The effect of dietary carbohydrate and calorie restriction on weight and metabolic health in overweight/obese individuals: a multi-center randomized controlled trial.

BACKGROUND: Both low-carbohydrate (LC) and calorie-restricted (CR) diets have been shown to have metabolic benefits. However, the two regimens have yet to be thoroughly compared. We conducted a 12-week randomized trial to compare the effects of these diets separately and in combination on both weight loss and metabolic risk factors in overweight/obese individuals. METHODS: A total of 302 participants were randomized to LC diet (n = 76), CR diet (n = 75), LC + CR diet (n = 76), or normal control (NC) diet (n = 75) using a computer-based random number generator. The primary outcome was the change in body mass index (BMI). The secondary outcomes included body weight, waist circumference, waist-to-hip ratio, body fat, and metabolic risk factors. All participants attended health education sessions during the trial. RESULTS: A total of 298 participants were analyzed. BMI change over 12 weeks was - 0.6 (95% CI, - 0.8 to - 0.3) kg/m2 in NC, - 1.3 (95% CI, - 1.5 to - 1.1) kg/m2 in CR, - 2.3 (95% CI, - 2.6 to - 2.1) kg/m2 in LC, and - 2.9 (95% CI, - 3.2 to - 2.6) kg/m2 in LC + CR. LC + CR diet was more effective than LC or CR diet alone at reducing BMI (P = 0.001 and P < 0.001, respectively). Furthermore, compared with the CR diet, the LC + CR diet and LC diet further reduced body weight, waist circumference, and body fat. Serum triglycerides were significantly reduced in the LC + CR diet group compared with the LC or CR diet alone. Plasma glucose, homeostasis model assessment of insulin resistance, and cholesterol concentrations (total, LDL, and HDL) did not change significantly between the groups during the 12-week intervention. CONCLUSIONS: The reduction of carbohydrate intake without restricting caloric intake is more potent to achieve weight loss over 12 weeks when compared to a calorie-restricted diet in overweight/obese adults. The combination of restricting carbohydrate and total calorie intake may augment the beneficial effects of reducing BMI, body weight, and metabolic risk factors among overweight/obese individuals. TRIAL REGISTRATION: The study was approved by the institutional review board of Zhujiang Hospital of Southern Medical University and registered at the China Clinical Trial Registration Center (registration number: ChiCTR1800015156).

IL-17 induces non-small cell lung cancer metastasis via GCN5-dependent SOX4 acetylation enhancing MMP9 gene transcription and expression.

Interleukin-17 (IL-17), a potent proinflammatory cytokine, can trigger the metastasis of non-small cell lung cancer (NSCLC). However, the underlying mechanism involved in IL-17-induced NSCLC cell metastasis remains unclear. In this study, we found that not only the expression of IL-17, IL-17RA, and/or general control nonrepressed protein 5 (GCN5), SRY-related HMG-BOX gene 4 (SOX4), and matrix metalloproteinase 9 (MMP9) was increased in the NSCLC tissues and in the IL-17-stimulated NSCLC cells, but also IL-17 treatment could enhance NSCLC cell migration and invasion. Further mechanism exploration revealed that IL-17-upregulated GCN5 and SOX4 could bind to the same region (-915 to -712 nt) of downstream MMP9 gene promoter driving its gene transcription. In the process, GCN5 could mediate SOX4 acetylation at lysine 118 (K118, a newly identified site) boosting MMP9 gene expression as well as cell migration and invasion. Moreover, the SOX4 acetylation or MMP9 induction and metastatic nodule number in the lung tissues of the BALB/c nude mice inoculated with the NSCLC cells stably infected by corresponding LV-shGCN5 or LV-shSOX4, LV-shMMP9 plus IL-17 incubation were markedly reduced. Overall, our findings implicate that NSCLC metastasis is closely associated with IL-17-GCN5-SOX4-MMP9 axis.

Highly sensitive Curcumin-conjugated nanotheranostic platform for detecting amyloid-beta plaques by magnetic resonance imaging and reversing cognitive deficits of Alzheimer's disease via NLRP3-inhibition.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder without effective therapy and lack diagnosis strategy for preclinical AD patients. There is an urgent need for development of both early diagnosis and therapeutic intervention of AD. RESULTS: Herein, we developed a nanotheranostics platform consisting of Curcumin (Cur), an anti-inflammatory molecule, and superparamagnetic iron oxide (SPIO) nanoparticles encapsulated by diblock 1,2-dio-leoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylene glycol)] (DSPE-PEG) that are modified with CRT and QSH peptides on its surface. Furthermore, we demonstrated that this multifunctional nanomaterial efficiently reduced ß-amyloid plaque burden specifically in APP/PS1 transgenic mice, with the process noninvasively detected by magnetic resonance imaging (MRI) and the two-dimensional MRI images were computed into three-dimension (3D) plot. Our data demonstrated highly sensitive in vivo detection of ß-amyloid plaques which more closely revealed real deposition of Aß than previously reported and we quantified the volumes of plaques for the first time based on 3D plot. In addition, memory deficits of the mice were significantly rescued, probably related to inhibition of NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasomes. CONCLUSIONS: Gathered data demonstrated that this theranostic platform may have both early diagnostic and therapeutic potential in AD.

Reversal of angiotensin ll-induced ß-cell dedifferentiation via inhibition of NF-κb signaling.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by pancreatic ß-cell failure, which arises from metabolic stress and results in ß cell dedifferentiation, leading to ß-cell death. Pathological activation of the renin-angiotensin system (RAS) contributes to increase cell stress, while RAS intervention reduces the onset of T2DM in high-risk populations and promotes insulin secretion in rodents. In this study, we investigated whether and how RAS induces ß-cell dedifferentiation and the mechanism underlying this process. METHODS: In vitro, with the methods of quantitative real-time reverse transcriptase-PCR (qRT-PCR) and western blotting, we examined the change of cell identity-related gene expression, progenitor like gene expression, cellular function, and nuclear factor kappa b (NF-κb) signaling activity in ß cell lines after exposure to angiotensin II (AngII) and disruption of RAS. In vivo, parallel studies were performed using db/db mice. Related protein expression was detected by Immunofluorescence analysis. RESULT: Activation of RAS induced dedifferentiation and impaired insulin secretion, eventually leading to ß-cell failure. Mechanistically, Angll induced ß-cell dedifferentiation via NF-κb signaling, while treatment with lrbesartan and sc-514 reversed the progenitor state of ß cells. CONCLUSION: The present study found that RAS might induce ß-cell dedifferentiation via angiotensin II receptor type 1 activation, which was promoted by NF-κb signaling. Therefore, blocking RAS or NF-kb signaling efficiently reversed the dedifferentiated status of ß cells, suggesting a potential therapy for patients with type 2 diabetes.

Circulating LncRNAs Analysis in Patients with Type 2 Diabetes Reveals Novel Genes Influencing Glucose Metabolism and Islet ß-Cell Function.

BACKGROUND/AIMS: The islet is an important endocrine organ to secrete insulin to regulate the metabolism of glucose and maintain the stability of blood glucose. Long noncoding RNAs (lncRNAs) are involved in a variety of biological functions and play key roles in many diseases, including type 2 diabetes (T2D). The aim of this study was to determine whether lncRNA-p3134 is associated with glucose metabolism and insulin signaling in pancreatic ß cells. METHODS: LncRNA microarray technology was used to identify the differentially expressed circulating lncRNAs in T2D patients. RT-PCR analyses were performed to determine the expression of lncRNA-p3134 in 30 pairs of diabetic and non-diabetic patients. The correlation of lncRNA-p3134 to clinical data from T2D patients was analyzed. LncRNA-p3134 was overexpressed in Min6 cells and db/db mice by adenovirus-mediated technology. CCK-8, TUNEL, Western blot, glucose-stimulated insulin secretion (GSIS), ELISAs and immunochemistry were performed to determine the effect of lncRNA-p3134 on proliferation, apoptosis and insulin secretion both in vitro and vivo. RESULTS: The circulating level of lncRNA-p3134 was higher in diabetic patients than in non-diabetic controls and was correlated with fasting blood glucose and HOMA-ß levels. The lncRNA-p3134 had risen by 4 times in serum exosomes but nearly unchanged in exosome-free samples. The secretion of lncRNA-p3134 was dynamically modulated by glucose in both Min6 cells and isolated mouse islet cells. LncRNA-p3134 positively regulate GSIS through promoting of key regulators (Pdx-1, MafA, GLUT2 and Tcf7l2) in ß cells. In addition, the overexpression of lncRNA-p3134 resulted in a decreased apoptosis ratio and partially reversed the glucotoxicity effects on GSIS function in Min6 cells. The restoration of insulin synthesis and secretion the increase of the insulin positive cells areas by upregulation of lncRNA-p3134 in db/db mice confirmed the compensatory role of lncRNA-p3134 to preserve ß-cell function. Furthermore, a protective effect of lncRNA-p3134 on GSIS by positive modulation of PI3K/Akt/mTOR signaling was also confirmed. After blocking the PI3K/AKT signals with their specific inhibitor, the effect of overexpressed lncRNA-p3134 on insulin secretion was obviously attenuated. CONCLUSION: Taken together, the results of this study provide new insights into lncRNA-p3134 regulation in pancreatic ß cells and provide a better understanding of novel mechanism of glucose homeostasis.

Accumulation of methylglyoxal increases the advanced glycation end-product levels in DRG and contributes to lumbar disk herniation-induced persistent pain.

Lumbar disk herniation (LDH) with discogenic low back pain and sciatica is a common and complicated musculoskeletal disorder. The underlying mechanisms are poorly understood, and there are no effective therapies for LDH-induced pain. In the present study, we found that the patients who suffered from LDH-induced pain had elevated plasma methylglyoxal (MG) levels. In rats, implantation of autologous nucleus pulposus (NP) to the left lumbar 5 spinal nerve root, which mimicked LDH, induced mechanical allodynia, increased MG level in plasma and dorsal root ganglion (DRG), and enhanced the excitability of small DRG neurons (<30 µm in diameter). Intrathecal injection of MG also induced mechanical allodynia, and its application to DRG neurons ex vivo increased the number of action potentials evoked by depolarizing current pulses. Furthermore, inhibition of MG accumulation by aminoguanidine attenuated the enhanced excitability of small DRG neurons and the mechanical allodynia induced by NP implantation. In addition, NP implantation increased levels of advanced glycation end products (AGEs) in DRG, and intrathecal injection of MG-derived AGEs induced the mechanical allodynia and DRG neuronal hyperactivity. Intrathecal injection of MG also significantly increased the expression of AGEs in DRG. Importantly, scavenging of MG by aminoguanidine also attenuated the increase in AGEs induced by NP implantation. These results suggested that LDH-induced MG accumulation contributed to persistent pain by increasing AGE levels. Thus generation of AGEs from MG may represent a target for treatment of LDH-induced pain.NEW & NOTEWORTHY Our study demonstrates that methylglyoxal accumulation via increasing advanced glycation end-product levels in dorsal root ganglion contributes to the persistent pain induced by lumbar disk herniation, which proposed potential targets for the treatment of lumbar disk herniation-induced persistent pain.

Systematic Review and Meta-Analysis of Randomized, Controlled Trials on the Effect of Exercise on Serum Leptin and Adiponectin in Overweight and Obese Individuals.

Previous reports have shown that exercise improves serum leptin and adiponectin abnormalities in overweight and obese individuals; however, results to date are controversial. Here we performed a systematic review and meta-analysis of the available randomized controlled trials (RCTs) of the possible beneficial action of exercise on serum leptin and adiponectin levels in overweight and obese individuals. We searched PubMed, EMbase, The Cochrane Library, and the Clinicaltrial.gov databases for relevant studies published between January 1980 and September 2015. Two independent reviewers extracted relevant data and assessed study quality and risk of bias. Data were pooled using a random-effects model for leptin and a fixed-effects model for adiponectin. Effect of size was expressed as mean difference (MD) with 95% confidence interval (CI). Heterogeneity was assessed (Cochran Q-statistic) and quantified (I 2 ). Twenty-eight RCTs (40 studies) were identified, of which 24 were on the effects of exercise on leptin (n=1 358) and 31 referred to changes in adiponectin (n=1 774). Our analysis revealed that exercise significantly reduced serum leptin (MD=-2.24 ng/ml; 95% CI, -3.26, -1.23; p<0.001) and increased adiponectin (MD=0.44 µg/ml; 95% CI, 0.13, 0.75; p=0.005) levels compared to no exercise as well as control (who were also overweight or obese). Exercise, particularly aerobic exercise, had a significant effect on serum leptin and a possible influence on adiponectin levels, suggesting its therapeutic implications.

Heterogeneity of cerebral atrophic rate in mild cognitive impairment and its interactive association with proteins related to microglia activity on longitudinal cognitive changes.

BACKGROUND: Heterogeneity of cerebral atrophic rate commonly exists in mild cognitive impairment (MCI), which may be associated with microglia-involved neuropathology and have an influence on cognitive outcomes. OBJECTIVE: We aim to explore the heterogeneity of cerebral atrophic rate among MCI and its association with plasma proteins related to microglia activity, with further investigation of their interaction effects on long-term cognition. SUBJECTS: A total of 630 MCI subjects in the ADNI database were included, of which 260 subjects were available with baseline data on plasma proteins. METHODS: Group-based multi-trajectory modeling (GBMT) was used to identify the latent classes with heterogeneous cerebral atrophic rates. Associations between latent classes and plasma proteins related to microglia activity were investigated with generalized linear models. Linear mixed effect models (LME) were implemented to explore the interaction effects between proteins related to microglia activity and identified latent classes on longitudinal cognitive changes. RESULTS: Two latent classes were identified and labeled as the slow-atrophy class and the fast-atrophy class. Associations were found between such heterogeneity of atrophic rates and plasma proteins related to microglia activity, especially AXL receptor tyrosine kinase (AXL), CD40 antigen (CD40), and tumor necrosis factor receptor-like 2 (TNF-R2). Interaction effects on longitudinal cognitive changes showed that higher CD40 was associated with faster cognitive decline in the slow-atrophy class and higher AXL or TNF-R2 was associated with slower cognitive decline in the fast-atrophy class. CONCLUSIONS: Heterogeneity of atrophic rates at the MCI stage is associated with several plasma proteins related to microglia activity, which show either protective or adverse effects on long-term cognition depending on the variability of atrophic rates.

Efficacy and Safety of DPP-4 Inhibitors and Metformin Combinations in Type 2 Diabetes: A Systematic Literature Review and Network Meta-Analysis.

Objective: Several oral antidiabetic regimens are available for treating type 2 diabetes mellitus (T2DM), dipeptidyl peptidase-4 inhibitors (DPP4i) being one of them. We conducted a network meta-analysis (NMA) comparing DPP4i plus metformin (Met) combination with other Met-based oral antidiabetic drug (OAD) combinations used in treating patients with T2DM. Methods: We searched PubMed and Embase from inception until 19th April, 2022 for phase II and phase III trials in patients with T2DM on Met-based traditional OADs. The primary outcome was assessed by change in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and 2-hour post-prandial blood glucose (2h-PPG). The secondary safety outcomes assessed were hypoglycemic events, serious adverse events (SAEs), cardiovascular (CV) events, and gastrointestinal (GI) events. Results: Sixty-two trials were included in the analysis. The combination of DPP4i + Met revealed a comparable mean reduction in HbA1c levels to the glinides (Gli) + Met combination (mean difference [MD]: -0.03%, 95% CI: 0.69, -0.65), although the difference was not statistically significant. The mean HbA1c reduction with DPP4i + Met was greater than with sulfonylureas (SU) + Met (MD: -0.05, 95% CI: -0.29, 0.39), thiazolidinedione (TZD) + Met (MD: -0.69, 95% CI: -1.39, -0.02), and SU + TZD (MD: 0.21; 95% CI: -1.30, 1.71), with no statistical significance. DPP4i + Met demonstrated a non-significant lower incidence of CV events in comparison to TZD + Met (RR: 1.01, 95% CI: 0.46, 2.45) and SU + Met (RR: 1.06, 95% CI: 0.61, 2.06). Conclusion: DPP4i in combination with Met was efficacious and had a well-tolerated safety profile compared with other traditional OADs. This combination can be considered as a suitable treatment option for patients with T2DM.

IL-17 induces NSCLC cell migration and invasion by elevating MMP19 gene transcription and expression through the interaction of p300-dependent STAT3-K631 acetylation and its Y705-phosphorylation.

The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer (NSCLC). Although researchers have disclosed that interleukin 17 (IL-17) can increase matrix metalloproteinases (MMPs) induction causing NSCLC cell metastasis, the underlying mechanism remains unclear. In the study, we found that IL-17 receptor A (IL-17RA), p300, p-STAT3, Ack-STAT3, and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17. p300, STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3, Ack-STAT3 and MMP19 level as well as the cell migration and invasion. Mechanism investigation revealed that STAT3 and p300 bound to the same region (-544 to -389 nt) of MMP19 promoter, and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity, p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17. Meanwhile, p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact, synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion. Besides, the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300, STAT3 or MMP19 gene plus IL-17 treatment, the nodule number, and MMP19, Ack-STAT3, or p-STAT3 production in the lung metastatic nodules were all alleviated. Collectively, these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation, which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.

The role of visual rating and automated brain volumetry in early detection and differential diagnosis of Alzheimer's disease.

BACKGROUND: Medial temporal lobe atrophy (MTA) is a diagnostic marker for mild cognitive impairment (MCI) and Alzheimer's disease (AD), but the accuracy of quantitative MTA (QMTA) in diagnosing early AD is unclear. This study aimed to investigate the accuracy of QMTA and its related components (inferior lateral ventricle [ILV] and hippocampus) with MTA in the early diagnosis of MCI and AD. METHODS: This study included four groups: normal (NC), MCI stable (MCIs), MCI converted to AD (MCIs), and mild AD (M-AD) groups. Magnetic resonance image analysis software was used to quantify the hippocampus, ILV, and QMTA. MTA was rated by two experienced neurologists. Receiver operating characteristic area under the curve (AUC) analysis was performed to compare their capability in differentiating AD from NC and MCI, and optimal thresholds were determined using the Youden index. RESULTS: QMTA distinguished M-AD from NC and MCI with higher diagnostic accuracy than MTA, hippocampus, and ILV (AUCNC = 0.976, AUCMCI = 0.836, AUCMCIs = 0.894, AUCMCIc = 0.730). The diagnostic accuracy of QMTA was superior to that of MTA, the hippocampus, and ILV in differentiating MCI from AD. The diagnostic accuracy of QMTA was found to remain the best across age, sex, and pathological subgroups analyzed. The sensitivity (92.45%) and specificity (90.64%) were higher in this study when a cutoff value of 0.635 was chosen for QMTA. CONCLUSIONS: QMTA may be a better choice than the MTA scale or the associated quantitative components alone in identifying AD patients and MCI individuals with higher progression risk.

Association of circulating visfatin level and metabolic fatty liver disease: An updated meta-analysis and systematic review.

BACKGROUND: The rate of incidence of metabolic dysfunction-related fatty liver disease (MAFLD) has rapidly increased globally in recent years, but early diagnosis is still a challenge. The purpose of this systematic review and meta-analysis is to identify visfatin for early diagnosis of MAFLD. METHODS: We strictly adhered to the relevant requirements of Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The systematic search was conducted in 7 sources (PubMed, Embase, Cochrane Library, CNKI, Wanfang, CBM, and ClinicalTrials.gov) until February 2024. The meta-analysis was performed using Stata 12. Outcomes were expressed in the form of standardized mean difference (SMD) and 95% confidence interval and were analyzed using meta-analysis. RESULTS: The results showed that there was no significant difference in circulating visfatin levels between patients with MAFLD and controls (SMD = 0.13 [-0.34, 0.60]). However, the outcomes indicated that the level of circulating visfatin was significantly higher in MAFLD patients in the Middle Eastern subgroup (SMD = 0.45 [0.05, 0.85]) and in the obese patient subgroup (SMD = 1.05 [0.18, 1.92]). No publication bias was detected, and sensitivity analysis confirmed the stability of the outcomes. CONCLUSION: The serum visfatin levels of MAFLD patients did not differ significantly from those of controls. However, visfatin concentrations in serum were statistically higher within Middle Eastern or obese MAFLD patients compared to controls. There is a need for further research to investigate visfatin's potential as a biomarker for MAFLD.

Magnesium-L-threonate treats Alzheimer's disease by modulating the microbiota-gut-brain axis.

JOURNAL/nrgr/04.03/01300535-202410000-00029/figure1/v/2024-02-06T055622Z/r/image-tiff Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-ß precursor protein and mutant human presenilin 1 (APP/PS1). Here, we performed 16S rRNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-L-threonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesium-L-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins (zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.

Isoniazid improves cognitive performance, clears Aß plaques, and protects dendritic synapses in APP/PS1 transgenic mice.

Background and objective: Alzheimer's disease (AD) is characterized by amyloid ß (Aß) aggregation and neuroinflammation. This study aimed to investigate the therapeutic effect of isoniazid (INH) against AD. Methods: The APP/PS1 transgenic mouse model of AD was adopted. The APP/PS1 mice received oral INH (45 mg/kg/d) for 14 days. The cognitive capability was assessed by the Morris Water Maze test. Amyloid plaques and Aß levels were determined by immunohistochemistry and ELISA assay. The dendritic spines were analyzed by DiOlistic labeling. Immunofluorescence staining was used to observe the microglia and astrocytes. Results: The Morris Water Maze test suggested that INH administration can effectively attenuate the reference memory deficit and improve the working memory of the APP/PS1 mice compared to the untreated mice (all p < 0.001). INH significantly decreased the Aß plaques in the hippocampus and cortex and reduced the levels of Aß1-40 and Aß1-42 in the brain homogenates, cerebrospinal fluid, and serum (all p < 0.001). INH also inhibited enzyme activities of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1, p < 0.05) and monoamine oxidase B (Mao-b, p < 0.01). INH significantly increased the protrusion density in the hippocampus (p < 0.01). Immunofluorescence staining revealed that INH significantly reduced the number of activated microglia and astrocytes around the Aß plaques (both p < 0.01). Conclusion: Isoniazid administration effectively improved cognitive performance, cleared Aß plaques, protected dendritic synapses, and reduced innate immune cells around the Aß plaques, suggesting that INH could be a potential drug for AD treatment.

Sublytic C5b-9 induces TIMP3 expression by glomerular mesangial cells via TRAF6-dependent KLF5 K63-linked ubiquitination in rat Thy-1 nephritis.

Rat Thy-1 nephritis (Thy-1N) is an experimental model for studying human mesangioproliferative glomerulonephritis (MsPGN), and its pathological features are glomerular mesangial cell (GMC) proliferation and extracellular matrix (ECM) accumulation. Although we have confirmed that renal lesions of Thy-1N rats are sublytic C5b-9-dependent, and ECM accumulation is related to tissue inhibitor of matrix metalloproteinase (TIMP) inhibiting matrix metalloproteinase (MMP) activity, whether sublytic C5b-9 can induce TIMP production by GMC in Thy-1N rat and the underlying mechanism remains unclear. In the study, we proved that the expressions of TIMP3, krϋppel-like transcription factor 5 (KLF5) and tumor necrosis factor receptor-associated factor 6 (TRAF6) were simultaneously up-regulated both in the renal tissues of Thy-1N rats (in vivo) and in the GMC exposed to sublytic C5b-9 (in vitro). Further mechanism exploration discovered that KLF5 and TRAF6 as two upstream molecules could induce TIMP3 gene transcription through binding to the same region i.e., -1801nt to -1554nt (GGGGAGGGGC) and -228nt to -46nt (GCCCCGCCCC) of TIMP3 promoter. In the process, TRAF6 mediated KLF5 K63-linked ubiquitination at K99 and K100 enhancing KLF5 nuclear localization and binding to TIMP3 promoter, augmenting its gene activation. Furthermore, the experiments in vivo exhibited that silencing KLF5, TRAF6 or TIMP3 gene could markedly lessen renal KLF5 K63-linked ubiquitination or TIMP3 induction, ECM accumulation and other pathological changes of Thy-1N rats. Besides, the positive expressions of above-mentioned these proteins and ECM accumulation and their correlation in the renal tissues of MsPGN patients were also demonstrated. Overall, our findings implicate that KLF5 and TRAF6 play a promoting role in sublytic C5b-9-triggered TIMP3 gene transcription and expression, which might provide a novel mechanistic insight into rat Thy-1N and human MsPGN.

Association of circulating omentin level and metabolic-associated fatty liver disease: a systematic review and meta-analysis.

Background: Metabolic-associated fatty liver disease (MAFLD) is closely associated with omentin, a novel adipokine that plays a vital role in metabolic balance. The literature about the relationship between circulating omentin and MAFLD is conflicting. Therefore, this meta-analysis evaluated circulating omentin levels in patients with MAFLD compared with healthy controls to explore the role of omentin in MAFLD. Methods: The literature search was performed up to April 8, 2022, using PubMed, Cochrane Library, EMBASE, CNKI, Wanfang, CBM, Clinical Trials Database and Grey Literature Database. This meta-analysis pooled the statistics in Stata and presented the overall results using the standardized mean difference (SMD) and 95% confidence interval (CI). Results: Twelve studies with 1624 individuals (927 cases and 697 controls) were included, and all of them were case-control studies. In addition, ten of twelve included studies were conducted on Asian participants. Patients with MAFLD had significantly lower circulating omentin levels than healthy controls (SMD=-0.950 [-1.724, -0.177], P=0.016). Subgroup analysis and meta-regression demonstrated that fasting blood glucose (FBG) might be the source of heterogeneity and was inversely associated with omentin levels (coefficient=-0.538, P=0.009). No significant publication bias existed (P>0.05), and outcomes were robust in the sensitivity analysis. Conclusion: Lower circulating omentin levels were associated with MAFLD, and FBG might be the source of heterogeneity. Since Asian studies accounted for a significant portion of the meta-analysis, the conclusion might be more applicable to the Asian population. By investigating the relationship between omentin and MAFLD, this meta-analysis laid the foundation for the development of diagnostic biomarkers and treatment targets. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022316369.

Identification of candidate genes associated with clinical onset of Alzheimer's disease.

Background and objective: Alzheimer's disease (AD) is the most common type of dementia, with its pathology like beta-amyloid and phosphorylated tau beginning several years before the clinical onset. The aim is to identify genetic risk factors associated with the onset of AD. Methods: We collected three microarray data of post-mortem brains of AD patients and the healthy from the GEO database and screened differentially expressed genes between AD and healthy control. GO/KEGG analysis was applied to identify AD-related pathways. Then we distinguished differential expressed genes between symptomatic and asymptomatic AD. Feature importance with logistic regression analysis is adopted to identify the most critical genes with symptomatic AD. Results: Data was collected from three datasets, including 184 AD patients and 132 healthy controls. We found 66 genes to be differently expressed between AD and the control. The pathway enriched in the process of exocytosis, synapse, and metabolism and identified 19 candidate genes, four of which (VSNL1, RTN1, FGF12, and ENC1) are vital. Conclusion: VSNL1, RTN1, FGF12, and ENC1 may be the essential genes that progress asymptomatic AD to symptomatic AD. Moreover, they may serve as genetic risk factors to identify high-risk individuals showing an earlier onset of AD.

The Correlation Between White Matter Hyperintensity Burden and Regional Brain Volumetry in Patients With Alzheimer's Disease.

Background: White matter hyperintensities (WMHs) and regional brain lobe atrophy coexist in the brain of patients with Alzheimer's disease (AD), but the association between them in patients with AD still lacks comprehensive investigation and solid imaging data support. Objective: We explored whether WMHs can promote the pathological process of AD by aggravating atrophy in specific brain regions and tried to explain the regional specificity of these relationships. Methods: A sample of 240 adults including 180 normal controls (NCs) and 80 cases with AD were drawn from the ADNI database. T1-weighted magnetic resonance imaging (MRI) and T2-weighted fluid-attenuated MRI of the participants were downloaded and were analyzed using AccuBrain® to generate the quantitative ratio of WMHs (WMHr, WMH volumes corrected by intracranial volume) and regional brain atrophy. We also divided WMHr into periventricular WMHr (PVWMHr) and deep WMHr (DWMHr) for the purpose of this study. The Cholinergic Pathways Hyperintensities Scale (CHIPS) scores were conducted by two evaluators. Independent t-test, Mann-Whitney U test, or χ2 test were used to compare the demographic characteristics, and Spearman correlation coefficient values were used to determine the association between WMHs and different regions of brain atrophy. Results: Positive association between WMHr and quantitative medial temporal lobe atrophy (QMTA) (r s = 0.281, p = 0.011), temporal lobe atrophy (r s = 0.285, p = 0.011), and insular atrophy (r s = 0.406, p < 0.001) was found in the AD group before Bonferroni correction. PVWMHr contributed to these correlations. By separately analyzing the relationship between PVWMHr and brain atrophy, we found that there were still positive correlations after correction in QMTA (r s = 0.325, p = 0.003), temporal lobe atrophy (r s = 0.298, p = 0.007), and insular atrophy (r s = 0.429, p < 0.001) in AD group. Conclusion: WMH severity tends to be associated with regional brain atrophy in patients with AD, especially with medial temporal lobe, temporal lobe, and insular lobe atrophy. PVWMHs were devoted to these correlations.

Magnesium-L-threonate exhibited a neuroprotective effect against oxidative stress damage in HT22 cells and Alzheimer's disease mouse model.

BACKGROUND: Oxidative stress results in the production of excess reactive oxygen species (ROS) and triggers hippocampal neuronal damage as well as occupies a key role in the pathological mechanisms of neurodegenerative disorders such as Alzheimer's disease (AD). A recent study confirmed that magnesium had an inhibitory effect against oxidative stress-related malondialdehyde in vitro. However, whether Magnesium-L-threonate (MgT) is capable of suppressing oxidative stress damage in amyloid ß (Aß)25-35-treated HT22 cells and the AD mouse model still remains to be investigated. AIM: To explore the neuroprotective effect of MgT against oxidative stress injury in vitro and in vivo, and investigate the mechanism. METHODS: Aß25-35-induced HT22 cells were preconditioned with MgT for 12 h. APPswe/PS1dE9 (APP/PS1) mice were orally administered with MgT daily for 3 mo. After MgT treatment, the viability of Aß25-35-treated HT22 cells was determined via conducting cell counting kit-8 test and the cognition of APP/PS1 mice was measured through the Morris Water Maze. Flow cytometry experiments were applied to assess the ROS levels of HT22 cells and measure the apoptosis rate of HT22 cells or hippocampal neurons. Expression of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X (Bax), hypoxia-inducible factor (HIF)-1α, NADPH oxidase (NOX) 4, Aß1-42 and phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway proteins was quantified by Western blot. RESULTS: In vitro data confirmed that Aß25-35-induced HT22 cells had a significantly lower cell viability, higher ROS level and higher apoptosis rates compared with those of control cells (all P < 0.001). MgT prevented the Aß25-35-triggered oxidative stress damage by elevating viability and decreasing ROS formation and apoptosis of HT22 cells (all P < 0.001). APP/PS1 mice exhibited worse cognitive performance and higher apoptosis rate of hippocampal neurons than wild-type (WT) mice (all P < 0.01). Meanwhile, significant higher expression of Aß1-42 and NOX4 proteins was detected in APP/PS1 mice than those of WT mice (both P < 0.01). MgT also ameliorated the cognitive deficit, suppressed the apoptosis of hippocampal neuron and downregulated the expression of Aß1-42 and NOX4 proteins in APP/PS1 mouse (all P < 0.05). Moreover, MgT intervention significantly downregulated HIF-1α and Bax, upregulated Bcl-2 and activated the PI3K/Akt pathway both in vitro and in vivo (all P < 0.05). CONCLUSION: MgT exhibits neuroprotective effects against oxidative stress and hippocampal neuronal apoptosis in Aß25-35-treated HT22 cells and APP/PS1 mice.

Relationship Between Skeletal Muscle Mass to Visceral Fat Area Ratio and Cardiovascular Risk in Type 2 Diabetes.

PURPOSE: Either visceral fat or muscle mass is identified to be correlated with cardiometabolic diseases, especially in type 2 diabetes (T2DM). But, the synergistical effect of visceral fat along with skeletal muscle on the risk of cardiovascular diseases (CVD) in T2DM still remains controversial. Thus, we investigated the relationship between skeletal muscle mass to visceral fat area ratio (SVR) and 10-yr CVD risk scores. PATIENTS AND METHODS: A total of 291 T2DM patients aged 40-80 years were enrolled in the current study. SVR was evaluated based on bioelectrical impedance measurements. Both Framingham risk score system and China-PAR risk model were applied to estimate future 10-yr CVD risk in T2DM population. RESULTS: The 10-yr CVD risk scores increased with the decreased SVR tertiles in T2DM (All P<0.001). SVR value was obviously lower in the high-risk group than that of low- or moderate-risk group (All P<0.05). However, no significant differences were observed in BMI among different CVD risk groups. Besides, SVR was correlated with Framingham risk score (r=-0.408; P<0.001) and China-PAR risk score (r=-0.336; P<0.001). HOMA-IR, triglycerides and blood pressure were also inversely related to SVR (All P<0.05). Furthermore, SVR value was independently correlated with both Framingham 10-yr CVD risk score (ß=-0.074, P=0.047) and China-PAR risk score (ß=-0.100, P=0.004) after adjustment for confounding factors, including age, gender, BMI, FPG, HbA1c, diabetes duration, albumin, creatinine, uric acid, smoking, blood pressure and blood lipid. The linear regression analysis was also conducted for men and women, respectively, indicating that the negative relationship between SVR and 10-yr CVD risk was observed in men but not in women. CONCLUSION: T2DM populations who have lower SVR value are more likely to increase CVD risk. SVR levels show marked and inverse correlation with estimated 10-yr CVD risk in T2DM, indicating that SVR could be a valuable parameter to assess the risk of CVD events in clinical practice, especially in men.