AZGP1 in POMC neurons modulates energy homeostasis and metabolism through leptin-mediated STAT3 phosphorylation.

Zinc-alpha2-glycoprotein (AZGP1) has been implicated in peripheral metabolism; however, its role in regulating energy metabolism in the brain, particularly in POMC neurons, remains unknown. Here, we show that AZGP1 in POMC neurons plays a crucial role in controlling whole-body metabolism. POMC neuron-specific overexpression of Azgp1 under high-fat diet conditions reduces energy intake, raises energy expenditure, elevates peripheral tissue leptin and insulin sensitivity, alleviates liver steatosis, and promotes adipose tissue browning. Conversely, mice with inducible deletion of Azgp1 in POMC neurons exhibit the opposite metabolic phenotypes, showing increased susceptibility to diet-induced obesity. Notably, an increase in AZGP1 signaling in the hypothalamus elevates STAT3 phosphorylation and increases POMC neuron excitability. Mechanistically, AZGP1 enhances leptin-JAK2-STAT3 signaling by interacting with acylglycerol kinase (AGK) to block its ubiquitination degradation. Collectively, these results suggest that AZGP1 plays a crucial role in regulating energy homeostasis and glucose/lipid metabolism by acting on hypothalamic POMC neurons.

Effects and plasma proteomic analysis of GLP-1RA versus CPA/EE, in combination with metformin, on overweight PCOS women: a randomized controlled trial.

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS. METHODS: In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-µg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA. RESULTS: Eighty(80%) patients completed the study. Both interventions improved menstrual cycle, polycystic ovaries, LH(luteinizing hormone) and HbA1c(hemoglobin A1c) levels after the 12-week treatment. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI (Body Mass Index), and waist circumference, FBG(fasting blood glucose), AUCI(area under curve of insulin),TC (Total Cholesterol), IL-6(Interleukin-6) and improving insulin sensitivity, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in improving hyperandrogenemia, including T(total testosterone), LH, LH/FSH(Luteinizing hormone/follicle-stimulating hormone), SHBG(sex hormone-binding globulin) and FAI (free androgen index). By contract, GLP-1RA+Met group only improved LH. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9). CONCLUSIONS: Both CPA/EE+Met and GLP-1RA + Met treatment improved reproductive functions in overweight PCOS women. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI, and waist, and improving metabolism, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in reducing hyperandrogenemia. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment. TRIAL REGISTRATION CLINICALTIALS. GOV TRIAL NO: NCT03151005. Registered 12 May, 2017, https://clinicaltrials.gov/ct2/show/NCT03151005 .

Dock5 Deficiency Promotes Proteinuric Kidney Diseases via Modulating Podocyte Lipid Metabolism.

Podocytes are particularly sensitive to lipid accumulation, which has recently emerged as a crucial pathological process in the progression of proteinuric kidney diseases like diabetic kidney disease and focal segmental glomerulosclerosis. However, the underlying mechanism remains unclear. Here, podocytes predominantly expressed protein dedicator of cytokinesis 5 (Dock5) is screened to be critically related to podocyte lipid lipotoxicity. Its expression is reduced in both proteinuric kidney disease patients and mouse models. Podocyte-specific deficiency of Dock5 exacerbated podocyte injury and glomeruli pathology in proteinuric kidney disease, which is mainly through modulating fatty acid uptake by the liver X receptor α  (LXRα)/scavenger receptor class B (CD36) signaling pathway. Specifically, Dock5 deficiency enhanced CD36-mediated fatty acid uptake of podocytes via upregulating LXRα in an m6 A-dependent way. Moreover, the rescue of Dock5 expression ameliorated podocyte injury and proteinuric kidney disease. Thus, the findings suggest that Dock5 deficiency is a critical contributor to podocyte lipotoxicity and may serve as a promising therapeutic target in proteinuric kidney diseases.

Microbiota: A potential orchestrator of antidiabetic therapy.

The gut microbiota, as a 'new organ' of humans, has been identified to affect many biological processes, including immunity, inflammatory response, gut-brain neural circuits, and energy metabolism. Profound dysbiosis of the gut microbiome could change the metabolic pattern, aggravate systemic inflammation and insulin resistance, and exacerbate metabolic disturbance and the progression of type 2 diabetes (T2D). The aim of this review is to focus on the potential roles and functional mechanisms of gut microbiota in the antidiabetic therapy. In general, antidiabetic drugs (α-glucosidase inhibitor, biguanides, incretin-based agents, and traditional Chinese medicine) induce the alteration of microbial diversity and composition, and the levels of bacterial component and derived metabolites, such as lipopolysaccharide (LPS), short chain fatty acids (SCFAs), bile acids and indoles. The altered microbial metabolites are involved in the regulation of gut barrier, inflammation response, insulin resistance and glucose homeostasis. Furthermore, we summarize the new strategies for antidiabetic treatment based on microbial regulation, such as pro/prebiotics administration and fecal microbiota transplantation, and discuss the need for more basic and clinical researches to evaluate the feasibility and efficacy of the new therapies for diabetes.

Serum Annexin A2 concentrations are increased in patients with diabetic cardiomyopathy and are linked to cardiac dysfunctions.

BACKGROUND: Diabetic cardiomyopathy (DbCM) is defined as the existence of abnormal myocardial structure and functions in the absence of other cardiac diseases, such as coronary artery disease, hypertension, and significant valvular disease, in individuals with diabetes. Although abundant epidemic evidence demonstrates that diabetes is independently associated with the risk of developing heart failure, DbCM is not normally diagnosed in clinical practices due to its exclusive diagnosis, and no diagnostic biomarker was applied in a clinical test. METHODS: To detect the concentrations of serum Annexin A2 in non-diabetic subjects, type 2 diabetic (T2DM) patients with or without DbCM, and analyzed its relationship to parameters of cardiac functions, glucose, lipid metabolism, and renal functions. 266 eligible participants were included and were divided into 3 groups including non-diabetic subjects (NGR), T2DM patients without DbCM (T2DM group), and the DbCM group. Echocardiography, coronary computed tomography angiography, electrocardiogram, blood pressure, thyroid function, and clinical and other biochemical parameters were measured in all participants. RESULTS: Serum Annexin A2 concentrations were higher in DbCM (P < 0.05) and T2DM (P < 0.05) groups compared with the NGR group, especially in DbCM patients. Correlation analysis showed that serum Annexin A2 levels were negatively associated with left ventricular (LV) ejection fraction (EF), LV fractional shortening (FS), the ratio of early (E-wave) and late (A-wave) LV diastolic filling velocities (E/A ratio), and estimated glomerular filtration rate (eGFR), and were positively correlated with age, blood urea nitrogen (BUN) and creatinine (Cr) (all P < 0.05). Multiple logistical regression analyses revealed that serum in both the second and the third tertiles of Annexin A2 concentration were significantly associated with DbCM. E/A ratio is the independent factor for Annexin A2 concentration when adjusted for LV FS%, BUN, and Cr. CONCLUSIONS: Circulating Annexin A2 concentrations might be induced in DbCM patients and were negatively associated with cardiac systolic and diastolic functions, which suggested it might be a predictor of early diagnosis in DbCM and might be a potential therapeutic target for DbCM.

SIK2 protects against renal tubular injury and the progression of diabetic kidney disease.

Despite optimal medical therapy, many patients with diabetic kidney disease (DKD) progress to end-stage renal disease. The identification of new biomarkers and drug targets for DKD is required for the development of more effective therapies. The apoptosis of renal tubular epithelial cells is a key feature of the pathogenicity associated with DKD. SIK2, a salt-inducible kinase, regulates important biological processes, such as energy metabolism, cell cycle progression and cellular apoptosis. In our current study, a notable decrease in the expression of SIK2 was detected in the renal tubules of DKD patients and murine models. Functional experiments demonstrated that deficiency or inactivity of SIK2 aggravates tubular injury and interstitial fibrosis in diabetic mice. Based on transcriptome sequencing, molecular mechanism exploration revealed that SIK2 overexpression reduces endoplasmic reticulum (ER) stress-mediated tubular epithelial apoptosis by inhibiting the histone acetyltransferase activity of p300 to activate HSF1/Hsp70. Furthermore, the specific restoration of SIK2 in tubules blunts tubular and interstitial impairments in diabetic and vancomycin-induced kidney disease mice. Together, these findings indicate that SIK2 protects against renal tubular injury and the progression of kidney disease, and make a compelling case for targeting SIK2 for therapy in DKD.

Pleiomorphism plurihormonal Pit-1-positive macroadenoma with central hyperthyroidism: a rare case report and literature review.

BACKGROUND: Thyrotropin-secreting pituitary neuroendocrine tumors (PitNETs) are rare pituitary adenomas that are occasionally accompanied by hypersecretion of other anterior pituitary hormones, such as growth hormone (GH) and prolactin (PRL). The clinical, biochemical, and pathological characteristics may represent diverse circumstances. CASE PRESENTATION: In this report, a 33-year-old female diagnosed with a TSH PitNET co-secreting GH presented no obvious clinical symptoms. The main characteristics were elevated thyroid-stimulating hormone (TSH), free tri-iodothyronine (FT3), and free thyroxine (FT4) levels accompanied by slightly elevated GH and insulin-like growth factor-1 (IGF-1) levels. Magnetic resonance imaging (MRI) detected a pituitary macroadenoma (18 × 16 × 16 mm) with cavernous sinus and suprasellar invasion. Immunohistochemistry revealed diffuse positivity for TSH, strong immunoreactivity for GH, and sporadic positivity for PRL. The electron microscope and double immunofluorescence staining confirmed a plurimorphous plurihormonal adenoma producing TSH, GH, and PRL. After preoperative somatostatin receptor ligand (SRL) treatment and transsphenoidal surgery, the patient achieved temporary clinical and biochemical remission. However, 3 months after surgery, the patient was suspected of having Hashimoto's thyroiditis due to higher thyroglobulin antibody (TGAb), thyroid peroxidase antibody (TPOAb), and thyroid receptor antibody (TRAb) and an enlarged thyroid nodule. During follow-up, thyroid function and TSH slowly transformed from transient hyperthyroidism to hypothyroidism. They were maintained in the normal range by L-T4. CONCLUSION: In the TSH PitNET, the positive immunohistochemistry for TSH, GH, and PRL translated into hormonal overproduction with TSH and GH.

An Asian case of combined 17α-hydroxylase/17,20-lyase deficiency due to homozygous p.R96Q mutation: A case report and review of the literature.

Background: Combined 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a very rare form of congenital adrenal hyperplasia (CAH) caused by mutations in the CYP17A1 gene. Almost 100 different mutations of the CYP17A1 gene have been reported, including p.R96Q mutation, but no case of p.R96Q mutation has been described in Asian populations. Case presentation: We describe a 22-year-old female patient of 46,XY karyotype, who presented with pseudohermaphrodism, primary amenorrhea, underdeveloped secondary sexual characteristics, delayed epiphyseal healing, hypertension, and hypokalemia. The diagnosis of 17-OHD was reached by measurement of steroid hormones and abdominal CT scan and confirmed by genetic sequencing, which revealed a homozygous p.R96Q missense mutation in the CYP17A1 gene. The patient received treatment with dexamethasone and estradiol, and 4 months of follow-up showed that both blood pressure and potassium were well controlled. Conclusions: This is the first Asian case of CAH caused by a homozygous p.R96Q missense mutation in the CYP17A1 gene. Herein, we highlight the role of inguinal hernia in the early diagnosis of female 17-OHD and the necessity of removing the ectopic testis.

Synchronous enhancement of upconversion and NIR-IIb photoluminescence of rare-earth nanoprobes for theranostics.

This study develops a multifunctional molecular optical nanoprobe (SiO2@Gd2O3: Yb3+/Er3+/Li+@Ce6/MC540) with a unique core-satellite form. The rare-earth doped nanodots with good crystallinity are uniformly embedded on the surface of a hydrophilic silica core, and the nanoprobe can emit near-infrared-IIb (NIR-IIb) luminescence for imaging as well as visible light that perfectly matches the absorption bands of two included photosensitizers under 980 nm irradiation. The optimal NIR-IIb emission and upconversion efficiency are attainable via regulating the doping ratios of Yb3+, Er3+ and Li+ ions. The relevant energy transfer mechanism was addressed theoretically that underpins rare-earth photoluminescence where energy back-transfer and cross relaxation processes play pivotal roles. The nanoprobe can achieve an excellent dual-drive photodynamic treatment performance, verified by singlet oxygen detections and live-dead cells imaging assays, with a synergistic effect. And a brightest NIR-IIb imaging was attained in tumoral site of mouse. The nanoprobe has a high potential to serve as a new type of optical theranostic agent for tumor.

Clinical Characteristics and Associated Factors of Colonic Polyps in Acromegaly.

PURPOSE: To investigate the clinical characteristics and associated factors of colonic polyps in patients with acromegaly. METHODS: Clinical characteristics and colonoscopy findings of 86 acromegaly patients who received treatment were retrospectively reviewed, and colonoscopy findings and the correlation with growth hormone (GH)-secreting pituitary adenoma (GHPA) volume and hormonal/metabolic levels were analyzed. RESULTS: The prevalence of colonic polyps in acromegaly patients was 40.7% and increased significantly with advanced age, especially in those ≥50 years. Multiple polyps (62.8%) and colonic polyps in the left colon (54.2%) were detected more frequently. Compared to acromegaly patients without polyps, those with polyps displayed higher insulin-like growth factor-1 × upper limit of normal (IGF-1×ULN) levels (P=0.03). IGF-1 levels and GHPA volumes in patients with polyps showed increasing trends, although the differences were not significant. GH levels were higher in patients with polyps of diameter ≤5 mm than those with polyps of diameter >5 mm (P=0.031). The univariate and multivariate logistic regression analysis revealed that GHPA volumes (OR: 1.09, 95% CI: 1.01-1.20; P=0.039) and IGF-1×ULN Q2 levels (OR: 6.51, 95% CI: 1.20-44.60; P=0.038) were independent factors for predicting the risk of colonic polyp occurrence in acromegaly patients. A nomogram was prepared to evaluate the risk of colonic polyps in acromegaly patients. CONCLUSION: The acromegalic patients are a population with a high prevalence of colonic polyps. GHPA volumes and IGF-1×ULN levels may be predictors of colonic polyp occurrence.

TRPC5 deletion in the central amygdala antagonizes high-fat diet-induced obesity by increasing sympathetic innervation.

Transient receptor potential channel 5 (TRPC5) is predominantly distributed in the brain, especially in the central amygdala (CeA), which is closely associated with pain and addiction. Although mounting evidence indicates that the CeA is related to energy homeostasis, the possible regulatory effect of TRPC5 in the CeA on metabolism remains unclear. Here, we reported that the expression of TRPC5 in the CeA of mice was increased under a high-fat diet (HFD). Specifically, the deleted TRPC5 protein in the CeA of mice using adeno-associated virus resisted HFD-induced weight gain, accompanied by increased food intake. Furthermore, the energy expenditure of CeA-specific TRPC5 deletion mice (TRPC5 KO) was elevated due to augmented white adipose tissue (WAT) browning and brown adipose tissue (BAT) activity. Mechanistically, deficiency of TRPC5 in the CeA boosted nonshivering thermogenesis under cold stimulation by stimulating sympathetic nerves, as the ß3-adrenoceptor (Adrb3) antagonist SR59230A blocked the effect of TRPC5 KO on this process. In summary, TRPC5 deletion in the CeA alleviated the metabolic deterioration of mice fed a HFD, and these phenotypic improvements were correlated with the increased sympathetic distribution and activity of adipose tissue.

Hepatic lipid accumulation induced by a high-fat diet is regulated by Nrf2 through multiple pathways.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is reportedly involved in hepatic lipid metabolism, but the results are contradictory, and the underlying mechanism remains unclear. Here, we focused on elucidating the effects of Nrf2 on hepatic adipogenesis and on determining the possible underlying mechanism. We established a non-alcoholic fatty liver disease (NAFLD) model in a high-fat diet (HFD)-fed Nrf2 knockout (Nrf2 KO) mice; further, a cell model of lipid accumulation was established using mouse primary hepatocytes (MPHs) treated with free fatty acids (FAs). Using these models, we investigated the relationship between Nrf2 and autophagy and its role in the development of NAFLD. We observed that Nrf2 expression levels were upregulated in patients with NAFLD and diet-induced obese mice. Nrf2 deficiency led to hepatic lipid accumulation in vivo and in vitro, in addition to, promoting lipogenesis mainly by increasing SREBP-1c activity. Moreover, Nrf2 deficiency attenuated autophagic flux and inhibited the fusion of autophagosomes and lysosomes in vivo and in vitro. Decreased autophagy caused reduced lipolysis in the liver. Importantly, chromatin immunoprecipitation-qPCR (ChIP-qPCR) and dual-luciferase assay results proved that Nrf2 bound to the LAMP1 promoter and regulated its transcriptional activity. Accordingly, we report that Nrf2-LAMP1 interaction plays an indispensable role in Nrf2-regulated hepatosteatosis. Our data collectively confirm that Nrf2 deficiency promotes hepatosteatosis by enhancing SREBP-1c activity and attenuating autophagy. Our findings provide a novel multi-pathway effect of Nrf2 on lipid metabolism in the liver. We believe that multi-target intervention of Nrf2 is a novel strategy for the treatment of NAFLD.

CTRP7 Is a Biomarker Related to Insulin Resistance and Oxidative Stress: Cross-Sectional and Intervention Studies In Vivo and In Vitro.

Objective: CTRP7 is a cytokine that is known to be associated with obesity. However, its relationship with insulin resistance (IR) and metabolic diseases remains unknown. The aim of this study is to investigate the relationship between CTRP7 and IR under in vivo and in vitro conditions. Methods: CTRP7 expression in mice and hepatocytes was determined using RT-qPCR and western blotting. Circulating CTRP7 concentrations were measured with an ELISA kit. EHC, OGTT, lipid-infusion, physical activity, and cold-stimulation experiments were performed in humans and mice. SOD, GSH, and MDA were measured by commercial kits. ROS levels were detected using dichlorofluorescein diacetate. Results: The expression levels of CTRP7 protein in the liver and fat of ob/ob and db/db mice were higher than that of WT mice. Individuals with IGT, T2DM, and obesity had higher circulating CTRP7 levels. CTRP7 levels were associated with HOMA-IR, obesity, and other metabolic parameters. During OGTT, serum CTRP7 levels gradually decreased, while CTRP7 levels significantly increased during EHC in response to hyperinsulinemia in healthy individuals without IR. In addition, lipid infusion-induced IR further increased serum CTRP7 levels in healthy adults. Physical activity increased serum CTRP7 levels in healthy individuals and CTRP7 protein expression in iWAT and skeletal muscle in mice. Under in vitro conditions, the expression of the CTRP7 protein was inhibited in a glucose concentration-dependent manner but was promoted by FFAs and insulin stimulation in hepatocytes. Furthermore, CTRP7 overexpression facilitated oxidative stress and suppressed the phosphorylation of insulin signaling molecules in hepatocytes. Conclusions: Our evidence shows that CTRP7 could be a useful biomarker and potential treatment target in IR and metabolic disorders.

Plasma Diaphanous Related Formin 1 Levels Are Associated with Altered Glucose Metabolism and Insulin Resistance in Patients with Polycystic Ovary Syndrome: A Case Control Study.

BACKGROUND: Diaphanous related formin 1 (DIAPH1) is a novel component of advanced glycation end product (AGE) signal transduction that was recently found to participate in diabetes-related disorders, obesity, and androgen hormones. We investigated whether plasma DIAPH1 levels were a potential prognostic predictor for polycystic ovary syndrome (PCOS). METHODS: The levels of circulating plasma DIAPH1 and indicators of glucose, insulin, lipid metabolism, liver enzymes, kidney function, sex hormones, and inflammation were measured in 75 patients with PCOS and 77 healthy participants. All of the participants were divided into normal-weight (NW) and overweight/obese (OW) subgroups. Statistical analyses were performed with R studio. RESULTS: PCOS patients manifested hyperandrogenism, increased luteinizing hormone/follicle-stimulating hormone (LH/FSH), and accumulated body fat and insulin resistance. Plasma DIAPH1 levels were significantly decreased in women with PCOS compared to control participants, and DIAPH1 levels were distinctly reduced in OW PCOS compared to OW control subjects (P < 0.001). DIAPH1 levels correlated with fasting blood glucose (FBG), total cholesterol (TC), the homeostasis model assessment of ß-cell function (HOMA-ß), and LH/FSH in all participants (FBG: r = 0.351, P < 0.0001; TC: r = 0.178, P = 0.029; HOMA-ß: r = -0.211, P = 0.009; LH/FSH: r = -0.172, P = 0.040). Multivariate logistic regression analysis revealed that plasma DIAPH1 levels were an independent risk factor for PCOS. A model containing DIAPH1, BMI, FBG, and testosterone was constructed to predict the risk of PCOS, with a sensitivity of 92.0% and a specificity of 80.9%. A nomogram was constructed to facilitate clinical diagnosis. CONCLUSIONS: These findings suggest the association of plasma DIAPH1 with glucose metabolism, insulin resistance, and sex hormones and support DIAPH1 as a potential predictive factor for PCOS.

Salt-Induced Hepatic Inflammatory Memory Contributes to Cardiovascular Damage Through Epigenetic Modulation of SIRT3.

BACKGROUND: High salt intake is the leading dietary risk factor for cardiovascular diseases. Although clinical evidence suggests that high salt intake is associated with nonalcoholic fatty liver disease, which is an independent risk factor for cardiovascular diseases, it remains elusive whether salt-induced hepatic damage leads to the development of cardiovascular diseases. METHODS: Mice were fed with normal or high-salt diet for 8 weeks to determine the effect of salt loading on liver histological changes and blood pressure, and salt withdrawal and metformin treatment were also conducted on some high-salt diet-fed mice. Adeno-associated virus 8, global knockout, or tissue-specific knockout mice were used to manipulate the expression of some target genes in vivo, including SIRT3 (sirtuin 3), NRF2 (NF-E2-related factor 2), and AMPK (AMP-activated protein kinase). RESULTS: Mice fed with a high-salt diet displayed obvious hepatic steatosis and inflammation, accompanied with hypertension and cardiac dysfunction. All these pathological changes persisted after salt withdrawal, displaying a memory phenomenon. Gene expression analysis and phenotypes of SIRT3 knockout mice revealed that reduced expression of SIRT3 was a chief culprit responsible for the persistent inflammation in the liver, and recovering SIRT3 expression in the liver effectively inhibits the sustained hepatic inflammation and cardiovascular damage. Mechanistical studies reveal that high salt increases acetylated histone 3 lysine 27 (H3K27ac) on SIRT3 promoter in hepatocytes, thus inhibiting the binding of NRF2, and results in the sustained inhibition of SIRT3 expression. Treatment with metformin activated AMPK, which inhibited salt-induced hepatic inflammatory memory and cardiovascular damage by lowering the H3K27ac level on SIRT3 promoter, and increased NRF2 binding ability to activate SIRT3 expression. CONCLUSIONS: This study demonstrates that SIRT3 inhibition caused by histone modification is the key factor for the persistent hepatic steatosis and inflammation that contributes to cardiovascular damage under high salt loading. Avoidance of excessive salt intake and active intervention of epigenetic modification may help to stave off the persistent inflammatory status that underlies high-salt-induced cardiovascular damage in clinical practice.

Recurrent moderate hypoglycemia accelerates the progression of Alzheimer's disease through impairment of the TRPC6/GLUT3 pathway.

Currently, the most effective strategy for dealing with Alzheimer's disease (AD) is delaying the onset of dementia. Severe hypoglycemia is strongly associated with dementia; however, the effects of recurrent moderate hypoglycemia (RH) on the progression of cognitive deficits in patients with diabetes with genetic susceptibility to AD remain unclear. Here, we report that insulin-controlled hyperglycemia slightly aggravated AD-type pathologies and cognitive impairment; however, RH significantly increased neuronal hyperactivity and accelerated the progression of cognitive deficits in streptozotocin-induced (STZ-induced) diabetic APP/PS1 mice. Glucose transporter 3-mediated (GLUT3-mediated) neuronal glucose uptake was not significantly altered under hyperglycemia but was markedly reduced by RH, which induced excessive mitochondrial fission in the hippocampus. Overexpression of GLUT3, specifically in the dentate gyrus (DG) area of the hippocampus, enhanced mitochondrial function and improved cognitive deficits. Activation of the transient receptor potential channel 6 (TRPC6) increased GLUT3-mediated glucose uptake in the brain and alleviated RH-induced cognitive deficits, and inactivation of the Ca2+/AMPK pathway was responsible for TRPC6-induced GLUT3 inhibition. Taken together, RH impairs brain GLUT3-mediated glucose uptake and further provokes neuronal mitochondrial dysfunction by inhibiting TRPC6 expression, which then accelerates progression of cognitive deficits in diabetic APP/PS1 mice. Avoiding RH is essential for glycemic control in patients with diabetes, and TRPC6/GLUT3 represents potent targets for delaying the onset of dementia in patients with diabetes.

[Developmental trend analysis and perspectives on researches related to hepatic glucose and lipid metabolism].

The balance of glucose and lipid metabolism is a coordinated result of multiple factors and organs, and is one of the fundamental requirements for the maintenance of human health. As the most important organ for human metabolism, liver plays a key role in regulating glucose and lipid metabolism. With the advances of researches, the number of publications related to hepatic glucose and lipid metabolism has increased rapidly, which posed a challenge for grasping the hot research topics and developmental trends of hepatic glucose and lipid metabolism in a short time. To solve such problem, we developed an information analysis method, which systematically analyzes the research status, research techniques, and hot research topics of the hepatic glucose and lipid metabolism research field through Medical Subject Headings (MeSH) of related papers and high-throughput experimental data. The results showed that the number of publications related to hepatic glucose and lipid metabolism, especially publications by Chinese scholars, has increased dramatically in this century, along with the remarkable increment of the numbers of authors and affiliations per paper. Such increment is in part positively correlated with the impact of publications. Nowadays, various types of high-throughput experimental techniques have become the main research methods for genetic studies of hepatic glucose and lipid metabolism. Transcription factors, such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element binding proteins (SREBPs), and NF-E2-related factor 2 (Nrf2), have become the new research hotspots. These results systematically showed the current focuses and developmental trends of hepatic glucose and lipid metabolism research, and the data analysis method developed in this work can also be applied to other research fields.

Pituitary P62 deficiency leads to female infertility by impairing luteinizing hormone production.

P62 is a protein adaptor for various metabolic processes. Mice that lack p62 develop adult-onset obesity. However, investigations on p62 in reproductive dysfunction are rare. In the present study, we explored the effect of p62 on the reproductive system. P62 deficiency-induced reproductive dysfunction occurred at a young age (8 week old). Young systemic p62 knockout (p62-/-) and pituitary-specific p62 knockout (p62flox/flox αGSUcre) mice both presented a normal metabolic state, whereas they displayed infertility phenotypes (attenuated breeding success rates, impaired folliculogenesis and ovulation, etc.) with decreased luteinizing hormone (LH) expression and production. Consistently, in an infertility model of polycystic ovary syndrome (PCOS), pituitary p62 mRNA was positively correlated with LH levels. Mechanistically, p62-/- pituitary RNA sequencing showed a significant downregulation of the mitochondrial oxidative phosphorylation (OXPHOS) pathway. In vitro experiments using the pituitary gonadotroph cell line LßT2 and siRNA/shRNA/plasmid confirmed that p62 modulated LH synthesis and secretion via mitochondrial OXPHOS function, especially Ndufa2, a component molecule of mitochondrial complex I, as verified by Seahorse and rescue tests. After screening OXPHOS markers, Ndufa2 was found to positively regulate LH production in LßT2 cells. Furthermore, the gonadotropin-releasing hormone (GnRH)-stimulating test in p62flox/flox αGSUcre mice and LßT2 cells illustrated that p62 is a modulator of the GnRH-LH axis, which is dependent on intracellular calcium and ATP. These findings demonstrated that p62 deficiency in the pituitary impaired LH production via mitochondrial OXPHOS signaling and led to female infertility, thus providing the GnRH-p62-OXPHOS(Ndufa2)-Ca2+/ATP-LH pathway in gonadotropic cells as a new theoretical basis for investigating female reproductive dysfunction.

Plasmon-induced double-field-enhanced upconversion nanoprobes with near-infrared resonances for high-sensitivity optical bio-imaging.

High-sensitivity optical imaging can be achieved through improving upconversion photoluminescence (UCPL) efficiency of localized surface plasmon resonance (LSPR)-enhanced excitation and emission. Herein, we report a type of UCPL nanoprobe, Au nanospheres assemblage@Gd2O3:Yb3+/Ln3+(Ln = Er, Ho, Tm), which exhibits emission enhancements from 46- to 96-fold as compared with its Au-free counterparts. The aggregation and interaction among Au nanospheres embedded inside the nanoprobe brings about three characteristic LSPR peaks in visible and near-infrared regions according to simulated and experimental absorption spectra, resulting in both excitation and emission fields simultaneously intensified all through the entire nanoprobe. We addressed a characteristic wavelength dependence on emission amplifications, which could be elucidated by a LSPR-enhanced UCPL mechanism and relevant rate equations that we addressed. The nanoprobe was verified to have a superior capability for optical bio-imaging with a negligible toxicityin vitroandin vivo. This study realizes a synchronous double-field-enhanced upconversion of optical nanoprobein situ, and may gain an insight into its mechanism underlying for LSPR-induced UCPL enhancement.