Association between magnesium depletion score and the prevalence of kidney stones in the low primary income ratio: a cross-sectional study of NHANES 2007-2018.

INTRODUCTION: To explore the association between magnesium depletion score (MgDS) and the prevalence of kidney stones in the low primary income ratio (PIR). METHOD: A cross-sectional study was conducted using data from the National Health and Nutrition Examination Survey 2007-2018. Within the low PIR, people aged ≥20 years with complete information on MgDS and kidney stones questionnaires were enrolled. Multivariable logistic regression and stratified logistic regression analyses were performed to examine the association between MgDS and the prevalence of kidney stones and recurrence of kidney stones by confounding factors adjusted. Stratified and interaction analysis was conducted to find whether some factors modified the association. In addition, sensitive analyses were also conducted to observe the stability. The work has been reported in line with the STROCSS criteria, Supplemental Digital Content 1, http://links.lww.com/JS9/C781. RESULT: A total of 7,600 adults were involved in the study, and the individuals were classified into four groups: 0 points for MgDS (n=3,814), 1 point for MgDS (n=2,229), 2 points for MgDS (n=1,020), and ≥3 points for MgDS (n=537). The multivariable logistic regression suggested that a positive association between MgDS and the prevalence of kidney stones (OR=1.123, 95%CI 1.019 to 1.238) in the fully-adjusted model. Compared with the lowest group, people with ≥3 points of MgDS had a had a significant relationship with kidney stones (OR=1.417, 95%CI 1.013 to 1.983). No significant association was observed between the recurrence of kidney stones and MgDS. The result of the sensitive analysis showed the robustness of the main analysis. CONCLUSION: The prevalence of kidney stones is inversely associated with MgDS, which suggests that maintaining a higher MgDS is accompanied by higher prevalence rates of kidney stones in the low PIR.

Association Between Physical Activity and the Prevalence of Kidney Stones in American Adults: Results From a Multiyear National Survey.

OBJECTIVE: To investigate the association between physical activity (PA) and the prevalence of kidney stones. METHODS: A cross-section study was conducted using data from National Health and Nutrition Examination Survey 2007-2018. PA was evaluated based on the Global Physical Activity Questionnaire. Multivariable logistic regression was performed to elucidate the association between PA (patterns, intensity, duration, and frequency of moderate and vigorous PA) and the prevalence of kidney stones after adjusting for potential confounders. Stratified and interaction analyses were conducted to detect potential effect modifiers. In addition, PA was assessed using metabolic equivalent and physical volume, and followed the regression above. Water intake was obtained from the day 2 dietary recall and was included in the sensitivity analysis. RESULTS: A total of 34,390 participants were included in the analysis. The multivariable logistic regression revealed that individuals who engaged in moderate PA for 30-60 minutes per day had a significant inverse association with the prevalence of kidney stones in the fully adjusted model (odds ratio=0.804, 95% confidence interval 0.700 to 0.923), while no more significant finding was observed for other PA parameters. Interaction and stratified analyses indicated no covariate modifying the association. The results above were robust in the sensitivity analysis. CONCLUSION: The duration of moderate PA (30-60 min/d) is inversely associated with the prevalence of kidney stones, while no more significant association was observed between other PA parameters (including patterns, intensity, duration, and frequency of vigorous PA, frequency of moderate PA) and kidney stones.

The predictive significance of chromobox family members in prostate cancer in humans.

PURPOSE: The Chromobox (CBX) family proteins are crucial elements of the epigenetic regulatory machinery and play a significant role in the development and advancement of cancer. Nevertheless, there is limited understanding regarding the role of CBXs in development or progression of prostate cancer (PCa). Our objective is to develop a unique prognostic model associated with CBXs to improve the accuracy of predicting outcomes of patients with PCa. METHODS: Data from TCGA and GEO databases were analyzed to assess differential expression, prognostic value, gene pathway enrichment, and immune cell infiltration. COX regression analysis was utilized to identify the independent prognostic factors that impact disease-free survival (DFS). The expression of CBX2 and FOXP3+ cells infiltration was verified by immunohistochemical staining of clinical tissue sections. In vitro proliferation, migration and invasion assay were conducted to examine the function of CBX2. RNA-seq was employed to examine the CBX2 related pathway enrichment. RESULTS: CBX2, CBX3, CBX4, and CBX8 were upregulated, while CBX6 and CBX7 were downregulated in PCa tissues. CBXs expression varied by stage and grade. Elevated expression of CBX1, CBX2, CBX3, CBX4 and CBX8 is correlated with poor outcome. CBX2 expression, T stage, and Gleason score were independent prognostic factors. The expression level of CBX2 in PCa tissues was significantly higher than that in adjacent normal tissues. More Treg infiltration was observed in the group with high CBX2 expression. CBX2 expression affected PCa cell growth, migration, and invasion. CONCLUSIONS: CBX2 is involved in the development and advancement of PCa, suggesting its potential as a reliable prognostic indicator for PCa patients.

Elucidating the role of MICAL1 in pan-cancer using integrated bioinformatics and experimental approaches.

Molecule interacting with CasL 1 (MICAL1) is a crucial protein involved in cell motility, axon guidance, cytoskeletal dynamics, and gene transcription. This pan-cancer study analyzed MICAL1 across 33 cancer types using bioinformatics and experiments. Dysregulated expression, diagnostic potential, and prognostic value were assessed. Associations with tumor characteristics, immune factors, and drug sensitivity were explored. Enrichment analysis revealed MICAL1's involvement in metastasis, angiogenesis, metabolism, and immune pathways. Functional experiments demonstrated its impact on renal carcinoma cells. These findings position MICAL1 as a potential biomarker and therapeutic target in specific cancers, warranting further investigation into its role in cancer pathogenesis.

Establishment of a prognostic risk prediction model incorporating disulfidptosis-related lncRNA for patients with prostate cancer.

PURPOSE: Prostate cancer (PCa) is one of the major tumor diseases that threaten men's health globally, and biochemical recurrence significantly impacts its prognosis. Disulfidptosis, a recently discovered cell death mechanism triggered by intracellular disulfide accumulation leading to membrane rupture, is a new area of research in the context of PCa. Currently, its impact on PCa remains largely unexplored. This study aims to investigate the correlation between long non-coding RNAs (lncRNAs) associated with disulfidptosis and the prognosis of PCa, seeking potential connections between the two. METHODS: Transcriptomic data for a PCa cohort were obtained from the Cancer Genome Atlas database. Disulfidptosis-related lncRNAs (DDRLs) were identified through differential expression and Pearson correlation analysis. DDRLs associated with biochemical recurrence-free survival (BRFS) were precisely identified using univariate Cox and LASSO regression, resulting in the development of a risk score model. Clinical factors linked to BRFS were determined through both univariate and multivariate Cox analyses. A prognostic nomogram combined the risk score with key clinical variables. Model performance was assessed using Receiver Operating Characteristic (ROC) curves, Decision Curve Analysis (DCA), and calibration curves. The functional impact of a critical DDRL was substantiated through assays involving CCK8, invasion, migration, and cell cloning. Additionally, immunohistochemical (IHC) staining for the disulfidptosis-related protein SLC7A11 was conducted. RESULTS: The prognostic signature included AC026401.3, SNHG4, SNHG25, and U73166.1 as key components. The derived risk score from these signatures stood as one of the independent prognostic factor for PCa patients, correlating with poorer BRFS in the high-risk group. By combining the risk score with clinical variables, a practical nomogram was created, accurately predicting BRFS of PCa patients. Notably, silencing AC026401.3 significantly hindered PCa cell proliferation, invasion, migration, and colony formation. IHC staining revealed elevated expression of the dithiosulfatide-related protein SLC7A11 in tumor tissue. CONCLUSIONS: A novel prognostic signature for PCa DDRLs, possessing commendable predictive power, has been constructed, simultaneously providing potential therapeutic targets associated with disulfidptosis, among which AC026401.3 has been validated in vitro and demonstrated inhibition of PCa tumorigenesis after its silencing.

Predictors of trimodality therapy in patients with muscle-invasive bladder cancer and effect on survival.

BACKGROUND: Due to its unique advantages over radical cystectomy (RC), trimodality therapy (TMT) is increasingly being utilized by patients diagnosed with muscle-invasive bladder cancer (MIBC) who are not suitable for or refuse RC. However, achieving a satisfactory oncological outcome with TMT requires strict patient selection criteria, and the comparative oncological outcomes of TMT versus RC remain controversial. METHODS: Patients diagnosed with non-metastatic MIBC who underwent TMT or RC were identified from the SEER database during 2004-2015. Before one-to-one propensity score matching (PSM), logistic regression was utilized to identify predictors of TMT. After matching, K-M curves were generated to estimate cancer-specific survival (CSS) and overall survival (OS) with log-rank to test the significance. Finally, we conducted univariate and multivariate Cox analyses to identify independent prognostic factors for CSS and OS. RESULTS: The RC and TMT groups included 5812 and 1260 patients, respectively, and the TMT patients were significantly older than the RC patients. Patients with advanced age, separated, divorced, or widowed (SDW) or unmarried marital status (married as reference), and larger tumor size (< 40 mm as reference) were more likely to be treated with TMT. After PSM, TMT was found to be associated with worse CSS and OS, and it was identified as an independent risk factor for both CSS and OS. CONCLUSION: MIBC patients may not be carefully evaluated prior to TMT, and some non-ideal candidates underwent TMT. TMT resulted in worse CSS and OS in the contemporary era, but these results may be biased. Strict TMT candidate criteria and TMT treatment modality should be required.

T1 mapping in evaluation of clinicopathologic factors for rectal adenocarcinoma.

OBJECTIVE: T1 mapping has been increasingly applied in the study of tumor. The purpose of this study was to evaluate the value of T1 mapping in evaluating clinicopathologic factors for rectal adenocarcinoma. MATERIALS AND METHODS: Eighty-six patients with rectal adenocarcinoma confirmed by surgical pathology who underwent preoperative pelvic MRI were retrospectively analyzed. High-resolution T2-weighted imaging (T2WI), T1 mapping, and diffusion-weighted imaging (DWI) were performed. T1 and apparent diffusion coefficient (ADC) parameters were compared among different associated tumor markers, tumor grades, stages, and structure invasion statuses. A receiver operating characteristic (ROC) analysis was estimated. RESULTS: T1 value showed significant difference between high- and low-grade tumors ([1531.5 ± 84.7 ms] vs. [1437.1 ± 80.3 ms], P < 0.001). T1 value was significant higher in positive than in negative perineural invasion ([1495.7 ± 89.2 ms] vs. [1449.4 ± 88.8 ms], P < 0.05). No significant difference of T1 or ADC was observed in different CEA, CA199, T stage, N stage, lymphovascular invasions, extramural vascular invasion (EMVI), and circumferential resection margin (CRM) (P > 0.05). The AUC under ROC curve of T1 value were 0.796 in distinguishing high- from low-grade rectal adenocarcinoma. The AUC of T1 value in distinguishing perineural invasion was 0.637. CONCLUSION: T1 value was helpful in assessing pathologic grade and perineural invasion correlated with rectal cancer.

Mechanism of prognostic marker SPOCK3 affecting malignant progression of prostate cancer and construction of prognostic model.

BACKGROUND: SPOCK3 is a secreted extracellular matrix proteoglycan. This study aimed to investigate the effect of SPOCK3 on the malignant progression of prostate cancer and to construct a prognostic model to predict DFS of patients with prostate cancer. METHODS: Clinical and transcriptome sequencing data for prostate cancer were download from the TCGA and GEO databases. The survival curve showed that SPOCK3 has prognostic significance. GO, KEGG, and GSEA enrichment analysis were used to investigate how SPOCK3 affects the malignant progression of prostate cancer. Based on ESTIMATE and ssGSEA, the relationship between SPOCK3 and immune cell infiltration in prostate cancer tissue was clarified. Univariate and multivariate COX regression analysis was used to identify the independent prognostic factors of prostate cancer OS and to construct a nomogram. The calibration curve and ROC curves were drawn to assess the nomogram's predictive power. RESULTS: The survival curve revealed that patients in the low-expression group of SPOCK3 had a poor prognosis. According to enrichment analysis, SOPCK3-related genes were enriched in collagen-containing extracellular matrix, PI3K-Akt, and MAPK signaling pathway. ESTIMATE analysis revealed that SPOCK3 expression was positively correlated with the interstitial score, immune score, and ESTIMATE score. The results of ssGSEA analysis revealed that the infiltration levels of Mast cells, NK cells, and B cells were higher in the SPOCK3 high expression group. Cox regression analysis showed that SPOCK3 expression level, T and Gleason score were independent risk factors of patient prognosis, and a nomogram was constructed. The ROC curve showed the AUCs of DFS at 2, 3, and 5 years. CONCLUSION: SPOCK3 is a protective factor for DFS in prostate cancer patients. SPOCK3 is significantly associated with immune cell infiltration. The prognostic model constructed based on SPOCK3 has excellent predictive performance.

LPS inhibits TRIM65 expression in macrophages and C57BL/6J mouse by activating the ERK1/2 signaling pathway.

Activated macrophages serve a key role in various inflammatory diseases, such as atherosclerosis and septic shock. Tripartite motif-containing protein 65 (TRIM65) has been previously reported to participate in tumor progression and lung inflammation. However, the molecular mechanisms that controls its expression under inflammatory conditions and its consequences in activated macrophages remain poorly understood. The present study first collected the tissues of C57BL/6J mice, smooth muscle cells, macrophages and endothelial cells to determine the expression and distribution of TRIM65 by reverse transcription-quantitative (RT-q) PCR and western blotting. Mouse and human macrophages were treated with LPS and C57BL/6J mice were intraperitoneally injected with LPS followed by isolation of spleen, lung, aorta and bone marrow. Following treatment, TRIM65 mRNA and protein level was examined by RT-qPCR and western blotting. The results showed that TRIM65 was highly expressed in organs of the immune system, such as the spleen, lymph node and thymus, but lowly expressed in heart, liver, brain and kidneys. TRIM65 was also highly expressed in macrophages and endothelial cells. TRIM65 mRNA and protein expression levels were found to be decreased in LPS-treated macrophages in vitro and in tissues isolated from C57BL/6J mice intraperitoneally injected with LPS in vivo. In addition, to identify the signaling pathways by which LPS regulates TRIM65 expression, inhibitors of MAPK and Akt signaling pathways were used to treat macrophages followed by examination the expression of TRIM65 by western blotting. The results demonstrated that LPS-inhibited TRIM65 expression was blocked by treatment with the ERK1/2 inhibitor U0126. Moreover, the RT-qPCR results showed that TRIM65 knockout potentiated LPS-induced expression of inflammatory cytokines in macrophages. Taken together, data from the present study suggest that LPS decreased TRIM65 expression in macrophages and C57BL/6J mouse by activating the ERK1/2 signaling pathway, whilst TRIM65 knockout promoted macrophage activation. This information may facilitate the development of potential therapeutic strategies for the prevention and treatment of inflammatory diseases, such as atherosclerosis.

SARS-CoV-2 E protein-induced THP-1 pyroptosis is reversed by Ruscogenin.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an emerging pathogenic coronavirus, has been reported to cause excessive inflammation and dysfunction in multiple cells and organs, but the underlying mechanisms remain largely unknown. Here we showed exogenous addition of SARS-CoV-2 envelop protein (E protein) potently induced cell death in cultured cell lines, including THP-1 monocytic leukemia cells, endothelial cells, and bronchial epithelial cells, in a time- and concentration-dependent manner. SARS-CoV-2 E protein caused pyroptosis-like cell death in THP-1 and led to GSDMD cleavage. In addition, SARS-CoV-2 E protein upregulated the expression of multiple pro-inflammatory cytokines that may be attributed to activation of NF-κB, JNK and p38 signal pathways. Notably, we identified a natural compound, Ruscogenin, effectively reversed E protein-induced THP-1 death via inhibition of NLRP3 activation and GSDMD cleavage. In conclusion, these findings suggested that Ruscogenin may have beneficial effects on preventing SARS-CoV-2 E protein-induced cell death and might be a promising treatment for the complications of COVID-19.

Nicaraven protects against endotoxemia-induced inflammation and organ injury through modulation of AMPK/Sirt1 signaling in macrophages.

Endotoxemia is a disease characterized by systemic inflammatory responses and organ injury caused by lipopolysaccharide (LPS) infection, with high mortality. Nicaraven (AVS), a potent hydroxyl radical scavenger, has been proven to regulate the inflammatory response in tumors. To investigate the protective effects and mechanisms of AVS in endotoxemia, mice were injected intraperitoneally with LPS to induce endotoxemia. AVS treatment significantly decreased the levels of pro-inflammatory cytokines in the serum, reduced neutrophil infiltration, attenuated multiple organ injury, and increased the survival rate in LPS-challenged mice. In the LPS-induced inflammatory model of macrophages, AVS inhibited macrophage activation, suppressed nitric oxide (NO) production, and inhibited the expression and secretion of pro-inflammatory cytokines. Mechanistically, AVS treatment up-regulated silence information regulator transcript-1 (Sirt1) expression in a time- and dose-dependent manner. AVS treatment activated the AMP-dependent protein kinase (AMPK)/Sirt1 signaling pathway and suppressed the activation of nuclear factor kappa B (NF-κB) in macrophages exposed to LPS. However, the anti-inflammatory effects of AVS could be reversed by the AMPK, the Sirt1 inhibitor, or the histone deacetylase inhibitor. We confirmed that the AMPK inhibitor inhibited AVS-mediated AMPK/Sirt1 activation and NF-κB p65 acetylation. These results suggested that AVS alleviated endotoxemia by activating the AMPK/Sirt1 signaling pathway in macrophages.

Association between visceral adiposity index and kidney stones in American adults: A cross-sectional analysis of NHANES 2007-2018.

Objective: To explore the association between Visceral Adiposity Index (VAI) and kidney stones in an American adult population. Materials and methods: National Health and Nutrition Examination Survey (NHANES) datasets from 2007 to 2018 were used. Participants aged ≥20 years who reported kidney stone history and VAI were included. Weighted proportions, multivariable analysis, generalized additive model (GAM), and spline smoothing were used to evaluate the associations between VAI and kidney stones by adjusting gender, age, race, education, marital status, poverty income ratio, smoking, alcohol, high blood pressure, diabetes, congestive heart failure, cancer, vigorous activity, moderate activity, HEI2015 total score, and energy. Results: Totally 13,871 American adults were included. All the participants were divided by the VAI into four groups according to the quartile: Q1 (11.96-42.89), Q2 (42.90-74.45), Q3 (74.45-131.43), and Q4 (131.45-611.34). The mean ± standard deviation of the VAI in the four groups were Q1 (29.07 ± 8.22), Q2 (57.53 ± 8.81), Q3 (99.52 ± 16.25), and Q4 (225.92 ± 95.83). In the fully adjusted multivariable model, VAI was positively correlated with urolithiasis [odds ratio (OR) = 1.001; 95% confidence interval (CI) 1.000-1.001]. Compared with the first quartile of VAI, the population in the fourth quartile of VAI had a higher prevalence of kidney stones (OR = 1.329; 95% CI 1.104-1.600). Subgroup analysis detected no significant interaction effect after adjusting for covariates. Conclusion: The value of VAI is positively correlated with the prevalence of kidney stones, which suggest VAI can be used to assess the potential risk of the prevalence of kidney stones.

Diagnostic Performance of Diffusion-Weighted Imaging for Colorectal Cancer Detection: An Updated Systematic Review and Meta-Analysis.

Background: Magnetic resonance imaging (MRI), which uses strong magnetic fields and radio waves (radiofrequency energy) to make images, is one of the best imaging methods for soft tissues and can clearly display unique anatomical structures. Diffusion-weighted imaging (DWI) has been developed for identifying various malignant tumors. Aim: To investigate the diagnostic value of DWI-MRI quantitative analysis in colorectal cancer detection. Methods: The PubMed, Cochrane Library, and Embase databases were searched from inception to May 29, 2020. Studies published in English that used DWI-MRI for diagnosing colorectal cancer were included. Case reports, letters, reviews, and studies conducted in non-humans or in-vitro experiments were excluded. The pooled diagnostic odds ratio (DOR) and hierarchical summary receiver operating characteristic (HSROC) curves were computed for DWI, and the area under the curve (AUC) and associated standard error (SE) and 95% confidence intervals (CIs) were also used. Results: In total, 15 studies with 1,655 participants were finally included in this meta-analysis. There were four prospective studies and 11 retrospective studies. Eight studies focused on rectal cancer, six on colorectal cancer, and one on colonic cancer. The performance of DWI-MRI for diagnosing colorectal cancer was accurate, with pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 0.88 (95% CI = 0.85-0.91), 0.92 (95% CI = 0.91-0.94), 30.36 (95% CI = 11.05-83.43), and 0.44 (95% CI = 0.30-0.64), respectively. The DOR and HSROC curves were 121 (95% CI = 56-261) and 0.92 (λ: 4.79), respectively. Conclusion: DWI showed high diagnostic accuracy for colorectal cancer detection. Further studies with large sample sizes and prospective design are needed to confirm these results.

Association between urine cobalt and prevalence of kidney stones in Americans aged ≥ 20 years old.

To determine whether urine cobalt (Co) is associated with the prevalence of kidney stones, we conducted a cross-sectional study of participants (≥ 20 years) involved in the National Health and Nutrition Examination Survey (NHANES) between 2007 and 2018. The urine Co level was divided into four groups: 0.02-0.22, 0.22-0.36, 0.36-0.58, and 0.58-37.40 µg/L. The independent correlation between urine Co and prevalence of kidney stones was determined by logistic regression analyses. A total of 10,744 participants aged over 20 years that were not pregnant were eligible. Among them, 1041 participants reported ever having developed kidney stones. Patients with kidney stones developed significantly higher urine Co than the non-stone participants. The kidney stone patients were more likely to have been smoking ≥ 100 cigarettes in life; have hypertension, diabetes, and cancer; and engage in heavy activity. Multivariate logistic regression indicated a significantly positive relationship between the urine Co level and occurrence of kidney stones (OR 1.059, 95% CI 1.018-1.102, P = 0.00430). Moreover, the outcome remained unchanged after some sophisticated factors were adjusted (OR 1.059, 95% CI 1.001-1.120, P = 0.04635), and kidney stones were significantly related to a higher level of Co (OR (95% CI) = 0.22-0.36 µg/L: 1.111 (0.869, 1.421); 0.36-0.58 µg/L: 1.392 (1.095, 1.770); 0.58-37.40 µg/L: 1.712 (1.351, 2.170), and P for trend < 0.00001). So, urine Co concentration is positively associated with the prevalence of kidney stones. However, more high-quality prospective studies are needed to elucidate the causal correlation between Co level and kidney stones.

Association Between Healthy Eating Index-2015 and Kidney Stones in American Adults: A Cross-Sectional Analysis of NHANES 2007-2018.

Purpose: To explore the association between Healthy Eating Index (HEI)-2015 and kidney stones in an American adult population. Materials and Methods: National Health and Nutrition Examination Survey (NHANES) datasets from 2007 to 2018 were used. Participants aged ≥ 20 years who reported kidney stone history and dietary recall were included. Weighted proportions, multivariable analysis and spline smoothing were used to evaluate the associations between HEI-2015 and nephrolithiasis by adjusting gender, age, race, poverty income ratio, body mass index, education level, marital status, smoking, alcohol intake, energy level, vigorous activity, moderate activity, and some comorbidities. Results: Totally 30 368 American adults were included, with weighted mean age [standard deviation (SD)] of 47.69 (16.85) years. The overall mean HEI-2015 score (SD) was 50.82 (13.80). In the fully-adjusted multivariable model, HEI-2015 was negatively correlated with urolithiasis [odds ratio (OR) = 0.991; 95% confidence interval (CI) 0.988 to 0.994]. Compared with the first quartile of HEI-2015, the population in the fourth quartile of HEI-2015 had a lower prevalence of kidney stones (OR = 0.716; 95% CI 0.635 to 0.807). The association was modified by education and vigorous activity. Conclusions: HEI-2015 is inversely associated with the prevalence of kidney stones, which means better diet quality is associated with a lower risk of nephrolithiasis.

CD38 Deficiency Protects Mice from High Fat Diet-Induced Nonalcoholic Fatty Liver Disease through Activating NAD+/Sirtuins Signaling Pathways-Mediated Inhibition of Lipid Accumulation and Oxidative Stress in Hepatocytes.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes. CD38 was initially identified as a lymphocyte surface antigen and then has been found to exist in a variety of cell types. Our previous studies showed that CD38-/- mice were resistant to high-fat diet (HFD)-induced obesity. However, the role and mechanism of CD38 in HFD-induced NAFLD is still unclear. Here, we reported that CD38-/- mice significantly alleviated HFD-induced hepatic steatosis. HFD or oleic acid (OA) remarkably increased the mRNA and protein expressions of CD38 in mouse hepatic tissues and primary hepatocytes or hepatic cell lines in vitro and in vivo, suggesting that CD38 might play a role in HFD-induced hepatic steatosis. We observed that CD38 deficiency markedly decreased HFD- or OA-induced the lipid accumulation and oxidative stress in CD38-/- livers or primary hepatocytes, respectively. In contrast, overexpression of CD38 in Hep1-6 cells aggravated OA-induced lipid accumulation and oxidative stress. Furthermore, CD38 deficiency markedly inhibited HFD- or OA-induced the expressions of NOX4, and increased the expression of PPARα, CPT1, ACOX1 and SOD2 in liver tissue and hepatocytes from CD38-/- mice, indicating that CD38 deficiency-mediated the enhancement of fatty acid oxidation and the inhibition of oxidative stress contributed to protecting NAFLD. More importantly, Ex527 (Sirt1 inhibitor) and 3-TYP (Sirt3 inhibitor) significantly enhanced OA-induced lipid accumulation and oxidative stress in CD38-/- primary hepatocytes, suggesting that the anti-lipid accumulation of CD38 deficiency might be dependent on NAD/Sirtuins-mediated enhancement of FAA ß-oxidation and suppression of oxidative stress in hepatocytes. In conclusion, we demonstrated that CD38 deficiency protected mice from HFD-induced NAFLD by reducing lipid accumulation and suppressing oxidative stress via activating NAD/Sirtuins signaling pathways.

Human amniotic mesenchymal stem cells-conditioned medium protects mice from high-fat diet-induced obesity.

BACKGROUND: Obesity is a metabolic disorder syndrome characterized by excessive fat accumulation that is related to many diseases. Human amniotic mesenchymal stem cells (hAMSCs) have a great potential for cell-based therapy due to their characteristics such as pluripotency, low immunogenicity, no tumorigenicity, potent paracrine effects, and no ethical concern. Recently, we observed that both hAMSCs and their conditioned medium (hAMSCs-CM) efficiently repaired skin injury, inhibited hepatocellular carcinoma, and alleviated high-fat diet (HFD)-induced diabetes. However, the effects and the underlying mechanisms of hAMSCs-CM on high-fat diet (HFD)-induced obesity were not explored. METHODS: The characteristics of hAMSCs were confirmed by flow cytometry, RT-PCR, and immunofluorescence. Obese mice were induced by administrating HFD for 15 weeks and simultaneously, the mice were intraperitoneally injected with hAMSCs-CM weekly to evaluate the effects of hAMSCs-CM on HFD-induced obesity. GTT and ITT assays were used to assess the effects of hAMSCs-CM on HFD-induced glucose tolerance and insulin resistance. The lipid accumulation and adipocytes hypertrophy in mouse adipose tissues were determined by histological staining, in which the alterations of blood lipid, liver, and kidney function were also examined. The role of hAMSCs-CM in energy homeostasis was monitored by examining the oxygen consumption (VO2), carbon dioxide production (VCO2), and food and water intake in mice. Furthermore, the expressions of the genes related to glucose metabolism, fatty acid ß oxidation, thermogenesis, adipogenesis, and inflammation were determined by western blot analysis, RT-PCR, and immunofluorescence staining. The roles of hAMSCs-CM in adipogenesis and M1/M2 macrophage polarization were investigated with 3T3-L1 preadipocytes or RAW264.7 cells in vitro. RESULTS: hAMSCs-CM significantly restrained HFD-induced obesity in mice by inhibiting adipogenesis and lipogenesis, promoting energy expenditure, and reducing inflammation. The underlying mechanisms of the anti-obesity of hAMSCs-CM might be involved in inhibiting PPARγ and C/EBPα-mediated lipid synthesis and adipogenesis, promoting GLUT4-mediated glucose metabolism, elevating UCP1/PPARα/PGC1α-regulated energy expenditure, and enhancing STAT3-ARG1-mediated M2-type macrophage polarization. CONCLUSION: Our studies demonstrated that hAMSCs significantly alleviated HFD-induced obesity through their paracrine effects. Obviously, our results open up an attractive therapeutic modality for the prevention and treatment of obesity and other metabolic disorders clinically. The cytokines, exosomes, or micro-vesicles secreted from hAMSCs significantly inhibited HFD-induced obesity in mice by inhibiting lipid production and adipogenesis, promoting energy consumption, and reducing inflammation.