摘要:
A549 cells were treated with different concentrations of anlotinib to create anlotinib‐resistant A549 cells (A549/anlotinib cells). miR‐181a‐3p mimics were transfected into A549/anlotinib cells. Meanwhile, A549 and A549/anlotinib cells were treated with β‐sitosterol at different concentrations. Cell Counting Kit‐8 (CCK‐8) was used to measure cell proliferation. The apoptosis level was detected by flow cytometry. Real‐time fluorescence quantitative PCR was used to detect the expression of miR‐181a‐3p. miR‐181a‐3p interaction with H/ACA ribonucleoprotein assembly factor (SHQ1) was predicted by miRDB and TargetScan Human databases and verified by luciferase reporter assay. The expressions of SHQ1, activating transcription factor 6 (ATF6) and glucose regulated protein 78 (GRP78) were detected by western blot. Our results show that β‐Sitosterol markedly promoted anlotinib‐resistant A549 cells apoptosis and inhibited the cell proliferation via activating SHQ1/UPR signaling via inhibiting miR‐181a‐3p. Abstract Anlotinib is used for the treatment of advanced non‐small cell lung cancer; however, the emergence of drug resistance limits its clinical application. β‐sitosterol may also be used to treat lung cancer, but there have been no studies evaluating β‐sitosterol against anlotinib‐resistant lung cancer. The purpose of this study was to determine the mechanism by which β‐sitosterol enhances the sensitivity of lung cancer cells to anlotinib. A549 cells were treated with different concentrations of anlotinib to generate anlotinib‐resistant cells (A549/anlotinib cells). miR‐181a‐3p mimics were transfected into A549/anlotinib cells. A549 and A549/anlotinib cells were treated with β‐sitosterol at various concentrations. The Cell Counting Kit‐8 (CCK‐8) assay was used to measure cell proliferation. Apoptosis was assessed by flow cytometry. Real‐time quantitative PCR was used to measure the expression of miR‐181a‐3p. The interaction of miR‐181a‐3p with the H/ACA ribonucleoprotein assembly factor (SHQ1) was predicted using the miRDB and TargetScan Human databases and verified with a luciferase reporter assay. The expression of SHQ1, activating transcription factor 6 (ATF6), and glucose‐regulated protein 78 (GRP78) were measured by western blot analysis. β‐Sitosterol effectively suppressed A549/anlotinib cell proliferation and promoted apoptosis. SHQ1 is a downstream target of miR‐181a‐3p. The expression of miR‐181a‐3p was inhibited; however, SHQ1 expression was increased by β‐sitosterol treatment of A549/anlotinib cells. The inhibition of SHQ1, ATF6, and GRP78 protein expression by β‐sitosterol in A549/anlotinib cells was rescued by increased miR‐181a‐3p. β‐Sitosterol markedly promotes anlotinib‐resistant A549 cell apoptosis and inhibits cell proliferation by activating SHQ1/UPR signaling through miR‐181a‐3p inhibition.
作者机构:
[Yi, Jian; Wang, Feiying; Ding, Rongzhen; Dai, Aiguo] Department of Respiratory Diseases, Medical School, Hunan University of Chinese Medicine, Changsha, China;[Yi, Jian; Wang, Feiying; Ding, Rongzhen; Dai, Aiguo] Hunan Provincial Key Laboratory of Vascular Biology and Translational Medicine, Changsha, China;[Ding, Rongzhen; Dai, Aiguo] Department of Respiratory Medicine, First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, China;[Sang, Shuliu] Shanghai University of Traditional Chinese Medicine, Shanghai, China;[Yi, Jian] Hunan Academy of Chinese Medicine, Changsha, China
摘要:
BACKGROUND: Lung adenocarcinoma (LUAD) with Pulmonary arterial hypertension (PAH) shows a poor prognosis. Detecting related genes is imperative for prognosis prediction. METHODS: The gene expression profiles of LUAD and PAH were acquired from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database, respectively. The co-expression modules associated with LUAD and PAH were evaluated using the Weighted Gene Co-Expression Network Analysis (WGCNA). The relationship between key gene expression with immune-cell infiltration and the tumor immune microenvironment (TIME) was evaluated. We confirmed the mRNA and protein levels in vivo and vitro. G6PD knockdown was used to conduct the colony formation assay, transwell invasion assay, and scratch wound assay of A549 cells. EDU staining and CCK8 assay were performed on G6PD knockdown HPASMCs. We identified therapeutic drug molecules and performed molecular docking between the key gene and small drug molecules. RESULTS: Three major modules and 52 overlapped genes were recognized in LUAD and PAH. We identified the key gene G6PD, which was significantly upregulated in LUAD and PAH. In addition, we discovered a significant difference in infiltration for most immune cells between high- and low-G6PD expression groups. The mRNA and protein expressions of G6PD were significantly upregulated in LUAD and PAH. G6PD knockdown decreased proliferation, cloning, and migration of A549 cells and cell proliferation in HPASMCs. We screened five potential drug molecules against G6PD and targeted glutaraldehyde by molecular docking. CONCLUSIONS: This study reveals that G6PD is an immune-related biomarker and a possible therapeutic target for LUAD and PAH patients.
摘要:
OBJECTIVES: Statistics on the rate of unconventional lymph node metastases (ULNM) at the time of one-stage radical surgery in tongue cancer patients. To assess whether an extended neck dissection group with additional removal of ULNs has a lower rate of neck recurrence compared to the traditional neck dissection group. MATERIALS AND METHODS: A total of 336 patients with TSCC who underwent radical surgery were recruited and underwent traditional or extended neck dissection. Compared to traditional neck dissection, the aim of extended neck dissection is designed to additional resect ULNs. RESULTS: In total, 180 patients underwent extended neck dissection, while 156 underwent traditional neck dissection. The incidence of ULNM was 11.67% (21/180) in patients treated with extended neck dissection. The incidence of ipsilateral neck recurrence was 9.49% and 0.56% in patients who underwent traditional and extended neck dissection, respectively (p = 0.0001). CONCLUSIONS: Extended neck dissection is effective for preventing neck recurrence in TSCC patients with ULNs. CLINICAL RELEVANCE: ULNM may be the main cause of neck recurrence after neck dissection in patients with tongue cancer. A better prognosis may be achieved by additional resection of ULNs on the basis of traditional neck dissection.
期刊:
Journal of Ethnopharmacology,2024年328:118126 ISSN:0378-8741
通讯作者:
Teng Li
作者机构:
[Yan, Qiuju; Hu, En; Yu, Zhe; Zhu, Wenxin; Wang, Yang; Wu, Yao; Cheng, Menghan; Tang, Tao; Li, Teng; Li, Zhilin] Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, PR China;[Yan, Qiuju; Hu, En; Yu, Zhe; Zhu, Wenxin; Wang, Yang; Wu, Yao; Cheng, Menghan; Tang, Tao; Li, Teng; Li, Zhilin] NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha, PR China;[Yan, Qiuju; Hu, En; Yu, Zhe; Zhu, Wenxin; Wang, Yang; Wu, Yao; Cheng, Menghan; Tang, Tao; Li, Teng; Li, Zhilin] National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, PR China;[Hu, En; Wang, Yang; Tang, Tao] Xiangya Hospital, Central South University, Jiangxi, Nanchang, PR China;[Zhang, Wei; Zheng, Fei] The College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, PR China
通讯机构:
[Teng Li] I;Institute of Integrative Medicine, Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, PR China<&wdkj&>NATCM Key Laboratory of TCM Gan, Xiangya Hospital, Central South University, Changsha, PR China<&wdkj&>National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, PR China<&wdkj&>Xiangya Hospital, Central South University, Jiangxi, Nanchang, PR China
摘要:
ETHNOPHARMACOLOGICAL RELEVANCE: The repairment of myelin sheaths is crucial for mitigating neurological impairments of intracerebral hemorrhage (ICH). However, the current research on remyelination processes in ICH remains limited. A representative traditional Chinese medicine, Buyang Huanwu decoction (BYHWD), shows a promising therapeutic strategy for ICH treatment. AIM OF THE STUDY: To investigate the pro-remyelination effects of BYHWD on ICH and explore the underlying mechanisms. MATERIALS AND METHODS: The collagenase-induced mice ICH model was created for investigation. BYHWD's protective effects were assessed by behavioral tests and histological staining. Transmission electron microscopy was used for displaying the structure of myelin sheaths. The remyelination and oligodendrocyte differentiation were evaluated by the expressions of myelin proteolipid protein (PLP), myelin basic protein (MBP), MBP/TAU, Olig2/CC1, and PDGFRα/proliferating cell nuclear antigen (PCNA) through RT-qPCR and immunofluorescence. Transcriptomics integrated with disease database analysis and experiments in vivo and in vitro revealed the microRNA-related underlying mechanisms. RESULTS: Here, we reported that BYHWD promoted the neurological function of ICH mice and improved remyelination by increasing PLP, MBP, and TAU, as well as restoring myelin structure. Besides, we showed that BYHWD promoted remyelination by boosting the differentiation of PDGFRα(+) oligodendrocyte precursor cells into olig2(+)/CC1(+) oligodendrocytes. Additionally, we demonstrated that the remyelination effects of BYHWD worked by inhibiting G protein-coupled receptor 17 (GPR17). miRNA sequencing integrated with miRNA database prediction screened potential miRNAs targeting GPR17. By applying immunofluorescence, RNA in situ hybridization and dual luciferase reporter gene assay, we confirmed that BYHWD suppressed GPR17 and improved remyelination by increasing miR-760-3p. CONCLUSIONS: BYHWD improves remyelination and neurological function in ICH mice by targeting miR-760-3p to inhibit GPR17. This study may shed light on the orchestration of remyelination mechanisms after ICH, thus providing novel insights for developing innovative prescriptions with brain-protective properties.
作者机构:
[Zibing Zhu; Yisi Tan; Jin Tan; Keke Zhu] Department of Stomatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China;[Chengyong Liu; Yetong Wang; Han Zhou; Xuan Zhu] Hunan University of Traditional Chinese Medicine, Changsha, China;[Rong Zhou] Changsha Hospital for Maternal and Child Health Care, Changsha, China;[Zhengrui Li] College of Stomatology, Shanghai Jiao Tong University, Shanghai, China;[Xufeng Huang] Faculty of Dentistry, University of Debrecen, Debrecen, Hungary
通讯机构:
[Keke Zhu] D;Department of Stomatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
摘要:
BACKGROUND: While observational studies and experimental data suggest a link between oral lichen planus (OLP) and oral cavity cancer (OCC), the causal relationship and the role of inflammatory cytokines remain unclear. METHODS: This study employed a univariable and multivariable Mendelian Randomization (MR) analysis to investigate the causal relationship between OLP and the risk of OCC. Additionally, the potential role of inflammatory cytokines in modulating this association was explored. Instrumental variables were derived from genetic variants associated with OLP (n = 377,277) identified in Finngen R9 datasets, with 41 inflammatory cytokines as potential mediators, and OCC (n = 4,151) as the outcome variable. Analytical methods including Inverse Variance Weighted (IVW), Weighted Median, MR-Egger, and MR-PRESSO were utilized to assess the causal links among OLP, inflammatory cytokines, and OCC risk. Multivariable MR (MVMR) was then applied to quantify the mediating effects of these cytokines in the relationship between OLP and increased OCC risk. RESULTS: MR analysis provided strong evidence of a causal relationship between OLP (OR = 1.417, 95% CI = 1.167-1.721, p < 0.001) and the risk of OCC. Furthermore, two inflammatory cytokines significantly influenced by OLP, IL-13 (OR = 1.088, 95% CI: 1.007-1.175, P = 0.032) and IL-9 (OR = 1.085, 95% CI: 1.005-1.171, P = 0.037), were identified. Subsequent analysis revealed a significant causal association only between IL-13 (OR = 1.408, 95% CI: 1.147-1.727, P = 0.001) and higher OCC risk, establishing it as a potential mediator. Further, MVMR analysis indicated that IL-13 (OR = 1.437, 95% CI = 1.139-1.815, P = 0.002) mediated the relationship between OLP and OCC, accounting for 8.13% of the mediation. CONCLUSION: This study not only elucidates the potential causal relationship between OLP and the risk of OCC but also highlights the pivotal mediating role of IL-13 in this association.
作者机构:
[潘思安] College of Acupuncture-moxibustion, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha 410208, China. pansian1989@126.com;[潘思安] College of Chinese Medicine, Hunan University of Chinese Medicine, Changsha 410208. pansian1989@126.com;[刘余; 袁菡钰; 李娟; 汪少华; 薛晓] College of Acupuncture-moxibustion, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha 410208, China;[岳增辉] College of Acupuncture-moxibustion, Tuina and Rehabilitation, Hunan University of Chinese Medicine, Changsha 410208, China. yue5381316@126.com. LA - eng
期刊:
Journal of Clinical Gastroenterology,2023年57(8):782-788 ISSN:0192-0790
通讯作者:
Tian, XF
作者机构:
[Huang, Caizhi; Tian, Xuefei; Tian, XF] Hunan Univ Chinese Med, Coll Integrated Chinese & Western Med, Dept Internal Med, Changsha, Peoples R China.;[Huang, Caizhi] Hunan Childrens Hosp, Dept Lab Med, Changsha, Peoples R China.;[Mei, Si] Hunan Univ Chinese Med, Dept Physiol, Changsha, Peoples R China.;[Zhang, Xue] Hunan Univ Chinese Med, Key Lab Tradit Chinese Med Mech Tumor Prevent & Tr, Changsha, Peoples R China.;[Tian, Xuefei; Tian, XF] Hunan Univ Chinese Med, Hunan Prov Univ, Key Lab Oncol Tradit Chinese Med, Changsha, Hunan, Peoples R China.
通讯机构:
[Tian, XF ] H;Hunan Univ Chinese Med, Coll Integrated Chinese & Western Med, Dept Internal Med, Changsha, Peoples R China.;Hunan Univ Chinese Med, Hunan Prov Univ, Key Lab Oncol Tradit Chinese Med, Changsha, Hunan, Peoples R China.
关键词:
gut microbiota, hepatocellular carcinoma, inflammation, dysbiosis
摘要:
Hepatocellular carcinoma (HCC) is an invasive primary liver cancer caused by multiple pathogenic factors and is a significant global health concern. With few effective therapeutic options, HCC is a heterogeneous carcinoma that typically arises in an inflammatory environment. Recent studies have suggested that dysbiotic gut microbiota is involved in hepatocarcinogenesis via multiple mechanisms. In this review, we discuss the effects of gut microbiota, microbial components, and microbiota-derived metabolites on the promotion and progression of HCC by feeding a persistent inflammatory milieu. In addition, we discuss the potential therapeutic modalities for HCC targeting the inflammatory status induced by gut microbiota. A better understanding of the correlation between the inflammatory milieu and gut microbiota in HCC may be beneficial for developing new therapeutic strategies and managing the disease.
摘要:
We describe a graphene oxide (GO)-based bioassay for the fluorometric determination of norA gene transcription (mRNA) in methicillin-resistant Staphylococcus aureus (MRSA). This approach is based on Nb.BbvCI-assisted target recycling (NATR) and T7 exonuclease (T7 Exo)-triggered cascade dual-recycling signal amplification (TTCDRSA). The system included GO, a capture probe (CP), an assistant probe (AP), two carboxyfluorescein (FAM)-labeled hairpins (HP1 and HP2), endonuclease Nb.BbvcI, and exonuclease T7. In the presence of a target, AP, together with the target RNA, can hybridise with CP via partial complementarity to one another and open its hairpin structure to form a triple complex that is recognised by Nb.BbvCI. Once the CP is cleaved, the released AP and target RNA can walk on the carboxylated graphene oxide (CGO) surface to bind with another CP which induces the next round of cleavage, accumulating many trigger probes (TPs). The TPs then activate TTCDRSA with the assistance of T7 Exo, HP1, and HP2 to produce large amounts of free FAMs. These free FAMs are repelled by GO and exhibit enhanced fluorescence signals at excitation/emission wavelengths of 480/514 nm. The limit of detection (LOD) of the bioassay was calculated to be 0.37 fM, and the linear range of the method ranged from 1 fM to 1 nM. More importantly, the bioassay also exhibited high sensitivity and selectivity for target RNA detection in real samples, which may open a new promising avenue for monitoring drug efflux and studying the mechanisms of drug actions.
期刊:
Journal of Pharmacy and Pharmacology,2023年75(5):666-676 ISSN:0022-3573
通讯作者:
Biao Tang
作者机构:
[Wang, Linlin; Xiao, Lan; Kang, Zhineng; Xiao, Qian; Tang, Biao] Hunan Univ Chinese Med, Basic Res Ctr Integrated Chinese & Western Med Pre, Changsha, Peoples R China.;[Tang, Biao] Hunan Univ Chinese Med, Med Sch, Xiangzui Rd, Changsha, Hunan, Peoples R China.
通讯机构:
[Biao Tang] B;Basic Research Center of Integrated Chinese & Western Medicine for Prevention & Treatment of Vascular Diseases, Hunan University of Chinese Medicine , Changsha , China
摘要:
OBJECTIVES: This study aimed to observe the effect of the combination of astragaloside IV (AST IV) and Panax notoginseng saponins (PNS) on cerebral ischaemia-reperfusion injury (CIRI) and explore the specific mechanism of the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated combination of AST IV and PNS against CIRI based on ferroptosis and inflammatory response. METHODS: The therapeutic effect and mechanism of AST IV and PNS were evaluated by constructing a Sprague-Dawley rat middle cerebral artery ischaemia-occlusion-reperfusion model. The specific mechanism of the combination of AST IV and PNS against CIRI was revealed through the combined intervention of the Nrf2-specific inhibitor brusatol. KEY FINDINGS: After AST IV and PNS treatment, the cerebral infarction area of the rats was reduced; behavioural performance was improved; Fe2+, malondialdehyde, lipid peroxidation, interleukin-6, interleukin-1β, tumour necrosis factor-α and myeloperoxidase levels were reduced; and glutathione and glutathione peroxidase 4 levels were increased. In addition, the expression of Nrf2 was significantly increased, the combined treatment was more effective than the single treatment, and the Nrf2 inhibitor brusatol could reverse the effects of the combined intervention of AST IV and PNS. CONCLUSIONS: The findings of this study suggest that combining AST IV and PNS attenuates CIRI by activating Nrf2 to inhibit ferroptosis and inflammatory responses.
期刊:
Drug Design, Development and Therapy,2023年17:3085-3101 ISSN:1177-8881
通讯作者:
Jin Tan
作者机构:
[Zhu, Keke; Tan, Jin; Zhou, Linghang; Qin, Yijie; Tan, Yisi; Dai, Yuzhe; Xiao, Yanbo; Wu, Dan; Wang, Zongkang] Department of Stomatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, People's Republic of China
通讯机构:
[Jin Tan] D;Department of Stomatology, The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, 410007, People’s Republic of China
摘要:
PURPOSE: Arecoline is one of the main toxic components of arecoline to cause oral mucosal lesions or canceration, which seriously affects the survival and life quality of patients. This study analyzed the mechanism of Jiawei Danxuan Koukang (JDK) in alleviating arecoline induced oral mucosal lesions, to provide new insights for the treatment of oral submucosal fibrosis (OSF) or cancerosis. METHODS: Metabolomics was applied to analyze the composition of JDK and serum metabolites. The active ingredients of JDK were analyzed by the combined ultra-high performance liquid chromatography and mass spectrometry. The target network of JDK, metabolites and OSF was analyzed by network pharmacology, and molecular docking. Oral mucosal lesions and fibrosis were analyzed by HE and Masson staining. Cell differentiation, proliferation and apoptosis were detected. The expressions of α-SMA, Collagen I, Vimentin, Snail, E-cadherin, AR and NOTCH1 were detected by Western blot. RESULTS: Arecoline induced the gradual atrophy and thinning of rat oral mucosal, collagen accumulation, the increase expressions of fibrosis-related proteins and Th17/Treg ratio. JDK inhibited arecoline-induced oral mucosal lesions and inflammatory infiltration. Arecoline induced changes of serum metabolites in Aminoacyl-tRNA biosynthesis, Alanine, aspartate and glutamate metabolism and Arginine biosynthesis pathways, which were reversed by M-JDK. Quercetin and AR were the active ingredients and key targets of JDK, metabolites and OSF interaction. Arecoline promoted the expression of AR protein, and the proliferation of oral fibroblasts. Quercetin inhibited the effect of arecoline on oral fibroblasts, but was reversed by AR overexpression. Arecoline induced NOTCH1 expression in CAL27 and SCC-25 cells, and promoted cell proliferation, but was reversed by M-JDK or quercetin. CONCLUSION: JDK improved the arecoline-induced OSF and serum metabolite functional pathway. Quercetin targeted AR protein to improve arecoline-induced OSF. JDK and quercetin inhibited arecoline-induced NOTCH1 protein expression in CAL27 and SCC-25 cells to play an anti-oral cancer role.
摘要:
Resistin-like molecules (RELMs) are highly cysteine-rich proteins, including RELMα, RELMβ, Resistin, and RELMγ. However, RELMs exhibit significant differences in structure, distribution, and function. The expression of RELMs is regulated by various signaling molecules, such as IL-4, IL-13, and their receptors. In addition, RELMs can mediate numerous signaling pathways, including HMGB1/RAGE, IL-4/IL-4Rα, PI3K/Akt/mTOR signaling pathways, and so on. RELMs proteins are involved in wide range of physiological and pathological processes, including inflammatory response, cell proliferation, glucose metabolism, barrier defense, etc., and participate in the progression of numerous diseases such as lung diseases, intestinal diseases, cardiovascular diseases, and cancers. Meanwhile, RELMs can serve as biomarkers, risk predictors, and therapeutic targets for these diseases. An in-depth understanding of the role of RELMs may provide novel targets or strategies for the treatment and prevention of related diseases.
通讯作者:
Liming Zhu<&wdkj&>Yongliang Jiang<&wdkj&>Aiguo Dai
作者机构:
[Li, Guang; Peng, Yanping; Zhu, Liming; Dai, Aiguo; Jiang, Yongliang; Meng, Fang; Li, San; Zhu, Hao; Zhang, Shaoze; Li, Cheng; Gu, Jing] Hunan Normal Univ, Hunan Prov Peoples Hosp, Affiliated Hosp 1, Dept Resp & Crit Care Med, Changsha, Hunan, Peoples R China.;[Liu, Pingping] Hunan Childrens Hosp, Dept Emergency, Key Lab Pediat Emergency Med Hunan Prov, Changsha, Hunan, Peoples R China.;[Yao, Huiling] Hunan Normal Univ, Hunan Prov Peoples Hosp, Affiliated Hosp 1, Dept Gen Med, Changsha, Hunan, Peoples R China.;[Dai, Aiguo] Hunan Univ Chinese Med, Med Sch, Dept Resp Dis, Changsha, Hunan, Peoples R China.;[Dai, Aiguo] Hunan Prov Key Lab Vasc Biol & Translat Med, Changsha, Hunan, Peoples R China.
通讯机构:
[Liming Zhu; Yongliang Jiang; Aiguo Dai] D;Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, P.R. China<&wdkj&>Department of Respiratory Diseases, Medical School, Hunan University of Chinese Medicine, Changsha, Hunan, P.R. China<&wdkj&>Hunan Province Key Laboratory of Vascular Biology and Translational Medicine, Changsha, Hunan, P.R. China<&wdkj&>Department of Respiratory and Critical Care Medicine, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, P.R. China
关键词:
Tfh/Tfr;hypoxia;pulmonary hypertension;regulatory B cells
摘要:
Chronic hypoxia promoted Breg cells differentiation in the early stage of HPH, which significantly decreased in the late stage. Insufficient Breg cells exacerbated pulmonary vascular remodelling and dysregulated Tfh/Tfr cells in HPH. Adoptive transfer of Breg cells ameliorated pulmonary vascular remodelling and dysregulated Tfh/Tfr cells in HPH. Abstract Hypoxia‐induced pulmonary hypertension (HPH) is a progressive and lethal disease characterized by the uncontrolled proliferation of pulmonary artery smooth muscle cells (PASMCs) and obstructive vascular remodelling. Previous research demonstrated that Breg cells were involved in the pathogenesis of pulmonary hypertension. This work aimed to evaluate the regulatory function of Breg cells in HPH. HPH mice model were established and induced by exposing to chronic hypoxia for 21 days. Mice with HPH were treated with anti‐CD22 or adoptive transferred of Breg cells. The coculture systems of Breg cells with CD4+ T cells and Breg cells with PASMCs in vitro were constructed. Lung pathology was evaluated by HE staining and immunofluorescence staining. The frequencies of Breg cells, Tfh cells and Tfr cells were analysed by flow cytometry. Serum IL‐21 and IL‐10 levels were determined by ELISA. Protein levels of Blimp‐1, Bcl‐6 and CTLA‐4 were determined by western blot and RT‐PCR. Proliferation rate of PASMCs was measured by EdU. Compared to the control group, mean PAP, RV/(LV + S) ratio, WA% and WT% were significantly increased in the model group. Anti‐CD22 exacerbated abnormal hemodynamics, pulmonary vascular remodelling and right ventricle hypertrophy in HPH, which ameliorated by adoptive transfer of Breg cells into HPH mice. The proportion of Breg cells on day 7 induced by chronic hypoxia was significantly higher than control group, which significantly decreased on day 14 and day 21. The percentage of Tfh cells was significantly increased, while percentage of Tfr cells was significantly decreased in HPH than those of control group. Anti‐CD22 treatment increased the percentage of Tfh cells and decreased the percentage of Tfr cells in HPH mice. However, Breg cells restrained the Tfh cells differentiation and expanded Tfr cells differentiation in vivo and in vitro. Additionally, Breg cells inhibited the proliferation of PASMCs under hypoxic condition in vitro. Collectively, these findings suggested that Breg cells may be a new therapeutic target for modulating the Tfh/Tfr immune balance in HPH.
摘要:
Respiratory diseases are an emerging public health concern, that pose a risk to the global community. There, it is essential to establish effective treatments to reduce the global burden of respiratory diseases. Astragaloside IV (AS-IV) is a natural saponin isolated from Radix astragali (Huangqi in Chinese) used for thousands of years in Chinese medicine. This compound has become increasingly popular due to its potential anti-inflammatory, antioxidant, and anticancer properties. In the last decade, accumulated evidence has indicated the AS-IV protective effect against respiratory diseases. This article presents a current understanding of AS-IV roles and mechanisms in combatting respiratory diseases. The ability of the agent to suppress oxidative stress, cell proliferation, and epithelial-mesenchymal transition (EMT), to attenuate inflammatory responses, and modulate programmed cell death (PCD) will be discussed. This review highlights the current challenges in respiratory diseases and recommendations to improve disease management.
期刊:
Drug Delivery,2022年29(1):1675-1683 ISSN:1071-7544
通讯作者:
Fangguo Lu
作者机构:
[Chen, Pingan; Ning, Yi; Wang, Xiaoqi; Lu, Fangguo; Hu, Jue; Xiao, Rong; Liu, Shiwu] Hunan Univ Chinese Med, Med Sch, Dept Microbiol, Changsha 410208, Hunan, Peoples R China.;[Li, Ling] Hunan Univ Chinese Med, Chinese Med Sch, Expt Ctr Mol Biol, Changsha, Hunan, Peoples R China.
通讯机构:
[Fangguo Lu] D;Department of Microbiology, The Medicine School of Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China
作者机构:
[Duan, Wentao] Cent South Univ, Dept Resp & Crit Care Med, Res Unit Resp Dis, Xiangya Hosp 2, Changsha 410011, Peoples R China.;[Huang, Jin; Zhu, Liming; Zhou, Wei; Ma, Jinling; Gu, Jing; Li, San; Jiang, Yan] Hunan Normal Univ, Dept Resp & Crit Care Med, Hunan Prov Peoples Hosp, Affiliated Hosp 1, Changsha 410016, Peoples R China.;[Zeng, Dan] Hunan Normal Univ, Inst Resp Dis, Hunan Prov Peoples Hosp, Affiliated Hosp 1, Changsha 410016, Peoples R China.;[Xiang, Xudong] Cent South Univ, Dept Emergency, Inst Emergency & Difficult Dis, Xiangya Hosp 2, Changsha 410011, Peoples R China.;[Dai, Aiguo] Hunan Univ Chinese Med, Med Sch, Dept Resp Dis, Key Lab Vasc Biol & Translat Med Hunan Prov, Changsha 410208, Peoples R China.
通讯机构:
[Zhu, Liming] D;Department of Respiratory and Critical Care Medicine, Hunan Provincial People’s Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha, China
摘要:
Exercise intolerance is one of the major symptoms of chronic obstructive pulmonary disease (COPD). Exercise training can benefit COPD patients, but the underlying mechanism remains unclear. The modified Total Body Recumbent Stepper (TBRS, Nustep-T4) can benefit patients with stroke, spinal cord injury and amyotrophic lateral sclerosis. Nevertheless, the effect of TBRS training alone on pulmonary rehabilitation (PR) in COPD patients remains largely unknown. We aimed to explore the effect of TBRS training on exercise capacity and the thioredoxin system (TRXS) in COPD patients to provide a novel rehabilitation modality and new theoretical basis for PR of COPD patients. Ninety stable COPD patients were randomly divided into a control group (NC group) and a TBRS training group (TBRS group), with 45 cases in each group. Subjects in the TBRS training group were scheduled to undergo TBRS endurance training triweekly for 12weeks under the guidance of a rehabilitation therapist. We assessed the primary outcome: exercise capacity (6-min walking distance, 6MWD); and secondary outcomes: perception of dyspnoea (mMRC, Borg), the COPD assessment test (CAT), the BODE index, pulmonary function, the number of acute exacerbations of COPD and oxidative stress (TRXS) at one-year follow-up. Compared with before the intervention and the control group, after the intervention, the TBRS training group, exhibited an increase in the 6MWD (from 366.92 ± 85.81 to 484.10 ± 71.90, 484.10 ± 71.90 vs 370.63 ± 79.87, P < 0.01), while the scores on the BORG, mMRC, BODE index, CAT, and the number of acute exacerbations of COPD were reduced, and the protein and mRNA expression levels of TRXS was significantly increased (P < 0.01). However, no differences were found in PF parameters in the comparison with before the intervention or between groups. TBRS training can effectively increase exercise capacity, while there are indications that it can alleviate COPD-related dyspnoea and reduce the number of acute exacerbations of COPD. Interestingly, long-term regular TBRS training may reduce oxidative stress associated with COPD to increase exercise capacity.
摘要:
BACKGROUND: Pulmonary hypertension (PH) is a progressive disorder lacking a validated and effective therapy which characterized by elevated pulmonary arterial pressure, vascular remodeling and eventual death. FDA approved sildenafil is being used as a first-line drug for PH, however, neither survival rates nor quality of life have been improved because of side effects and patient noncompliance. Thus, the exploration of novel therapeutic drugs is urgently needed. Astragaloside IV (ASIV) exhibits a protective effect on HPH, but its mechanisms of action is unclear. HYPOTHESIS: CD4+T cell subsets, Tfh and Tfr cells, may contribute to the development of chronic hypoxia-induced PH (HPH). We hypothesized that ASIV could effectively ameliorates pulmonary vascular remodeling of HPH by restraining the Tfh cell response and expanding Tfr cell response. METHODS AND RESULTS: HPH mice model was established by exposure to chronic hypoxia for 21 days. Mice were randomly assigned to six groups: NaCl group, model group, SN group (100mg/kg of sildenafil), low-dose group (20mg/kg of ASIV), medium-dose group (40mg/kg of ASIV) and high-dose group (80mg/kg of ASIV). Primary culture and identification of distal pulmonary artery smooth muscle cells (PASMCs) in mice were established. Here, we demonstrated that ASIV treatment could significantly ameliorate the increase of mean PAP, RV/ (LV+S) ratio and PAMT in HPH mice. ASIV inhibited Tfh cell differentiation and IL-21 production, but promoted Tfr cell differentiation and TGF-β, IL-10 production. Chronic hypoxia promoted germinal center B cell responses, which inhibited by ASIV. ASIV regulated Tfh and Tfr cell differentiation by inhibiting the phosphorylation of mTOR signaling pathway, and the effect of ASIV-H was better than that observed in the SN group. ASIV inhibited the proliferation, migration and adhesion of PASMCs in vitro. Moreover, ASIV significantly downregulated the protein level of RhoA and upregulated the protein level of p27 in PASMCs under hypoxic condition. CONCLUSION: Collectively, ASIV may regulate Tfh and Tfr cell responses to subsequently repress pulmonary vascular remodeling and hypoxic pulmonary hypertension.
作者机构:
[Zhao, Tian Hao; Ye, Chun; Xu, Yan Zhe; Jiang, Yi Xuan; Zhou, Fang Liang; Qiu, Dan; Ren, Ting; Dai, Bin; Zhang, Bo; Hu, Jue; Lu, Jun; Wei, Ke; Xiao, Rong; Lu, Fang Guo; Chen, Kai Qin] Hunan Univ Chinese Med, Med Coll, Changsha 410208, Hunan, Peoples R China.;[Hu, Jue; Wei, Ke; Lu, Fang Guo] Hunan Univ Chinese Med, Hunan Prov Key Lab Integrated Tradit Chinese & We, Changsha 410208, Hunan, Peoples R China.
通讯机构:
[Ke Wei] M;Medical College, Hunan University of Chinese Medicine, Changsha, China<&wdkj&>Hunan Provincial Key Laboratory of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
摘要:
BACKGROUND: Myocarditis is a myocardial injury that can easily cause adolescent death. Traditional research models of animal invasion with viral components, lipopolysaccharide (LPS) or porcine myocardial myosin, among others, have the shortcomings of potential biological safety hazards and high animal mortality. OBJECTIVE: To explore the construction of a novel myocarditis model with cyclosporine A and the potential genes and pathways associated with it. METHODS: BALB/c mice were used in this study, and cyclosporin A and LPS were injected into the peritoneal cavity of mice. The successful establishment of the model was assessed by detecting serum myocardial injury markers and inflammatory factors levels, HE, IHC staining, and RT-qPCR methods. Key genes were obtained using the GSE35182 dataset from the GEO database and validated with the RT-qPCR method. RESULTS: We found that a large number of inflammatory cells infiltrated the myocardium of mice in each group of Cyclosporin A constructed model, while the expression of inflammatory factor indicators was increased, and this model has the characteristics of high degree of local inflammation in myocardial tissue, low mortality, and safe and non-toxic treatment. Using GSE35182 data, we selected 18 Hub genes and validated Hub genes in myocardial tissue with RT-qPCR and found that multiple signaling pathways such as Toll-likereceptor signaling pathway(TLRs), Rap1 signal pathway(Rap1), and Chemokine signaling pathway may be involved in the development of myocarditis. CONCLUSION: Cyclosporin A can construct a new myocarditis model, and TLRs, Chemokines and Rap1 signaling pathways may be the core pathways of myocarditis.