Factors associated with skeletal muscle mass in middle-aged men living with HIV.

BACKGROUND: Despite extensive research on muscle loss in people living with HIV (PLWH), the prevalence and contributing factors specifically among middle-aged men remain unclear. This study aimed to determine the prevalence of low muscle mass within this demographic and to identify associated factors. METHODS: A total of 378 men living with HIV were enrolled in the study. They were classified into low muscle mass group if they displayed a skeletal muscle index (SMI) <7.00 kg/m2 or fell within the lowest quintile of SMI based on the criteria established by the Asian Working Group for Sarcopenia 2019. RESULTS: Out of the 378 men living with HIV enrolled, 351 had normal muscle mass, while 27 (7.1%) had low muscle mass. Antiretroviral drugs Zidovudine (AZT) (OR = 0.246, P = 0.022) and higher serum albumin levels (OR = 0.899, P = 0.026) were found to be protective factors against low muscle mass according to quintile grouping. Strong positive associations between SMI and body mass index (BMI), nutritional risk index (NRI), oedema index and fat-free mass index (FFMI) (R > 0.5, P < 0.001) were observed. In addition, both BMI (sensitivity = 0.741, specificity = 0.906) and NRI (sensitivity = 0.963, specificity = 0.601) had high sensitivity and specificity in diagnosing low muscle mass, with critical values of 19.85 and 114.177 for BMI and NRI, respectively. The oedema index was the most effective measure of body composition in detecting abnormal fluid retention with high sensitivity (92.6%) and moderate specificity (71.8%) in identifying individuals with low muscle mass. Notably, PLWH with low muscle mass participants had a significantly higher prevalence (92.6%) of a high oedema index compared with those with normal muscle mass (28.2%). This observation indicates that individuals with HIV who experience reduced muscle mass is commonly accompanied with abnormal fluid retention within the body. CONCLUSIONS: Antiretroviral medication types, specifically Zidovudine, BMI and NRI can be independent risk factors for low muscle mass in men with HIV. These factors, along with BMI, could be used conveniently to predict low muscle mass. Furthermore, the association between the oedema index and muscle mass suggests that observing signs of oedema may indicate a risk of low muscle mass in PLWH.

Diallyl trisulfide induces pyroptosis and impairs lung CSC-like properties by activating the ROS/Caspase 1 signaling pathway.

Lung cancer stem cells (CSCs) drive continuous cancer growth and metastatic dissemination; thus, there is an urgent requirement to acquire effective therapeutic strategies for targeting lung CSCs. Diallyl trisulfide (DATS), a garlic organosulfide, possesses suppressive potential in lung cancer; however, its underlying mechanism is still unclear. In this study, we identified DATS as a pyroptosis inducer in lung cancer cells. DATS-treated A549 and H460 cells exhibited pyroptotic cell death, with characteristic large bubbles appearing on their plasma membrane and LDH release. DATS induced cell death, arrested the cell cycle at the G2/M phase, and inhibited colony formation in lung cancer cells. Meanwhile, we found that DATS significantly suppressed the malignant features by impairing lung CSC-like properties, including sphere formation ability, CD133 positive cell number, and lung CSCs marker expression. Mechanistically, DATS induced cell pyroptosis via increasing the expression of NLRP3, ASC, Pro Caspase 1, Cleaved Caspase 1, GSDMD, GSDMD-N, and IL-1ß. The verification experiments showed that the effects of DATS on pyroptosis and lung CSC-like properties were weakened after Caspase 1 inhibitor VX-765 treatment, indicating that DATS activated NLRP3 inflammasome-mediated pyroptosis by targeting Caspase 1 in lung cancer cells. Moreover, DATS increased ROS overproduction and mitochondrial dysfunction, which contributed to DATS-induced pyroptosis of lung cancer cells. NAC treatment reversed the effects of DATS on pyroptosis and CSC-like properties. In vivo experiment further confirmed that DATS restrained tumor growth. Together, our results suggest that DATS promotes pyroptosis and impairs lung CSC-like properties by activating ROS/Caspase 1 signaling pathway, thereby retarding lung cancer progression.

Drug-eluting beads versus conventional transarterial chemoembolization for the treatment of unresectable hepatocellular carcinoma: A meta-analysis.

BACKGROUND: Transarterial chemoembolization (TACE) consists of conventional TACE (cTACE) and drug-eluting beads TACE (DEB-TACE). The benefits of the 2 treatments remain controversial. We conduct this meta-analysis to assess the efficacy and safety of the 2 methods for the patients with unresectable hepatocellular carcinoma. METHODS: In order to get a sound conclusion, we did thorough search all relevant studies with clear and stringent keyword criteria on the main databases. Objective tumor response rate, overall survival (OS) rate and adverse events were calculated and analyzed by RevMan 5.3 software. The random-effects or fixed-effects model was applied to pool the estimates according to Cochran Q test and I2 statistics. RESULTS: Twenty-four studies involving 2987 patients were eligible. DEB-TACE significantly improved objective tumor response rate (OR) (risk ratio [RR] = 1.27, 95% confidence interval [CI] [1.08, 1.48]; P = .003). While as for 1-year, 2-year, 3-year, 5-year OS rates, there were no evidences to indicate that DEB-TACE was significantly better than cTACE (RR = 1.05, 95% CI [0.99, 1.11]; P = .08), (RR = 1.02, 95% CI [0.93, 1.11]; P = .68), (RR = 0.92, 95% CI [0.77, 1.10]; P = .37), (RR = 0.92, 95% CI [0.47, 1.80]; P = .81), respectively. Adverse events rate (AE) was also similar in both groups (RR = 1.11, 95% CI [0.99,1.26]; P = .08). CONCLUSION: This meta-analysis demonstrates that DEB-TACE is not superior than cTACE regarding to OS and AE. However, DEB-TACE still be considered to provide a better objective tumor response rate for patients with unresectable hepatocellular carcinoma.

Labdane and ent-halimane diterpenoids with STAT3-inhibitory activity from Leonurus sibiricus.

Nine undescribed labdane diterpenoids (1-9) and one undescribed ent-halimane diterpenoid (10) were isolated from the aerial parts of Leonurus sibiricus, together with four known analogues (11-14) during our searching for naturally occurring antitumor agents. Their structures were established by detailed spectroscopic analyses and electronic circular dichroism analysis. Compound 4 possessed a rare 10-epi labdane scaffold. All compounds except 5 were evaluated for their inhibitory activities against interleukin (IL)-6-stimulated signal transducer and activator of transcription (STAT3) expression using a luciferase reporter assay. Compound 1 showed the most inhibitory effect with the IC50 value 20.31 µM. Compound 1 inhibited the activation of JAK2/STAT3 signal pathway through binding to Gln326 of STAT3 in CNE cells. The antiproliferative evaluation of compound 1 against CNE, CAL-27, A549 and PANC-1 cells demonstrated that CNE cells were the most sensitive to 1. Furthermore, compound 1 showed moderate efficacy in inhibiting cell migration, invasion, and epithelial-mesenchymal transition in CNE cells. In addition, compound 1 also promoted ferroptosis in CNE cells in a dose-dependent manner. These results suggest that compound 1 might be a potential candidate lead for treating nasopharyngeal carcinoma.

Diallyl trisulfide inhibits gastric cancer stem cell properties through ΔNp63/sonic hedgehog pathway.

Gastric cancer is one of the deadliest malignant tumors, and half of the patients develop recurrences or metastasis within 5 years after eradication therapy. Cancer stem cells (CSCs) are considered to be important in this progress. The sonic hedgehog (SHH) pathway plays an important role in the maintenance of gastric CSCs characteristics. The p63 proteins are vital transcription factors belonging to the p53 family, while their functions in regulating CSCs remain unclear. The preventive effects of dietary diallyl trisulfide (DATS) against human gastric cancer have been verified. However, whether DATS can target gastric CSCs are poorly understood. Here, we investigated the role of ΔNp63/SHH pathway in gastric CSCs and the inhibitory effect of DATS on gastric CSCs via ΔNp63/SHH pathway. We found that ΔNp63 was upregulated in serum-free medium cultured gastric tumorspheres compared with the parental cells. Overexpression of ΔNp63 elevated the self-renewal capacity and CSC markers' levels in gastric sphere-forming cells. Furthermore, we found that ΔNp63 directly bound to the promoter region of Gli1, the key transcriptional factor of SHH pathway, to enhance its expression and to activate SHH pathway. In addition, it was revealed that DATS effectively inhibited gastric CSC properties both in vitro and in vivo settings. Activation of SHH pathway attenuated the suppressive effects of DATS on the stemness of gastric cancer. Moreover, DATS suppression of gastric CSC properties was also diminished by ΔNp63 upregulation through SHH pathway activation. These findings illustrated the role of ΔNp63/SHH pathway in DATS inhibition of gastric cancer stemness. Taken together, the present study suggested for the first time that DATS inhibited gastric CSCs properties by ΔNp63/SHH pathway.

Human amniotic mesenchymal stem cell-conditioned medium inhibited LPS-induced cell injury and inflammation by modulating CD14/TLR4-mediated signaling pathway in monocytes.

Human amniotic mesenchymal stem cells (hAMSCs) have attracted considerable attention as a promising regenerative therapy. Many studies reported that the conditioned medium of hAMSCs (AM-CM) exerted anti-inflammatory and immunomodulatory functions, while its underlying mechanism is poorly understood. In this study, we first confirmed that AM-CM (25%, 50%, 100%) was optimal for anti-inflammation at 24 h. Lipopolysaccharide (LPS)-induced alteration of cell morphology, the decrease of cell proliferation, and the upregulation of cell apoptosis were significantly reversed in AM-CM-treated THP-1 cells. 25% and 50% AM-CM significantly decreased LPS-induced intracellular reactive oxygen species (ROS) production and proinflammatory cytokines secretion. Mechanistically, we found that AM-CM treatment suppressed LPS-induced activation of MAPK and NF-κB pathways by inhibiting CD14/TLR4 in THP-1 cells. Meanwhile, activation of NLRP3 inflammasome was also dose-dependently attenuated by AM-CM treatment. Thus, AM-CM may exert positive influences on the inflammation microenvironment and provide a novel strategy for improving tissue regeneration.

Destruction of the cellular antioxidant pool contributes to resveratrol-induced senescence and apoptosis in lung cancer.

Resveratrol (RES) has various pharmacological bioactivities and its anticancer effects in lung cancer have been proven. However, the underlying mechanisms of action of RES in lung cancer remain unclear. This study focused on Nrf2-mediated antioxidant systems in RES-treated lung cancer cells. A549 and H1299 cells were treated with various concentrations of RES at different times. RES decreased cell viability, inhibited cell proliferation, and increased the number of senescent and apoptotic cells in a concentration- and time-dependent manner. Moreover, RES-induced lung cancer cell arrest at the G1 phase was accompanied by changes in apoptotic proteins (Bax, Bcl-2, and cleaved caspase 3). Furthermore, RES induced a senescent phenotype along with changes in senescence-related markers (senescence-associated ß-galactosidase activity, p21, and p-γH2AX). More importantly, with prolonged exposure time and increased exposure concentration, intracellular reactive oxygen species (ROS) continuously accumulated, resulting in a decrease in Nrf2 and its downstream antioxidant response elements, including CAT, HO-1, NQO1, and SOD1. Meanwhile, RES-induced ROS accumulation and cell apoptosis were reversed by N-acetyl-l-cysteine treatment. Taken together, these results suggest that RES disturb lung cancer cellular homeostasis by destroying the intracellular antioxidant pool to increase ROS production. Our findings provide a new perspective on RES intervention in lung cancer.

Cytotoxic Terpenes from the Flowers of Inula japonica against Human Hepatocarcinoma Cells.

Two new 1,10-seco-eudesmanolides (1 and 2) were isolated from the flowers of Inula japonica together with two eudesmanolide analogs (3 and 4) and two monoterpene derivatives (5 and 6). Their structures were established on the basis of detailed spectroscopic analyses and electronic circular dichroism data. All isolates were evaluated for their antiproliferative activities against human hepatocarcinoma HepG2 and SMMC-7721 cells. Japonipene B (3) exhibited the most potent effect with the IC50 values of 14.60±1.62 and 22.06±1.34 µM against HepG2 and SMMC-7721 cells, respectively. Furthermore, japonipene B (3) showed significant efficacies of arresting the cell cycle at the S/G2-M stages, inducing mitochondria-mediated apoptosis, and inhibiting cell migration in HepG2 cells.

Flavokawain A suppresses the vasculogenic mimicry of HCC by inhibiting CXCL12 mediated EMT.

BACKGROUND: Hepatocellular carcinoma has high ability of vascular invasion and metastasis. Vasculogenic mimicry (VM) is closely related to the metastasis and recurrence of hepatocellular carcinoma (HCC). According to previous research, Chloranthus henryi has anti-tumor effect, but its molecular mechanism in the treatment of HCC has not yet been stated. PURPOSE: In our study, we aimed to investigate the effect of the extract of Chloranthus henryi in HCC and its target and molecular mechanism. We hoped to explore potential drugs for HCC treatment. STUDY DESIGN/METHODS: In this study, we isolated a chalcone compound from Chloranthus henryi, compound 4, identified as flavokawain A (FKA). We determined the anti-HCC effect of FKA by MTT and identified the target of FKA by molecular docking and CETSA. Hepatoma cells proliferation, migration, invasion, and VM formation were examined using EDU, wound healing, transwell, vasculogenic mimicry, and IF. WB, RT-PCR, and cell transfection were used to explore the mechanism of FKA on hepatoma cells. Tissue section staining is mainly used to demonstrate the effect of FKA on HCC in vivo. RESULTS: We confirmed that FKA can directly interact with CXCL12 and HCC proliferation, migration, invasion, and VM formation were all inhibited through reversing the EMT progress in vitro and in vivo through the PI3K/Akt/NF-κB signaling pathway. Additionally, by overexpressing and knocking down CXCL12, we got the same results. CONCLUSION: FKA attenuated proliferation, invasion and metastatic and reversed EMT in HCC via PI3K/Akt/HIF-1α/NF-κB/Twist1 pathway by targeting CXCL12. This study proposed that FKA may be a candidate drug and prospective strategy for HCC therapy.

Low-dose phthalates promote breast cancer stem cell properties via the oncogene ΔNp63α and the Sonic hedgehog pathway.

BACKGROUND: The omnipresence of human phthalate (PAE) exposure is linked to various adverse health issues, including breast cancer. However, the effects of low-dose PAE exposure on breast cancer stem cells (BCSCs) and the underlying mechanism remain unexplored. METHODS: BCSCs from breast cancer cell lines (MDA-MB-231 and MCF-7) were enriched using a tumorsphere formation assay. Gene and protein expression was detected by measurement of quantitative real-time reverse transcription PCR, western blot, and immunofluorescence assays. Transient transfection assays were used to evaluate the involvement of Gli1, a signaling pathway molecule and ΔNp63α, an oncogene in influencing the PAE-induced characteristics of BCSCs. RESULTS: PAE (butylbenzyl phthalate, BBP; di-butyl phthalate, DBP; di-2-ethylhexyl phthalate, DEHP) exposure of 10-9 M significantly promoted the tumorsphere formation ability in BCSCs. Breast cancer spheroids with a 10-9 M PAE exposure had higher levels of BCSC marker mRNA and protein expression, activated sonic hedgehog (SHH) pathway, and increased mRNA and protein levels of an oncogene, ΔNp63α. Furthermore, suppression of the SHH pathway attenuated the effects of PAEs on BCSCs. And the overexpression of ΔNp63α enhanced PAE-induced characteristics of BCSCs, while low expression of ΔNp63α inhibited the promotion effects of PAEs on BCSCs and the SHH pathway. CONCLUSION: Low-dose PAE exposure promoted the stem cell properties of BCSCs in a ΔNp63α- and SHH-dependent manner. The influence of low-dose exposure of PAEs and its relevance for the lowest observed effect concentrations requires further investigation, and the precise underlying mechanism needs to be further explored.

Evaluation of toxicological effects of bisphenol S with an in vitro human bone marrow mesenchymal stem cell: Implications for bone health.

As the use of bisphenol A (BPA) has been restricted in consumer products, bisphenol S (BPS) is one major alternative to BPA for various materials, leading to growing concerns about its health risks in human beings. However, little is known about the toxic effects of BPS on bone health. We employed human bone marrow mesenchymal stem cells (hBMSCs) for the in vitro assessment of BPS on cell proliferation, differentiation, and self-renewal. Our study revealed that BPS at concentrations of 10-10-10-7 M increased cell viability but induced the morphological changes of hBMSCs. Moreover, BPS decreased ROS generation and increased Nrf2 expression. Furthermore, BPS not only activated ERα/ß expression but also increased ß-catenin expression and induced the replicative senescence of hBMSCs. Furthermore, we found that the upregulation of ß-catenin induced by BPS was mediated, in part, by ER signaling. Overall, our results suggested BPS exposure caused the homeostatic imbalance of hBMSCs.

Resveratrol suppresses lung cancer by targeting cancer stem-like cells and regulating tumor microenvironment.

Increasing evidence indicate that cancer stem cells (CSCs) are the key driver of tumor initiation and recurrence. The cellular and soluble components of the tumor microenvironment (TME) impact on cancer initiation and progression, such as cytokines and chemokines. Thus, targeting CSCs and TME is a novel anti-cancer approach. Resveratrol (RES), a bioactive phytochemical extracted from various plants, exhibits tumor-suppressing activities in lung cancer, yet the mechanism remains poorly understood. Our data showed that the expression level of IL-6 was positively correlated with the presence of lung cancer stem-like cells (LCSCs) in human lung cancer tissues. In vitro results showed that IL-6 was highly elevated in lung cancer sphere-forming cells and could enhance the stemness of LCSCs, including tumor sphere formation ability, the percentage of CD133 positive cells, and the expression of LCSC specific markers (CD133, ALDH1A1 and Nanog). Simultaneously, our results confirmed that RES effectively inhibited LCSC properties, downregulated Wnt/ß-catenin signaling and reduced IL-6 level in vitro and in vivo. Furthermore, we found RES treatment attenuated the activation of Wnt/ß-catenin signaling by LiCl (GSK3ß agonist). IL-6-promoted LCSC properties and Wnt/ß-catenin signaling was also reversed by RES. Taken together, these data illustrated that RES inhibited lung cancer by targeting LCSCs and IL-6 in TME. The novel findings from this study provided evidence that RES exhibited multi-target effects on suppression of lung cancer and could be a novel potent cancer-preventive compound.

Jianpi Huayu decoction inhibits the epithelial-mesenchymal transition of hepatocellular carcinoma cells by suppressing exosomal miR-23a-3p/Smad signaling.

ETHNOPHARMACOLOGICAL RELEVANCE: Jianpi Huayu decoction (JHD) is a traditional Chinese medicinal preparation used to treat a variety of malignant tumors including HCC, although the underlying mechanism remains unknown. Exosomes in the tumor microenvironment mediate intercellular signaling among cancer cells, but precise contributions to hepatocellular carcinoma (HCC) progression are still elusive. AIM OF THE STUDY: In this work, the main objective was to examine the mechanisms underlying anti-tumor effects of JHD and the potential contributions of exosomal signaling. MATERIALS AND METHODS: LC-MS/MS was used for quality control of JDH preparation, while nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM) and western blotting were used for verification of exosomes. In vitro assays included CCK8, wound healing assay, transwell invasion assay, qRT-PCR and western blotting were performed to investigate the effects of JHD on HCC cells and the molecular mechanism. Furthermore, the effects of JHD on subcutaneous tumor model of nude mice were also determined. RESULTS: JHD inhibited the proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of cultured HCC cells. Further, exosomes isolated from EMT-induced HCC cells promoted the migration, invasion and EMT of other cultured HCC cells, while exosomes isolated from EMT-induced HCC cells after JHD treatment had little effect. In addition, JHD reduced the expression of exosomal miR-23a-3p in cultured HCC cells. miR-23a-3p was significantly up-regulated in tumor compared with that in adjacent non-cancerous tissues of patients with HCC. HCC patients with high miR-23a-3p expression had poor overall survival after hepatectomy. Meanwhile, miR-23a-3p enhanced HCC cell proliferation, EMT, and expression of Smad signaling proteins. More importantly, overexpression of miR-23a-3p can reverse the inhibition of EMT and Smad signaling pathway caused by JHD treatment. In vivo assays, treatment with JHD also reduced the growth of HCC-derived tumors in nude mice, reduced the expression of miR-23a-3p in serum exosomes and the level of EMT in tumor cells. CONCLUSIONS: the antitumor effects of JHD on HCC are mediated at least in part by inhibition of EMT due to downregulation of exosome-mediated intercellular miR-23a-3p transfer and subsequent blockade of Smad signaling. Disrupting this exosomal miR-23a-3p/Smad signaling pathway may be an effective treatment.

ΔNp63α mediates sulforaphane suppressed colorectal cancer stem cell properties through transcriptional regulation of Nanog/Oct4/Sox2.

Cancer stem cells (CSCs) play a key role in cancer initiation, development, metastasis, and recurrence. Previously, we found that sulforaphane (SFN), a natural compound obtained from cruciferous vegetables, inhibited colorectal CSCs via the downregulation of TAp63α. However, the role of ΔNp63α, another critical isoform of p63 which has been considered to contribute to cancer progression, in SFN-mediated colorectal CSCs inhibition remains unclear. Here, we showed that ΔNp63α expression was enhanced in sphere-forming colorectal cancer cells. Overexpression of ΔNp63α promoted the properties of CSCs, while downregulation of ΔNp63α suppressed those properties. Besides, ΔNp63α was found to activate the transcription of core CSCs genes including Nanog, Oct4, and Sox2. Furthermore, in vitro and in vivo experiments illustrated the regulatory effects of SFN on ΔNp63α and colorectal CSCs. These findings suggested for the first time that ΔNp63α activated the transcription of Nanog, Oct4, Sox2 and mediated the interventional effects of SFN on colorectal CSCs, thus providing a novel mechanism by which SFN inhibits colorectal CSCs.

Bmi-1-RING1B prevents GATA4-dependent senescence-associated pathological cardiac hypertrophy by promoting autophagic degradation of GATA4.

AIMS: Senescence-associated pathological cardiac hypertrophy (SA-PCH) is associated with upregulation of foetal genes, fibrosis, senescence-associated secretory phenotype (SASP), cardiac dysfunction and increased morbidity and mortality. Therefore, we conducted experiments to investigate whether GATA4 accumulation induces SA-PCH, and whether Bmi-1-RING1B promotes GATA4 ubiquitination and its selective autophagic degradation to prevent SA-PCH. METHODS AND RESULTS: Bmi-1-deficient (Bmi-1-/- ), transgenic Bmi-1 overexpressing (Bmi-1Tg ) and wild-type (WT) mice were infused with angiotensin II (Ang II) to stimulate the development of SA-PCH. Through bioinformatics analysis with RNA sequencing data from cardiac tissues, we found that Bmi-1-RING1B and autophagy are negatively related to SA-PCH. Bmi-1 deficiency promoted GATA4-dependent SA-PCH by increasing GATA4 protein and hypertrophy-related molecules transcribed by GATA4 such as ANP and BNP. Bmi-1 deficiency stimulated NF-κB-p65-dependent SASP, leading to cardiac dysfunction, cardiomyocyte hypertrophy and senescence. Bmi-1 overexpression repressed GATA4-dependent SA-PCH. GATA4 degraded by Bmi-1 was mainly dependent on autophagy rather than proteasome. In human myocardium, p16 positively correlated with ANP and GATA4 and negatively correlated with LC3B, Bmi-1 and RING1B; GATA4 positively correlated with p62 and negatively correlated with Bmi-1 and LC3B. With increased p16 protein levels, ANP-, BNP- and GATA4-positive cells or areas increased; however, LC3B-positive cells or areas decreased in human myocardium. GATA4 is ubiquitinated after combining with Bmi-1-RING1B, which is then recognised by p62, is translocated to autophagosomes to form autophagolysosomes and degraded. Downregulated GATA4 ameliorated SA-PCH and cardiac dysfunction by reducing GATA4-dependent hypertrophy and SASP-related molecules. Bmi-1 combined with RING1B (residues 1-179) and C-terminus of GATA4 (residues 206-443 including zinc finger domains) through residues 1-95, including a RING-HC-finger. RING1B combined with C-terminus of GATA4 through the C-terminus (residues 180-336). Adeno-associated viral vector serotype 9 (AAV9)-cytomegalovirus (CMV)-Bmi-1-RING1B treatment significantly attenuated GATA4-dependent SA-PCH through promoting GATA4 autophagic degradation. CONCLUSIONS: Bmi-1-RING1B maintained cardiac function and prevented SA-PCH by promoting selective autophagy for degrading GATA4. TRANSLATIONAL PERSPECTIVE: AAV9-CMV-Bmi-1-RING1B could be used for translational gene therapy to ubiquitinate GATA4 and prevent GATA4-dependent SA-PCH. Also, the combined domains between Bmi-1-RING1B and GATA4 in aging cardiomyocytes could be therapeutic targets for identifying stapled peptides in clinical applications to promote the combination of Bmi-1-RING1B with GATA4 and the ubiquitination of GATA4 to prevent SA-PCH and heart failure. We found that degradation of cardiac GATA4 by Bmi-1 was mainly dependent on autophagy rather than proteasome, and autophagy agonists metformin and rapamycin could ameliorate the SA-PCH, suggesting that activation of autophagy with metformin or rapamycin could also be a promising method to prevent SA-PCH.

Amniotic membrane mesenchymal stem cells-based therapy improves Bmi-1-deficient mandible osteoporosis through stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption.

Mandible osteoporosis with age is characterized by greater fragility and accompanied with abnormal oral function. Mesenchymal stem cell transplantation can ameliorate osteoporosis. Bmi-1 is a transcriptional repressor which is an important regulator of cell cycle, stem cells self-renewal, and cell senescence. Here, we use a new kind of membrane mesenchymal stem cells (MSCs), amniotic membrane mesenchymal stem cells (AMSCs), to explore therapeutic effects on Bmi-1-deficient caused mandible osteoporosis. Phenotypes of mandibles from 5-week-old Bmi-1-deficient mice with AMSCs-based therapy were compared with age-matched Bmi-1-deficient mandibles without AMSCs-based therapy and wild-type mice. Bmi-1-deficient mice without AMSCs-based therapy displayed mandible osteoporosis accompanied with the rising senescence-associated molecules and imbalance redox homeostasis. Results showed that the alveolar bone volume, cortical thickness, type I collagen and osteocalcin immunopositive areas, mRNA expression levels of alkaline phosphatase, superoxide dismutase, gluathione reductase, and protein expression level of Runx2 were all reduced significantly in Bmi-1-/- mandibles. Protein levels of PPARγ, p16, p21, p53, and redox gene levels of Bnip3l, Cdo1, Duox1, and Duox2 were up-regulated in mandibles from vehicle-transplanted Bmi-1-/- mice. Also, osteoclasts were activated in Bmi-1-/- alveolar bone. Transplanted AMSCs migrated into mandibles and improved all the parameters in Bmi-1-/- mandibles with AMSCs-based therapy. These findings indicate that AMSCs-based therapy could rescue mandible osteoporosis induced by Bmi-1 deficiency through stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption. Our findings implied that AMSCs-based therapy had preventative and therapeutic potential for mandible osteoporosis.

Sirt1 Mediates Vitamin D Deficiency-Driven Gluconeogenesis in the Liver via mTorc2/Akt Signaling.

As an active form of vitamin D (VD), 1,25-dihydroxyvitamin D (1,25(OH)2D3) is involved in the development of many metabolic diseases, such as diabetes, autoimmune diseases, and tumours. While prospective epidemiological studies have consistently implicated VD deficiency in the regulation of glucose metabolism and insulin sensitivity, the specific mechanism remains unclear. Here, we generated 1α(OH)ase-null mice (targeted ablation of the 25-hydroxyvitamin D 1α hydroxylase enzyme) and found that these mice developed hepatic glucose overproduction, glucose intolerance, and hepatic insulin resistance accompanied by reduced Sirtuin 1 (Sirt1) expression. The chromatin immunoprecipitation (ChIP) and a luciferase reporter assay revealed that 1,25(OH)2D3-activated VD receptor (VDR) directly interacted with one VD response element (VDRE) in the Sirt1 promoter to upregulate Sirt1 transcription, triggering a cascade of serine/threonine kinase (AKT) phosphorylation at S473 and FOXO1 phosphorylation at S256. This phosphorylation cascade reduced the expression of gluconeogenic genes, eventually attenuating glucose overproduction in the liver. In addition, a signaling pathway was found to modulate gluconeogenesis involving VDR, Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), AKT, and FOXO1, and Sirt1 and FOXO1 were identified as key modulators of dysregulated gluconeogenesis due to VD deficiency.

Interleukin-17A mediates tobacco smoke-induced lung cancer epithelial-mesenchymal transition through transcriptional regulation of ΔNp63α on miR-19.

Interleukin-17A (IL-17A) is an essential inflammatory cytokine in the progress of carcinogenesis. Tobacco smoke (TS) is a major risk factor of lung cancer that influences epithelial-mesenchymal transition (EMT) process. However, the potential mechanism by which IL-17A mediates the progression of lung cancer in TS-induced EMT remains elusive. In the present study, it was revealed that the IL-17A level was elevated in lung cancer tissues, especially in tumor tissues of cases with experience of smoking, and a higher IL-17A level was correlated with induction of EMT in those specimens. Moreover, the expression of ΔNp63α was increased in IL-17A-stimulated lung cancer cells. ΔNp63α functioned as a key oncogene that bound to the miR-17-92 cluster promoter and transcriptionally increased the expression of miR-19 in lung cancer cells. Overexpression of miR-19 promoted EMT in lung cancer with downregulation of E-cadherin and upregulation of N-cadherin, while its inhibition suppressed EMT. Finally, the upregulated levels of IL-17A, ΔNp63α, and miR-19 along with the alteration of EMT-associated biomarkers were found in lung tissues of TS-exposed mice. Taken together, the abovementioned results suggest that IL-17A increases ΔNp63α expression, transcriptionally elevates miR-19 expression, and promotes TS-induced EMT in lung cancer. These findings may provide a new insight for the identification of therapeutic targets for lung cancer.