC samples were conducted to select the target gene ABCC10 transporter. The Cancer Genome Atlas data was analyzed to figure out the correlation between the clinical manifestation and ABCC10 expression. ABCC10 knock-down in CRC cells was conducted to identify its role in the Oxaliplatin resistance. Cell counting kit-8 assay was conducted to identify the CRC cell viability and Oxaliplatin IC50. Flow cytometry was conducted to detect the cell apoptosis exposed to Oxaliplatin. The intracellular Oxaliplatin accumulation was measured by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. CRC patients with higher ABCC10 were prone to relapse and metastasis. Differential ABCC10 expression in multiple CRC cell lines revealed a strong positive correlation between ABCC10 expression level and decreased Oxaliplatin response. In ABCC10 knock-down CRC cells the Oxaliplatin sensitivity was evidently elevated due to an increase of intracellular Oxaliplatin accumulation resulted from the diminished drug efflux. To explore a strategy to block ABCC10 in CRC cells, we paid a special interest in the endoplasmic reticulum stress (ERS) / unfolded protein response (UPR) that plays a dual role in tumor development. We found that neither the inhibition of ERS nor the induction of mild ERS had anti-CRC effect. However, the CRC cell viability was profoundly decreased and the pro-apoptotic factor CHOP and apoptosis were increased by the induction of intense ERS. Significantly, the Oxaliplatin sensitivity of CRC cells was enhanced in response to the intense ERS, which was blocked by inhibiting IRE1α branch of UPR. Finally, we figured out that the intense ERS down-regulated ABCC10 expression via regulated IRE1-dependent decay activity. Oxaliplatin was a substrate of ABCC10 efflux transporter. The intense ERS/IRE1α enhanced Oxaliplatin efficacy through down-regulating ABCC10 in addition to inducing CHOP. We suggested that introduction of intense ERS/UPR could be a promising strategy to restore chemo-sensitivity when used in combination with Oxaliplatin or other chemotherapeutic drugs pumped out by ABCC10.

新型冠状病毒肺炎(简称新冠肺炎)疫情防控期间,为了实现"停课不停学",我教研室开展了对《正常人体形态学实验》(微观)课程线上教学的实践与探索.《正常人体形态学实验》(微观)是《组织胚胎学》课程中的重要组成部分,是对组织胚胎学理论课程的重要补充.本文介绍了此次线上实验教学的具体实施情况,并对学生对线上实验教学的总体感受及评价进行了问卷调查分析,对整个线上教学过程进行了总结和讨论,以期为将来开展线上、线下混合式教学改革提供参考.

IntroductionThe gene encoding β2-adrenergic receptor (ADRB2) is a candidate gene for chronic obstructive pulmonary disease (COPD), yet the results are not often reproducible. We aimed to assess the association of ADRB2 genetic polymorphisms (rs1042713, rs1042714, and rs1800888) with COPD risk and COPD-related phenotypes via a meta-analysis.Material and methodsLiterature search, quality evaluation, and data extraction were completed independently and in duplicate. Effect-size estimation is expressed as odds ratio (OR) or weighted mean difference (WMD) with 95% confidence interval (CI).ResultsTotal 15 articles were meta-analyzed, including 12 articles (2917/8807 patients/controls) for COPD risk, and 6 articles (18350 subjects) for COPD-related phenotypes. Overall, there was no detectable significance for the association of rs1042713 (OR, 95% CI: 1.02, 0.88-1.19) and rs1042714 (1.01, 0.85-1.20) with COPD risk, and only marginal significance retained for rs1800888 (1.31, 1.00-1.72). In subsidiary analyses, the association of rs1042713 and rs1042714 with COPD risk was significant in populations of Asian origin (OR: 1.66 and 1.351, 95% CI: 1.13-2.44 and 1.02-1.79). Additionally, carriers of rs1042713 AA genotype had significantly lower levels of FEV1 (WMD, 95% CI: -0.011 L, -0.026 to -0.004) than carriers of GG genotypes, and FVC% predicted levels were significantly increased for the comparisons of rs1042713 AA genotype (6.914, 4.829 to 8.999) and AG genotype (4.249, 2.925 to 5.573) with GG genotype. There were low probabilities of publication bias.ConclusionsOur findings suggest that contribution of ADRB2 genetic polymorphisms to COPD risk is small and ethnicity-dependent, and to COPD-related phenotypes is significant.

Carcinoembryonic antigen (CEA) is highly expressed in embryo and colorectal cancer (CRC) and has been widely used as a marker for CRC. Emerging evidence has demonstrated that elevated CEA levels promote CRC progression. However, the mechanism of the increased CEA expression in patients with primary and recurrent CRC is still an open question. In this study, we showed that c-KIT, ELK1, and CEA were hyperexpressed in patients with CRC, especially patients with recurrent disease. From bioinformatics analysis, we picked ELK1 as a candidate transcription factor (TF) for CEA; the binding site of ELK1 within the CEA promoter was confirmed by chromatin immunoprecipitation and dual luciferase reporter assays. Overexpression of ELK1 increased CEA expression in vitro, while knockdown of ELK1 decreased CEA. Upregulated ELK1 promoted the adhesion, migration, and invasion of CRC cells, however knockdown of CEA blocked the activities of ELK1-overexpressed CRC cells. Furthermore, we explored the role of c-KIT-ERK1/2 signaling in activation of ELK1. Blocking c-KIT signaling using Imatinib or ISCK03 reduced p-ELK1 expression and consequently decreased CEA levels in CRC cells, as did blocking the ERK1/2 pathway by U0126. Compared with wild type littermates, the c-kit loss-of-functional Wadsm/m mice showed lowered c-KIT, ELK1, and CEA expression. In conclusion, our study revealed that ELK1, which was activated by c-KIT-ERK1/2 signaling, was a key TF for CEA expression. Blocking ELK1 or its upstream signaling could be an alternative way to decelerate CRC progression. Besides being a biomarker for CRC, CEA could be used for guiding targeted therapy.

The risk of colitis and colorectal cancer increases markedly throughout adult life, endangering the health and lives of elderly individuals. Previous studies have proposed that bacterial translocation and infection are the main risk factors for these diseases. Therefore, in the present study, we aimed to identify the underlying mechanism by focusing on the mucus barrier function and mucin-typeO-glycosylation. We evaluated alterations in the colon mucus layer in 2-, 16-, and 24-month-old mice and aged humans. Aged colons showed defective intestinal mucosal barrier and changed mucus properties. ThemiR-124-3pexpression level was significantly increased in the aged distal colonic mucosa, which was accompanied by an increase in pathogens and bacterial translocation. Meanwhile, T-synthase, the rate-limiting enzyme inO-glycosylation, displayed an age-related decline in protein expression. Further experiments indicated thatmiR-124-3pmodulatedO-glycosylation by directly targeting T-synthase. Moreover, young mice overexpressingmiR-124-3pexhibited abnormal glycosylation, early-onset, and more severe colitis. These data suggest thatmiR-124-3ppredisposes to senile colitis by reducing T-synthase, and themiR-124-3p/T-synthase/O-glycans axis plays an essential role in maintaining the physiochemical properties of colonic mucus and intestinal homeostasis.

目的 以临床结直肠肿瘤患者标本和原位癌小鼠模型以及小鼠腹腔巨噬细胞为研究对象,探讨结直肠肿瘤微环境中胶原蛋白促进肿瘤相关巨噬细胞极化的作用.方法 应用免疫荧光染色检测结直肠癌患者肿瘤组织巨噬细胞的分布,检测原位癌模型小鼠肿瘤组织巨噬细胞的量和分布;Masson染色肿瘤组织内胶原纤维.提取小鼠腹腔巨噬细胞,接种于不同浓度Ⅰ型胶原蛋白包被的培养皿,Real-time PCR检测巨噬细胞的肿瘤坏死因子(TNF)、诱导型一氧化氮合酶(iNOS)、CD163、CD206等基因表达.结果 人结肠癌组织标本和小鼠原位癌模型可见巨噬细胞主要分布于肿瘤组织的间质,主要为M1型,肿瘤实质部分巨噬细胞主要为M2型;细胞实验表明,胶原蛋白明显促进巨噬细胞向促进炎症抑制肿瘤的M1型巨噬细胞极化,抑制巨噬细胞向促进肿瘤的M2型极化;Masson染色可见间质内含有大量胶原纤维,而肿瘤实质细胞周围胶原纤维较少.结论 胶原蛋白具有促进巨噬细胞向M1型极化的作用,而肿瘤实质细胞周围胶原纤维减少,可能与巨噬细胞向M2型极化,发挥促进肿瘤发生发展的作用有关.

人脐带血(human umbilical cord blood,HUCB)是胎儿出生时脐带内及胎盘近胎儿一侧血管内的血液,已有研究[1]证明人脐血中含有丰富的造血干细胞及间充质干细胞(mesenchymal stem cells,MSCs).人脐血间充质干细胞(cord blood-mesenchymal stem cells,CB-MSCs)其形态和生物学特点与骨髓MSCs极为相似,同样具有自我更新和多向分化的潜能,在一定的实验条件下可以分化为骨、脂肪、肌肉,甚至可以跨胚层分化为神经样细胞[2-3],这就为细胞移植提供了一种新的种子细胞来源.

Aging is a significant risk factor for gastrointestinal dysmotility, but aging-associated differences between different organs and the exact time to start degenerating have remained obscure. Here we evaluated alterations of interstitial cells of Cajal, enteric neurons and connexin43 expression in the stomach, jejunum and colon in 2-, 12-, 16-, 20- and 24-month-old mice, as well as in aged human colon. Interstitial cells of Cajal, cholinergic and nitrergic neurons within the whole digestive tract were reduced over time, but their loss first appeared in stomach, then in intestine, helping to understand that gastric function was first impaired during aging. The decrease of connexin43 expression occurred before interstitial cells of Cajal and neurons loss, suggesting that connexin43 might be the major target influenced during senescence. Furthermore, changes in expressions of pro-inflammatory cytokines (tumour necrosis factor-α, interleukin-1β, interleukin-6) and apoptosis-related proteins (B-cell lymphoma-2, caspase-3) which indicated “inflammaging”, might contribute to the loss of enteric neurons and interstitial cells of Cajal in aged gastrointestinal tract. Our results provide possible therapeutic time window for beneficial intervention for geriatric patients with gastrointestinal motility disorders.