Epicardial adipose tissue volume highly correlates with left ventricular diastolic dysfunction in endogenous Cushing's syndrome.

BACKGROUND: Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS: A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS: A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION: CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.

This study explored the potential risk factors of LVDD in endogenous CS by incorporating body composition parameters. EATV was identified as an independent risk factor for LVDD. Targeted therapeutic interventions to reduce excessive cortisol-induced EAT accumulation may be promising to mitigate the risk of LVDD development in patients with CS.

The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.

Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.

Recent Advances in Hydrogel Technology in Delivering Mesenchymal Stem Cell for Osteoarthritis Therapy.

Osteoarthritis (OA), a chronic joint disease affecting over 500 million individuals globally, is characterized by the destruction of articular cartilage and joint inflammation. Conventional treatments are insufficient for repairing damaged joint tissue, necessitating novel therapeutic approaches. Mesenchymal stem cells (MSCs), with their potential for differentiation and self-renewal, hold great promise as a treatment for OA. However, challenges such as MSC viability and apoptosis in the ischemic joint environment hinder their therapeutic effectiveness. Hydrogels with biocompatibility and degradability offer a three-dimensional scaffold that support cell viability and differentiation, making them ideal for MSC delivery in OA treatment. This review discusses the pathological features of OA, the properties of MSCs, the challenges associated with MSC therapy, and methods for hydrogel preparation and functionalization. Furthermore, it highlights the advantages of hydrogel-based MSC delivery systems while providing insights into future research directions and the clinical potential of this approach.

Fibrinogen-to-prealbumin and C-reactive protein-to-prealbumin ratios as prognostic indicators in severe fever with thrombocytopenia syndrome.

Background: The primary aim of this study is to investigate the correlation between serum levels of fibrinogen-to-prealbumin ratio (FPR) and C-reactive protein-to-prealbumin ratio (CPR) and prognostic outcomes among patients with severe fever with thrombocytopenia syndrome (SFTS). SFTS, characterized by elevated mortality rates, represents a substantial public health challenge as an emerging infectious disease. Methods: The study included 159 patients with SFTS. Clinical and laboratory data were compared between the survival and death groups. Univariate and multivariate logistic regression analysis were utilized to identify independent risk factors for mortality. The predictive efficacy of FPR and CPR was evaluated using receiver operating characteristic (ROC) curve. Survival analysis was conducted using the Kaplan-Meier curve and the log-rank test was employed for comparison. Results: The death group exhibited significantly elevated levels of FPR and CPR compared to the survival group (P < 0.05). Multivariate logistic regression analysis confirmed that both FPR and CPR independently correlated with a poorer prognosis among patients with SFTS. The ROC curve analysis indicated that FPR and CPR had superior predictive capabilities compared to C-reactive protein and fibrinogen. Kaplan-Meier survival analysis demonstrated that patients with SFTS who have FPR > 0.045 (log-rank test; χ2 = 17.370, P < 0.001) or CPR > 0.05 (log-rank test; χ2 = 19.442, P < 0.001) experienced significantly lower survival rates within a 30-day follow-up period. Conclusion: Elevated levels of FPR and CPR serve as distinct risk factors for mortality among patients with SFTS, indicating their potential to predict an unfavorable prognosis in these patients.

Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation.

Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca-/-(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca-/-(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

A case of mild partial androgen insensitivity syndrome in a juvenile boy.

Androgen insensitivity syndrome (AIS) is a rare disorder with X-linked recessive inheritance in 46 XY patients. The clinical manifestations vary between patients, especially regarding external genitalia development. Herein, the case of AIS in a 13-year-old male, who was born with hypospadias and presented to the hospital with gynaecomastia that had developed from 8 years of age, is reported. No micropenis, cryptorchidism or bifid scrotum were found. Testis volume was 12 ml on both sides. His testosterone and luteinizing hormone levels were normal compared with sex- and age-adjusted reference range. His bone age was approximately 13 years according to Greulich-Pyle assessment. Sequence analysis of the androgen receptor (AR) gene revealed a mutation (c.2041A>G) in exon 4, a novel mutation site in the AR gene. Prediction analysis suggested this to be a disease-causing variant. A milder clinical presentation and normal hormone levels in cases of partial AIS might differ from the usually reported signs and symptoms. A diagnosis of AIS should not be ignored in teenage patients who present with gynaecomastia and hypospadias, but normal hormone levels.

Clinical effect of laparoscopic radical resection of colorectal cancer based on propensity score matching.

BACKGROUND: The incidence of colorectal cancer (CRC) is increasing annually. Laparoscopic radical resection of CRC is a minimally invasive procedure preferred in clinical practice. AIM: To investigate the clinical effect of laparoscopic radical resection of CRC on the basis of propensity score matching (PSM). METHODS: The clinical data of 100 patients who received inpatient treatment for CRC at Changde Hospital, Xiangya School of Medicine, Central South University (The First People's Hospital of Changde City) were analyzed retrospectively. The control group included patients who underwent open surgery (n = 43), and those who underwent laparoscopic surgery formed the observation group (n = 57). The baseline information of both groups was equipoised using 1 × 1 PSM. Differences in the perioperative parameters, inflammatory response, immune function, degree of pain, and physical status between the groups were analyzed. RESULTS: Thirty patients from both groups were successfully matched. After PSM, baseline data showed no statistically significant differences between the groups: (1) Perioperative parameters: The observation group had a longer surgery time, less intraoperative blood loss, earlier first ambulation and first anal exhaust times, and shorter gastric tube indwelling time than the control group; (2) Inflammatory response: 24 h after surgery, the levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) between groups were higher than preoperatively. IL-6, CRP, and TNF-α levels in the observation group were lower than in the control group; (3) Immune function: At 24 h after surgery, counts of CD4-positive T-lymphocytes (CD4+) and CD4+/CD8-positive T-lymphocytes (CD8+) in both groups were lower than those before surgery, whereas CD8+ was higher than that before surgery. At 24 h after surgery, both CD4+ counts and CD4+/CD8+ in the observation group were higher than those in the control group, whereas CD8+ counts were lower; (4) Degree of pain: The visual analog scale scores in the observation group were lower than those in the control group at 24 and 72 h after surgery; and (5) Physical status: One month after surgery, the Karnofsky performance score in the observation group was higher than that in the control group. CONCLUSION: Laparoscopic radical resection of CRC has significant benefits, such as reducing postoperative pain and postoperative inflammatory response, avoiding excessive immune inhibition, and contributing to postoperative recovery.

CircRNA_102046 Affects the Occurrence and Development of Ischemic Stroke by Regulating the miR-493-5p/ROCK1 Signaling.

In our previous studies, the results have revealed that circRNA_102046 is significantly upregulated in plasma of patients with ischemic stroke, which closely related to NIHSS score. Human neural stem cells (hNSCs) were used for characterization and subcellular localization of circRNA_102046, and hNSCs OGD/R model was generated. The proliferation of cells was examined by CCK-8 assay. The expression levels of associated molecules were evaluated using RT-qPCR, immunofluorescence staining or western blotting. The binding and co-localization of associated molecules were also evaluated by RIP and FISH assay. Furthermore, MCAO mouse model was established to examine the effects of circRNA_102046 on the progression of ischemic stroke. Expression of circRNA_102046 was detected in the cytoplasma of hNSCs. Then OGD/R cell model was established, where the levels of circRNA_102046 was significantly up-regulated. Furthermore, knockdown of circRNA_102046 was able to enhance the proliferation and differentiation of OGD/R hNSCs. In further downstream molecular studies, the results indicated that circRNA_102046 could participate in the occurrence and development of ischemic stroke through targeting miR-493-5p. In addition, ROCK1 was identified as the putative target of miR-493-5p, and circRNA_102046 regulates the proliferation and differentiation of hNSCs via the miR-493-5p/ROCK1 signaling. More importantly, the infarct volumes of MCAO mice were remarkably reduced after the treatment with sh-circRNA_102046, which also up- and down-regulate the expression of miR-493-5p and ROCK1, respectively. Elucidating this novel pathway provides a theoretical basis for the development of new diagnostic approach and targeted treatment for ischemic stroke.

High Doses of Exogenous Glucagon Stimulate Insulin Secretion and Reduce Insulin Clearance in Healthy Humans.

Glucagon is generally defined as a counterregulatory hormone with a primary role to raise blood glucose concentrations by increasing endogenous glucose production (EGP) in response to hypoglycemia. However, glucagon has long been known to stimulate insulin release, and recent preclinical findings have supported a paracrine action of glucagon directly on islet ß-cells that augments their secretion. In mice, the insulinotropic effect of glucagon is glucose dependent and not present during basal euglycemia. To test the hypothesis that the relative effects of glucagon on hepatic and islet function also vary with blood glucose, a group of healthy subjects received glucagon (100 ng/kg) during fasting glycemia or experimental hyperglycemia (∼150 mg/dL) on 2 separate days. During fasting euglycemia, administration of glucagon caused blood glucose to rise due to increased EGP, with a delayed increase of insulin secretion. When given during experimental hyperglycemia, glucagon caused a rapid, threefold increase in insulin secretion, as well as a more gradual increase in EGP. Under both conditions, insulin clearance was decreased in response to glucagon infusion. The insulinotropic action of glucagon, which is proportional to the degree of blood glucose elevation, suggests distinct physiologic roles in the fasting and prandial states.

YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths.

N6-methyladenosine (m6A) is a critical regulator in the fate of RNA, but whether and how m6A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m6A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.

LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis.

Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB-/- bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

Case report: Autosomal recessive type 3 Stickler syndrome caused by compound heterozygous mutations in COL11A2.

Background: Stickler syndrome (SS) is a group of hereditary collagenopathies caused by a variety of collagen and non-collagen genes. Affected patients have characteristic manifestations involving ophthalmic, articular, craniofacial and auditory disorders. SS is classified into several subtypes according to clinical and molecular features. Type 3 SS is an ultra-rare disease, known as non-ocular SS or otospondylomegaepiphyseal dysplasia (OSMED) with only a few pathogenic COL11A2 variants reported to date. Case presentation: A 29-year-old Chinese male was referred to our hospital for hearing loss and multiple joint pain. He presented a phenotype highly suggestive of OSMED, including progressive sensorineural deafness, spondyloepiphyseal dysplasia with large epiphyses, platyspondyly, degenerative osteoarthritis, and sunken nasal bridge. We detected compound heterozygous mutations in COL11A2, both of which were predicted to be splicing mutations. One is synonymous mutation c.3774C>T (p.Gly1258Gly) supposed to be a splice site mutation, the other is a novel intron mutation c.4750 + 5 G>A, which is a highly conservative site across several species. We also present a review of the current known pathogenic mutation spectrum of COL11A2 in patients with type 3 SS. Conclusion: Both synonymous extonic and intronic variants are easily overlooked by whole-exome sequencing. For patients with clinical manifestations suspected of SS syndrome, next-generation whole-genome sequencing is necessary for precision diagnosis and genetic counseling.

Sphenoid sinus is a rare site for tumor-induced osteomalacia: A case report and literature review.

Background: In this paper, we present a rare case of tumor-induced osteomalacia (TIO) and a literature review of this rare disease. Methods: A case of TIO of the isolated sphenoid sinus was reported. Furthermore, the clinical features of TIO in the sphenoid sinus and other sinonasal sinuses were also reviewed and summarized. Results: A 35-year-old man with muscle weakness and lower back pain came to the Department of Neurology. No obvious neurological disease was found; however, magnetic resonance imaging of the extremities accidentally showed a tumor in the axilla. Bone scintigraphy showed suspicious bone metastasis. Hypophosphatemia was neglected. Interestingly, 2-deoxy-2-[fluorine-18]fluoro-d-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) detected a tumor in the axilla and another in the sphenoid sinus, but only the tumor in the sphenoid sinus had somatostatin receptor (SSTR) expression in 68-gallium 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid octreotate (Ga-68 DOTATATE) PET/CT. The sphenoid sinus tumor was proven to be a phosphaturic mesenchymal tumor (PMT), and the phosphate levels returned to normal after surgery. The literature review showed only 17 cases of TIOs that occurred in the sphenoid sinus, with an average age of 43.3 ± 13.7 years. Only three cases of TIOs in the sphenoid sinus did not invade the nasal cavity or other paranasal sinuses, which could be identified as isolated sphenoid sinus diseases. We compared the clinical features of sphenoid TIOs with those of non-sphenoid sinonasal TIOs, and it was found that the concentration of 1,25-dihydroxy vitamin D in the group with sphenoid TIOs was much higher than that in the group with non-sphenoid sinonasal TIOs. A total of 153 cases of TIOs in the sinonasal sinus were reviewed. The ethmoid sinus was found to be the major site (64.7%), followed by the nasal cavity (50.3%), maxillary sinus (19.0%), frontal sinus (16.4%), and sphenoid sinus (11.8%). There were 66 patients (43.1%) who showed tumors invading more than one sinus. Most of the tumors (69.3%) were diagnosed as PMTs by pathology, followed by hemangiopericytoma (14.3%). Immunostaining was beneficial in the differential diagnosis of these tumors; however, larger sample sizes are needed for better accuracy. Conclusion: TIO in the sinonasal sinus, especially in the sphenoid sinus, is rare. Moreover, isolated sphenoid sinus disease can be easily misdiagnosed. When the clinical manifestation of osteomalacia is atypical, associating it with sphenoid sinus disease is even more difficult. Thus, TIO in the sphenoid sinus needs further exploration.

Ischemia promotes acyl-CoAs dephosphorylation and propionyl-CoA accumulation.

INTRODUCTION: Our untargeted metabolic data unveiled that Acyl-CoAs undergo dephosphorylation, however little is known about these novel metabolites and their physiology/pathology relevance. OBJECTIVES: To understand the relationship between acyl-CoAs dephosphorylation and energy status as implied in our previous work, we seek to investigate how ischemia (energy depletion) triggers metabolic changes, specifically acyl-CoAs dephosphorylation in this work. METHODS: Rat hearts were isolated and perfused in Langendorff mode for 15 min followed by 0, 5, 15, and 30 minutes of global ischemia. The heart tissues were harvested for metabolic analysis. RESULTS: As expected, ATP and phosphocreatine were significantly decreased during ischemia. Most short- and medium-chain acyl-CoAs progressively increased with ischemic time from 0 to 15 min, whereas a 30-minute ischemia did not lead to further change. Unlike other acyl-CoAs, propionyl-CoA accumulated progressively in the hearts that underwent ischemia from 0 to 30 min. Progressive dephosphorylation occurred to all assayed acyl-CoAs and free CoA regardless their level changes during the ischemia. CONCLUSION: The present work further confirms that dephosphorylation of acyl-CoAs is an energy-dependent process and how this dephosphorylation is mediated warrants further investigations. It is plausible that dephosphorylation of acyl-CoAs and limited anaplerosis are involved in ischemic injuries to heart. Further investigations are warranted to examine the mechanisms of acyl-CoA dephosphorylation and how the dephosphorylation is possibly involved in ischemic injuries.

Terminal group effects of DOPO-conjugated flame retardant on polyamide 6: Thermal stability, flame retardancy and mechanical performances.

Two DOPO-conjugated flame retardants with or without amino terminal groups (DOPO-NH2 and DIDOPO, respectively) were synthesized and incorporated into polyamide 6 (PA6). Results demonstrated the DOPO-NH2 endowed superior thermal, flame retardant and mechanical performances to PA6 composites. With the same loading of 15 wt%, DOPO-NH2 can catalyze the PA6 matrix more effectively and result in more residues at high temperature. The PA6 composites containing DOPO-NH2 exhibited higher LOI (28.0%) compared to 25.0% for the sample containing DIDOPO, and the lower heat release capacity and peak heat release rate. Furthermore, the overall mechanical properties of PA6 composites containing DOPO-NH2 outperformed the samples containing DIDOPO, even superior to that for PA6. Such a significant difference can be mainly attributed to the existence of amino-terminal group, which can interact with carboxyl group in PA6 as confirmed by dynamic mechanical analysis, improving the compatibility between the flame retardant and PA6 matrix.

m6A modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress.

Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N6-methyladenosine (m6A) and stabilized by IGF2BP1, a cellular m6A reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of m6A-modified E7 mRNA to form distinct heat-induced m6A E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between m6A RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.

Tirzepatide induces a thermogenic-like amino acid signature in brown adipose tissue.

OBJECTIVES: Tirzepatide, a dual GIP and GLP-1 receptor agonist, delivered superior glycemic control and weight loss compared to selective GLP-1 receptor (GLP-1R) agonism in patients with type 2 diabetes (T2D). These results have fueled mechanistic studies focused on understanding how tirzepatide achieves its therapeutic efficacy. Recently, we found that treatment with tirzepatide improves insulin sensitivity in humans with T2D and obese mice in concert with a reduction in circulating levels of branched-chain amino (BCAAs) and keto (BCKAs) acids, metabolites associated with development of systemic insulin resistance (IR) and T2D. Importantly, these systemic effects were found to be coupled to increased expression of BCAA catabolic genes in thermogenic brown adipose tissue (BAT) in mice. These findings led us to hypothesize that tirzepatide may lower circulating BCAAs/BCKAs by promoting their catabolism in BAT. METHODS: To address this question, we utilized a murine model of diet-induced obesity and employed stable-isotope tracer studies in combination with metabolomic analyses in BAT and other tissues. RESULTS: Treatment with tirzepatide stimulated catabolism of BCAAs/BCKAs in BAT, as demonstrated by increased labeling of BCKA-derived metabolites, and increases in levels of byproducts of BCAA breakdown, including glutamate, alanine, and 3-hydroxyisobutyric acid (3-HIB). Further, chronic administration of tirzepatide increased levels of multiple amino acids in BAT that have previously been shown to be elevated in response to cold exposure. Finally, chronic treatment with tirzepatide led to a substantial increase in several TCA cycle intermediates (α-ketoglutarate, fumarate, and malate) in BAT. CONCLUSIONS: These findings suggest that tirzepatide induces a thermogenic-like amino acid profile in BAT, an effect that may account for reduced systemic levels of BCAAs in obese IR mice.

Dose-response association between sedentary time and incident of diabetes in Chinese middle-aged and older adults: The 4C study.

AIMS: To investigate the dose-response relationship of total sedentary time with incident diabetes in Chinese middle-aged and older adults. METHODS: The present study followed 100,525 participants aged ≥ 40 years old from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was a prospective study conducted in 25 communities across mainland China. Associations between sedentary time and incident diabetes were assessed with Cox regression and restricted cubic splines. RESULTS: During a median follow-up of 3.8 years, 7,529 participants developed diabetes. After adjustment for multiple variables, high levels of sedentary time (≥ 30 h/week) was associated with increased risk for developing diabetes (hazards ratio, 1.08; 95 % confidence intervals 1.02, 1.14) compared with low levels of sedentary time (<20 h/week). Restricted cubic spline analyses revealed an inverted U-shaped relation between sedentary time with diabetes. Subgroup analyses found that the observed association remained significant in subgroup of individuals with body mass index (BMI) ≥ 25 kg/cm2 or diastolic blood pressure (DBP) ≥ 90 mm Hg. However, the significant association was diminished in participants with sufficient physical activity (PA) (P = 0.22). CONCLUSIONS: The multicenter, population-based, prospective study suggested an inverted U-shaped relation between sedentary time with diabetes. PA alleviated the deleterious effects associated with sedentary time.

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.

Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, whereas in contrast, ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY-depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels because of its increased conversion to malonyl CoA and palmitate. Together, these data indicate that in fat diet-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or malonyl CoA but rather by activities of DNL enzymes.