Inhibiting H2AX Can Ameliorate Myocardial Ischemia/Reperfusion Injury by Regulating P53/JNK Signaling Pathway.

Myocardial ischemia-reperfusion (I/R) injury is a significant area of focus in cardiovascular disease research. I/R injury can increase intracellular oxidative stress, leading to DNA damage. H2AX plays a crucial role in DNA repair. This study utilized mouse and cell models of myocardial I/R to investigate the impact of H2AX on cardiomyocytes during I/R. This study initially assessed the expression of H2AX in MI/R mice compared to a sham surgery group. Subsequently, cardiac function, infarct area, and mitochondrial damage were evaluated after inhibiting H2AX in MI/R mice and a negative control group. Furthermore, the study delved into the molecular mechanisms by analyzing the expression of H2AX, P53, p-JNK, SHP2, p-SHP2, p-RAS, parkin, Drp1, Cyt-C, Caspase-3, and Caspase-8 in cardiomyocytes following the addition of JNK or P53 agonists. The results from western blotting in vivo indicated significantly higher H2AX expression in the MI/R group compared to the sham group. Inhibiting H2AX improved cardiac function, reduced myocardial infarct area, and mitigated mitochondrial damage in the MI/R group. In vitro experiments demonstrated that inhibiting H2AX could attenuate mitochondrial damage and apoptosis in myocardial cells by modulating the P53 and JNK signaling pathways. These findings suggested that inhibiting H2AX may alleviate myocardial I/R injury through the regulation of the P53/JNK pathway, highlighting H2AX as a potential target for the treatment of myocardial ischemia/reperfusion injury.

MicroRNA­194­5p attenuates hypoxia/reoxygenation­induced apoptosis in H9C2 cardiomyocytes by inhibiting the over­activation of RAC1 protein.

Ras­related C3 botulinum toxin substrate 1 (RAC1), a member of the Rac family of guanosine triphosphate phosphohydrolases, has been suggested to be a regulator of myocardial injury during ischemia and reperfusion (I/R). Whether microRNAs (miRs) are involved in the regulation of the aforementioned process remains to be elucidated. In the present study, an in vitro model of H9C2 cardiomyocytes was used to establish the overexpression of RAC1 following hypoxia and reoxygenation (H/R). Overexpression of RAC1 in H/R­cultured cardiomyocytes could lead to cellular accumulation of reactive oxygen species (ROS) and facilitate the induction of apoptosis of H9C2 cardiomyocytes during H/R. Subsequent bioinformatic analysis indicated that RAC1 was the target of miRNA­194­5p. Further experiments showed that miR­194­5p attenuated the accumulation of cellular ROS and alleviated the induction of apoptosis of H9C2 cardiomyocytes caused by H/R, which was accompanied by the reduction in the expression levels of the RAC1 protein. Taken together, these results indicated that upregulation of miR­194­5p may function as a self­regulated cardioprotective response against RAC1­mediated ROS accumulation and cardiomyocyte apoptosis. Exogenous administration of miR­194­5p may be a novel target to ameliorate I/R injury­induced myocardial apoptosis.

Eczema as a protective factor for brain cancer: a meta-analysis.

BACKGROUND: Brain cancer is one of the most aggressive cancer types owing to poor treatment effects. Epidemiological studies have demonstrated that allergies may increase the disease risk. Therefore, this study evaluated the association between eczema and the risk of various brain cancers. METHODS: We systematically searched the PubMed and Embase databases from their inception until June 23, 2022. Two reviewers independently reviewed and screened the articles, extracted data, assessed the study quality, and pooled the results. Stata software was used to generate pooled odds ratios and 95% confidence intervals (CIs). RESULTS: We included 20 studies comprising 5,117,222 patients that investigated the relationship between eczema and brain cancer. Eczema was significantly inversely associated with the risk of brain cancer (odds ratio [OR], 0.82; 95% CI, 0.77-0.87), glioma (OR, 0.53; 95% CI, 0.14-2.02), meningioma (OR, 0.74; 95% CI, 0.66-0.84), and acoustic neuroma (OR, 0.60; 95% CI, 0.41-0.88). Interesting, The strong correlation between eczema and the reduced risk of brain cancer was observed in people over 16 years old (OR, 0.79; 95% CI, 0.71-0.88), but not in those under 16 years old (OR, 0.94; 95% CI, 0.79-1.11). In addition, subgroup analyses found that eczema significantly decreased the glioma risk in Europeans (OR, 0.73; 95% CI, 0.65-0.82) but not Australians (OR, 0.53; 95% CI, 0.14-2.02) or Americans (OR, 1.01; 95% CI, 0.69-1.46). CONCLUSION: Eczema may be considered as a potential protective factor of brain cancer in population aged over 16 years. However, this relationship requires verification using large-scale clinical data.

A pooled analysis of the association between sarcopenia and osteoporosis.

BACKGROUND: Sarcopenia is a progressive generalized skeletal muscle disorder that causes the accelerated loss of muscle mass and function. Osteoporosis is a systemic condition of the skeleton that results in low bone mass and quality. Several studies have suggested that osteoporosis and sarcopenia are interrelated; however, a few studies indicate the lack of a significant association between sarcopenia and osteoporosis. We aimed to evaluate the association between sarcopenia and osteoporosis via a systematic review and pooled analysis. METHODS: From the inception of the PubMed and Embase databases until September 2022, we conducted a systematic search for studies evaluating the relationship between sarcopenia and osteoporosis. Study appraisal and synthesis methods: We included observational studies that provided 95% confidence intervals (CIs) and risk estimates. Two reviewers independently extracted data and assessed the quality of the research. The random-effects model was applied to the pool analysis, and the odds ratios (ORs) and 95% CIs were finally calculated. RESULTS: The primary statistic was the mutual risk between sarcopenia and osteoporosis. According to the inclusion criteria, 56 studies (796,914 participants) were finally included. Sarcopenia was significantly correlative to the risk of osteoporosis (OR, 3.06; 95% CI, 2.30-4.08), and each standard deviation increase in relative appendicular skeletal muscle mass was significantly related to a decreased risk of osteoporosis (OR, 0.65; 95% CI, 0.56-0.75). Osteoporosis observably referred to a higher risk of sarcopenia (OR, 2.63; 95% CI, 1.98-3.49). CONCLUSION: Our research indicated that sarcopenia and osteoporosis are highly positively correlated. Osteoporosis is closely associated with the risk of sarcopenia. Our finding highlights the importance of sarcopenia screening for those at risk of osteoporosis, and vice versa. However, heterogeneity was noted among the studies, and this might have influenced the accuracy of the results. Therefore, the results of our study should be interpreted with caution.

Potential Correlation Between Eczema and Hematological Malignancies Risk: A Systematic Review and Meta-Analysis.

Background: Eczema characterized by itch, sleeplessness, and adverse effects on quality of life is associated with a risk of hematological malignancies. However, there is a controversy pertaining to whether this association implies a greater or lesser risk of hematological cancers. We aimed to explore the link between eczema and hematological malignancies risk. Methods: We systematically searched PubMed and Embase databases from their inception to February 17, 2022. Two reviewers independently screened articles, extracted data and assessed study quality, respectively. The odds ratios and 95% confidence intervals (CIs) were pooled by using fixed or random-effects models. Results: 29 studies involving 2,521,574 participants examined the contribution of eczema to hematological malignancies. We found that eczema significantly increased the risk of Hodgkin's lymphoma (1.44; 95% CI, 1.07-1.95), myeloma (1.15; 95% CI, 1.04-1.28), and significantly decreased the risk of lymphocytic leukemia (0.91; 95% CI, 0.84-0.99); however, it is not significantly associated with Non-Hodgkin's lymphoma, and myelocytic leukemia. Conclusion: Eczema has been shown to be associated with the risk of hematological cancer, this association still needs to be verified in large randomized controlled trials. Systematic Review Registration: https://inplasy.com/, INPLASY202260097.

hsa_circ_0000523/miR-let-7b/METTL3 axis regulates proliferation, apoptosis and metastasis in the HCT116 human colorectal cancer cell line.

Circular RNAs (circRNAs/circs) have gained attention as a class of potential biomarkers for the early detection of multiple cancers. However, the functions and mechanisms of circRNAs in the oncogenesis of human colorectal cancer (CRC) remain to be elucidated. The present study aimed to investigate the roles of hsa_circ_0000523 and its parental gene methyltransferase-like 3 (METTL3) in regulating cell proliferation, apoptosis and invasion in the HCT116 human CRC cell line. To uncover the regulated function of hsa_circ_0000523 in HCT116 cells, a dual-luciferase reporter assay, flow cytometry, reverse transcription-quantitative PCR, Cell Counting Kit-8 assay, cell invasion and western blot assay were used. In HCT116 cells, hsa_circ_0000523 indirectly regulated METTL3 expression by suppressing the transcription of microRNA (miR)-let-7b. The expression of METTL3 promoted cell proliferation and suppressed apoptosis. In the present study, it was found that miR-let-7b promoted cell viability and inhibited apoptosis and invasion, while circ_0000523 exerted the opposite effects. Higher levels of METTL3 expression were associated with more aggressive tumor invasion. The present results suggest that circRNAs and METTL3 may be applied for highly sensitive diagnosis of CRC and for predicting prognosis in patients who have undergone therapy.

LncRNA4474 inhibits renal fibrosis by regulating hepatocyte nuclear factor-1ß through miR-615 modulation.

Long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) are involved in the development and progression of renal fibrosis. lncRNAs can regulate target messenger RNAs (mRNAs) by competitively binding to miRNAs. However, research on lncRNA-miRNA-mRNA interactions remains inadequate. Therefore, the aim of the present study was to investigate the possible function of lncRNA-miRNA-mRNA interactions in chronic renal fibrosis. The relationships among the expression levels of lncRNA4474, miR-615, and hepatocyte nuclear factor-1ß (HNF-1ß) mRNAs were determined through RNA sequencing. The biological roles of lncRNA4474, miR-615, and HNF-1ß in renal fibrosis were investigated with gain-of-function and loss-of-function experiments. Results showed that miR-615 expression increased in unilateral ureteral obstruction rats, accompanied by decreased lncRNA4474 and HNF-1ß mRNA expression. The overexpression of HNF-1ß attenuated the development of chronic renal fibrosis, whereas HNF-1ß knockdown promoted the development. Increase in HNF-1ß expression downregulated and upregulated the expression levels of miR-615 and lncRNA4474, respectively, thereby attenuating renal fibrosis progression. Furthermore, lncRNA4474 promoted the expression of HNF-1ß by inhibiting miR-615 expression, whereas miR-615 regulated the expression of HNF-1ß and thus activated the Wnt signaling pathway. This study demonstrated that the overexpression of lncRNA4474 may attenuate fibrosis progression, accompanied by the downregulation of miR-615 and upregulation of HNF-1ß. Hence, this study provides novel information that can be useful in the early diagnosis and treatment of renal fibrosis.

Long non-coding RNA taurine upregulated gene 1 is downregulated in osteoporosis and influences the osteogenic differentiation of bone marrow mesenchymal stem cells.

BACKGROUND: With aging, an imbalance in bone remodeling leading to increased bone resorption and decreased bone formation is thought to contribute to osteoporosis. Osteoblastic differentiation of bone marrow mesenchymal stem cells (BMMSCs) plays a vital role in the pathogenesis of osteoporosis. However, the detailed molecular mechanisms of osteoporosis remain incompletely understood. Given that long non-coding RNA taurine upregulated gene 1 (lnc TUG1) plays a critical role in the osteogenic differentiation, and microRNA-23b (miR-23b) as a putative sponge for lnc TUG1 has upregulated expression in osteoporosis. Therefore, this study investigated the roles of TUG1/miR-23b in osteoporotic pathology. MATERIAL AND METHODS: TUG1 and miR-23b expression in the plasma of osteoporotic patients were evaluated by quantitative real-time PCR (qRT-PCR). The osteogenic differentiation in human BMMSCs was evaluated by qRT-PCR, western blot, Alizarin red staining after knockdown of TUG1 by small interfering RNA (siRNA) treatment. RESULTS: Decreased expression of TUG1 and increased expression of miR-23b evident in the plasma of patients with osteoporosis than in that of age- and sex-matched healthy controls. Additionally, increased miR-23b expression inhibited runt-related transcription factor 2 (RUNX2), osteocalcin, and osteopontin expression and reduced calcified nodule formation based on the results of qRT-PCR, western blot, and Alizarin Red S staining. CONCLUSION: The study for the first time reported that silence of lncRNA TUG1 significantly suppressed the osteogenic differentiation of BMMSCs possibly by targeting the miR-23b/RUNX2 signaling pathway. This mechanism of TUG1/miR-23b/RUNX2 signaling within the osteogenic differentiation of BMMSCs might provide new insight for the development of lncRNA-directed diagnostic and therapeutic strategies for osteoporosis.

Osteoporosis Is Characterized by Altered Expression of Exosomal Long Non-coding RNAs.

Osteoporosis is a metabolic bone disease characterized by a decrease in bone mass and degradation of the bone microstructure, which increases bone fragility and risk of fracture. However, the molecular mechanisms of osteoporosis remain unclear. The current study attempts to elucidate the role of exosomal long non-coding RNA in the pathology of osteoporosis. Peripheral blood was collected from persons with (OP) or without (NC) osteoporosis, and the serum exosomes were extracted using ultra centrifugation process. Total RNA of exosomes was isolated, and the lncRNAs profiling was done using RNA-Seq experiments. In silico analysis resulted in identification of 393 differentially expressed (DE) lncRNAs in OP vs. NC, with 296 that were up-regulated and 97 were down-regulated. Bioinformatics analysis of potential target mRNAs of lncRNAs with cis-acting mechanism showed that mRNAs co-located with DE lncRNAs were highly enriched in osteoporosis-related pathways, including regulation of insulin secretion, activation of MAPK activity, cellular response to metal ions, fucosylation and proteolysis. Together these results suggest that lncRNAs of serum exosomes could play a significant role in development of osteoporosis and such information may be helpful in developing diagnostic markers and therapeutic modules for osteoporosis.

The Analysis for Anemia Increasing Fracture Risk.

BACKGROUND Fractures are a major public health problem for elderly people throughout the world. Anemia is also a common, important health problem among elderly populations. The aim of this article was to estimate the association between anemia and fracture incidence via a systematic review and meta-analysis. MATERIAL AND METHODS The participant, intervention, observation, and study design (PICOS) reporting guidelines were followed, and databases were searched from their inception to May 2020 to identify relevant studies. When heterogeneity was significant, and a random-effects model was used. Subgroup analysis was conducted to explore the source of heterogeneity based on sex, study design, and region. RESULTS We found that anemia significantly increased fracture risk [relative risk (RR)=1.26, 95% confidence interval (CI)=1.14-1.39, P<0.001], specifically, hip fracture (RR=1.44, 95% CI=1.29-1.61), spine fracture (RR=1.15, 95% CI=1.08-1.23), and nonspine fracture (RR=1.42, 95% CI=1.33-1.52). Males with anemia had a 1.51-fold higher fracture risk, females had a 1.09-fold higher fracture risk. And the association was stronger in Asian (RR=1.22, 95% CI=1.07-1.40), but not in American and European study populations. CONCLUSIONS In conclusion, a significantly increased fracture risk was observed, and anemia can be a predictor of fracture risk.

An updated analysis of opioids increasing the risk of fractures.

OBJECTIVE: To assess the relationship between opioid therapy for chronic noncancer pain and fracture risk by a meta-analysis of cohort studies and case-control studies. METHODS: The included cohort studies and case-control studies were identified by searching the PubMed and EMBASE databases from their inception until May 24, 2019. The outcome of interest was a fracture. This information was independently screened by two authors. When the heterogeneity among studies was significant, a random effects model was used to determine the overall combined risk estimate. RESULTS: In total, 12 cohort studies and 6 case-control studies were included. We used the Newcastle-Ottawa Scale (NOS) to evaluate the quality of the included literature, and 14 of the studies were considered high-quality studies. The overall relative risk of opioid therapy and fractures was 1.78 (95% confidence interval (CI) 1.53-2.07). Subgroup analyses revealed sources of heterogeneity, sensitivity analysis was stable, and no publication bias was observed. CONCLUSIONS: The meta-analysis showed that the use of opioids significantly increased the risk of fracture.