Metabolic associated fatty liver disease (MAFLD) is fundamentally driven by an imbalance in hepatic fatty-acid flux: the influx of fatty acids exceeds the liver’s capacity for disposal, resulting in excessive hepatic lipid accumulation, predominantly in the form of triglycerides (TGs). The occurrence and progression of MAFLD depend on disordered regulation across multiple metabolic steps, including fatty-acid uptake, de novo lipogenesis (DNL), fatty-acid oxidation (FAO), and very low-density lipoprotein (VLDL) export. Forkhead box protein O1 (FOXO1) is a key transcriptional regulator within the hepatic network coordinating glucose and lipid metabolism. Under metabolic stress and insulin resistance (IR), FOXO1 expression is frequently increased, whereas its inhibitory phosphorylation is reduced. These changes enhance FOXO1 nuclear localization and transcriptional activity, thereby reprogramming the expression of genes related to metabolism in the liver. Because hepatic lipid deposition is the central pathological feature of MAFLD, the functional status of FOXO1 directly influences hepatic lipid homeostasis. Growing evidence suggests that FOXO1 can exert bidirectional, environment-dependent effects on hepatic lipid accumulation; however, the molecular basis for this functional switch remains incompletely understood. This review systematically summarizes the biological functions and regulatory mechanisms of FOXO1 and its roles in hepatic lipid metabolism, with a particular focus on its crosstalk with insulin signaling. FOXO1 expression is shaped by RNA modifications and epigenetic regulation mediated by non-coding RNAs. Its transcriptional output is precisely governed by post-translational modifications—such as phosphorylation and acetylation—as well as by coordinated nucleocytoplasmic shuttling. Notably, these regulatory patterns vary markedly across nutritional states, degrees of insulin resistance, and stages of disease. In the fed state, insulin/IGF-1 signaling activates the PI3K-AKT pathway, promoting the inhibitory phosphorylation of FOXO1 and facilitating additional modifications, including acetylation, methylation, and ubiquitination. Together, these events drive FOXO1 export from the nucleus and dampen its transcriptional activity, suppressing gluconeogenesis and constraining lipogenic programs. Conversely, during fasting or when insulin signaling is weakened, FOXO1 inhibition is relieved. FOXO1 accumulates in the nucleus, binds to DNA, and regulates the transcription of downstream target genes. Mechanistically, FOXO1 can aggravate hepatic lipid accumulation by activating genes involved in TG synthesis while repressing FAO-related pathways, thereby favoring storage over oxidation. However, under specific conditions, FOXO1 may also alleviate the hepatic lipid burden by promoting TG hydrolysis and enhancing VLDL secretion, thereby reducing the net hepatic lipid load. In addition, lipotoxic signals mediated by ceramides and diacylglycerols (Cer/DAG) activate atypical protein kinase C (aPKC), further exacerbating the disruption of the AKT-FOXO1 axis. This vicious cycle ultimately produces a metabolic paradox in which increased hepatic glucose output coexists with persistent, insulin-independent lipogenesis, accelerating MAFLD progression. Importantly, FOXO1 regulation is not uniform: during early metabolic overload, insulin-mediated suppression may remain effective, whereas in advanced insulin resistance, the loss of AKT control permits sustained FOXO1 activity. Such stage-dependent dynamics may help explain why FOXO1 can either promote steatosis or, in certain contexts, support programs that facilitate lipid turnover. Accordingly, interventions should be liver-specific and tuned to the disease stage, aiming to curb maladaptive FOXO1 signaling while preserving its capacity to promote triglyceride hydrolysis and VLDL secretion when advantageous. Overall, this review offers an important perspective on MAFLD pathogenesis, emphasizing FOXO1 as a potential therapeutic target and providing a theoretical basis for developing liver-specific, disease-course-dependent precision interventions.

Introduction: Insulin autoimmune syndrome (IAS), or Hirata syndrome, is characterized by hyperinsulinemic hypoglycemia resulting from the presence of high titers of insulin autoantibodies (IAAs) in the absence of exogenous insulin. We present a rare case of IAS. Case: A 75-year-old female with underlying hypertension, dyslipidemia, and osteoporosis presented with symptoms suggestive of spontaneous hypoglycemia of 3 months duration. She was non-diabetic with no history of antidiabetic agents or exogenous insulin use. Notably, she had taken traditional medications 1 month prior to onset of symptoms. Her fasting blood glucose was 2 mmol/L. Serum insulin was significantly elevated at >1,000 iui/mL and serum C peptide was 2,950 pmol/L, consistent with hyperinsulinemic hypoglycemia. Blood sulfonylurea level was not available. Her complete blood count and renal and liver function were normal. Thyroid function test was normal, and a short corticotropin stimulation test showed adequate cortisol response. Computed tomography (CT) pancreas, endoscopic ultrasound and PET-CT scan with Galium-68 DOTATATE showed no evidence of insulinoma. Serum IAAs were raised at 175 IU/mL, which confirmed a diagnosis of IAS. The patient was managed with dietary modifications and advised for frequent, small meals with low glycemic index, incorporating oral raw cornstarch. She was also started on oral diazoxide 100 mg twice daily (3 mg/kg/day) due to persistent hypoglycemia. She responded well to diazoxide with no more spontaneous hypoglycemia, however, developed fluid retention which was managed with oral diuretics. Subsequently, we managed to taper and stop the diazoxide after 18 months of treatment. Patient remains well with no further episodes of hypoglycemia. Conclusion IAS may be triggered by medications or viral infections, occurs more frequently in people with autoimmune conditions, and shows genetic predisposition. However, as in our patient, IAS may be idiopathic, and the cause remains unknown. IAS is frequently self-limiting, and our patient experienced spontaneous remission with no further hypoglycemic episodes after discontinuation of treatment.
Hypoglycemia ; Insulins

Introduction: Subacute thyroiditis (SAT) and acute suppurative thyroiditis (AST) are two distinct inflammatory conditions but share many overlapping clinical and biochemical features, which may pose a diagnostic challenge. We report a case of SAT mimicking AST. Case: A 39-year-old female presented with a 3-week history of painful neck swelling and symptoms of thyrotoxicosis, including palpitations, heat intolerance, and diaphoresis. She had no family history of thyroid disease. On examination, she was febrile and had a smooth and tender goiter. Her blood tests showed leukocytosis with elevated erythrocyte sedimentation rate and C-reactive protein. Her thyroid function test (TFT) showed thyroid-stimulating hormone of 0.023 mIU/L and free thyroxine 4 of 32.15 pmol/L. An urgent ultrasound revealed a large, ill-defined heterogeneously hypoechoic lesion predominantly at the left lobe of the thyroid gland with mild intralesional vascularity. These were reported as features of thyroiditis with infective or early suppurative changes. Fine needle aspiration (FNA) of the lesion was attempted by the radiologist but was unsuccessful. She was treated with intravenous antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), but symptoms persisted. Repeated ultrasound and computed tomography scans about 1 week later confirmed an enlarged thyroid gland with no obvious lesion or collection within the gland. The diagnosis was revised to SAT, and prednisolone 15 mg OD was started. This resulted in rapid improvement in her symptoms and inflammatory markers. Four weeks later, she remained asymptomatic, and prednisolone was gradually tapered off. Serial TFT monitoring showed a classic triphasic pattern with an initial hyperthyroid phase, followed by hypothyroidism before returning to euthyroidism. Conclusion SAT can present with a focal lesion on the ultrasound during the early stage of the disease, making it difficult to distinguish from a thyroid abscess due to overlapping features. Good clinical judgement guided by FNA and appropriate follow-up imaging may be helpful in differentiating between the two conditions.
Thyroiditis, Subacute ; Thyroiditis, Suppurative

OBJECTIVE: To investigate the clinical efficacy of bilateral targeted puncture in percutaneous vertebroplasty(PVP) based on the vertebral osteodense zone. METHODS: A retrospective analysis was conducted on 76 patients with fresh symptomatic osteoporotic vertebral compression fractures, characterized by the presence of a dense zone, who underwent percutaneous vertebroplasty (PVP) between January 2021 and December 2021. All patients involved single-level vertebral fractures. There were 19 males and 57 females, aged from 62 to 88 years old, with an average of (68.5±12.5) years old. All patients underwent bilateral transpedicular puncture procedures. Preoperative CT or MRI was utilized to ascertain the relative position of the bone osteodense zone within the vertebral body (specifically, whether this zone is situated in the upper one-third or one-quarter of the left or right sagittal plane). Considering the head and tail regions of the dense zone as puncture targets, the puncture points and paths were meticulously planned, and the working channel was subsequently established. Under continuous monitoring by a C-arm X-ray machine, bone cement was carefully and gradually injected. The operation time, bone cement injection volume, and bone cement leakage were recorded. The visual analogue scale (VAS) and Oswestry disablity index (ODI) were used to evaluate the effectiveness of the operation. ODI and anterior height (AH) of the vertebral body were used to evaluate the efficacy. RESULTS: All patients successfully completed the surgery and were followed up for (8.0±1.0) months. The operation time was (36.57±11.25) min, the volume of bone cement injection was(6.07±1.19) ml, and 21 patients of bone cement leakage. There were 3 patients with the VAS exceeded 4 points two days postoperatively, indicating suboptimal pain management. At the three time points of pre-operation, 2 days post-operation and 6 months post-operation, the VAS scores were(7.82±1.29), (2.11±0.44), and (2.04±0.67) respectively;the ODI percentages were(75.65±7.23)%, (29.45±4.16)%, and(28.68±5.62)%;and the AH values were (11.02±1.30), (12.87±3.91), and (12.91±3.86) cm. The differences were all statistically significant(P<0.05). The aforementioned three indices demonstrated significant improvement at both 2 days and 6 months post-operation (all P<0.05). There were no statistically significant differences in these indices between the 2-day and 6-month post-operative periods(P>0.05). The postoperative outcome was satisfactory and durable, with no evidence of vertebral height reduction. CONCLUSION Bilateral targeted puncture based on the osteodense dense zone within the vertebral body can achieve bilateral symmetrical and upright full vertebral bone cement reinforcement without increasing bone cement leakage, achieving good early efficacy and preventing late vertebral collapse. This has positive significance for further improving the efficacy of percutaneous vertebroplasty.
Humans ; Male ; Female ; Vertebroplasty/methods* ; Aged ; Middle Aged ; Aged, 80 and over ; Retrospective Studies ; Spinal Fractures/surgery* ; Fractures, Compression/surgery* ; Punctures ; Bone Cements ; Osteoporotic Fractures/surgery*

OBJECTIVES: To investigate the current status and influencing factors of sleep disorders in school-age children with asthma, providing a scientific basis for improving sleep quality and quality of life of asthmatic children. METHODS: This study selected school-age children with asthma admitted to the Children's Hospital of Nanjing Medical University from March 2022 to March 2024 as subjects. A questionnaire was used to assess their sleep conditions, and based on the assessment results, the participants were divided into a sleep disorder group (106 children) and a non-sleep disorder group (181 children). Multivariate logistic regression analysis was conducted to identify the influencing factors of sleep disorders in asthmatic children. RESULTS: A total of 287 asthmatic children were included, of which 106 (36.9%) had sleep disorders. Multivariate logistic regression analysis showed that being older than 10 years, obesity, poor medication adherence, unhealthy family functioning, passive smoking, and participation in only some physical activities were all risk factors for sleep disorders in school-aged children with asthma (P<0.05). CONCLUSIONS The incidence of sleep disorders in school-age children with asthma is relatively high and influenced by multiple factors, including age, obesity, poor medication adherence, unhealthy family functioning, passive smoking, and limited participation in physical activities. To improve the sleep quality and quality of life of asthmatic children, corresponding intervention measures should be implemented targeting these influencing factors.
Humans ; Asthma/complications* ; Child ; Male ; Female ; Sleep Wake Disorders/etiology* ; Logistic Models ; Quality of Life ; Adolescent ; Risk Factors

OBJECTIVES: To investigate the clinical features and prognosis of children with non-Down-syndrome-related acute megakaryoblastic leukemia (non-DS-AMKL). METHODS: A retrospective analysis was conducted on the medical data of 17 children with non-DS-AMKL who were admitted to Children's Hospital of The First Affiliated Hospital of Zhengzhou University from January 2013 to December 2023, and their clinical features, treatment, and prognosis were summarized. RESULTS: Among the 17 children with non-DS-AMKL, there were 8 boys and 9 girls. Fourteen patients had an onset age of less than 36 months, with a median age of 21 months (range:13-145 months). Immunophenotyping results showed that 16 children were positive for CD61 and 13 were positive for CD41. The karyotype analysis was performed on 16 children, with normal karyotype in 6 children and abnormal karyotype in 9 children, among whom 5 had complex karyotype and 1 had no mitotic figure. Detected fusion genes included EVI1, NUP98-KDM5A, KDM5A-MIS18BP1, C22orf34-BRD1, WT1, and MLL-AF9. Genetic alterations included TET2, D7S486 deletion (suggesting 7q-), CSF1R deletion, and PIM1. All 17 children received chemotherapy, among whom 16 (94%) achieved complete remission after one course of induction therapy, and 1 child underwent hematopoietic stem cell transplantation (HSCT) and remained alive and disease-free. Of all children, 7 experienced recurrence, among whom 1 child received HSCT and died of graft-versus-host disease. At the last follow-up, six patients remained alive and disease-free. CONCLUSIONS Non-DS-AMKL primarily occurs in children between 1 and 3 years of age. The patients with this disorder have a high incidence rate of chromosomal abnormalities, with complex karyotypes in most patients. Some patients harbor fusion genes or gene mutations. Although the initial remission rate is high, the long-term survival rate remains low.
Humans ; Male ; Female ; Leukemia, Megakaryoblastic, Acute/etiology* ; Child, Preschool ; Infant ; Child ; Retrospective Studies ; Prognosis ; Down Syndrome/complications*

OBJECTIVE: To explore the effect and mechanism of DNA methyltransferase 1 (DNMT1) knockout on the inhibition of acute myeloid leukemia (AML) by natural killer (NK) cells. METHODS: The peripheral blood NK cells of AML patients and controls were collected, and the mRNA and protein level of DNMT1 were measured by PCR and Western blot, respectively. The DNMT1 knockout mice were constructed to obtain NK^DNMT1-/- cells. The NK cells were stimulated with interleukin (IL)-12, IL-15, and IL-18 to construct memory NK cells, and then the interferon-γ (IFN-γ) levels were measured by ELISA. After co-culturing with memory NK cells and HL60 cells, the killing effect of NK^DNMT1-/- cells on HL60 cells was detected by LDH assay. Then, the HL60 cell apoptosis and NK cell NKG2D level were measured by flow cytometry. The perforin and granzyme B protein levels of NK cells were measured by Western blot. The AML model mice were constructed by injecting HL60 cells into the tail vein, meanwhile, memory NK cells were also injected, and then the mouse weights, CD33 positive rates, and survival time were detected. RESULTS: The mRNA and protein levels of DNMT1 in NK cells of AML patients were significantly higher than those in the control group (both P < 0.01), while the IFN-γ level induced by interleukin was significantly lower than that in the control group (P < 0.05). Compared with NK^DNMT1+/+ cells, the ability of NK^DNMT1-/- cells to secrete IFN-γ after interleukin stimulation was significantly increased (P < 0.05). The killing and apoptosis-inducing effects of NK^DNMT1-/- cells on HL60 cells were significantly stronger than those of NK^DNMT1+/+ cells (both P < 0.05). The NKG2D level and expression of perforin and granzyme B of NK^DNMT1-/- cells were significantly increased compared with NK^DNMT1+/+ cells (all P < 0.05). Compared with AML mice injected with NK^DNMT1+/+ cells, AML mice injected with NK^DNMT1-/- cells showed significantly increased body weight, decreased CD33 positive rate, and prolonged survival time (all P < 0.05). CONCLUSION Knocking out DNMT1 can enhance the inhibitory effect of NK cells on AML, which may be related to enhancing NK cell memory function.
Killer Cells, Natural/metabolism* ; Animals ; Leukemia, Myeloid, Acute ; Humans ; DNA (Cytosine-5-)-Methyltransferase 1 ; Mice ; Mice, Knockout ; HL-60 Cells ; Apoptosis ; Interferon-gamma/metabolism* ; Granzymes/metabolism* ; Perforin/metabolism* ; NK Cell Lectin-Like Receptor Subfamily K/metabolism*

Cardiovascular disease (CVD) remains one of the leading causes of mortality among adults globally, with continuously rising morbidity and mortality rates. Metabolic disorders are closely linked to various cardiovascular diseases and play a critical role in their pathogenesis and progression, involving multifaceted mechanisms such as altered substrate utilization, mitochondrial structural and functional dysfunction, and impaired ATP synthesis and transport. In recent years, the potential role of peroxisome proliferator-activated receptors (PPARs) in cardiovascular diseases has garnered significant attention, particularly peroxisome proliferator-activated receptor alpha (PPARα), which is recognized as a highly promising therapeutic target for CVD. PPARα regulates cardiovascular physiological and pathological processes through fatty acid metabolism. As a ligand-activated receptor within the nuclear hormone receptor family, PPARα is highly expressed in multiple organs, including skeletal muscle, liver, intestine, kidney, and heart, where it governs the metabolism of diverse substrates. Functioning as a key transcription factor in maintaining metabolic homeostasis and catalyzing or regulating biochemical reactions, PPARα exerts its cardioprotective effects through multiple pathways: modulating lipid metabolism, participating in cardiac energy metabolism, enhancing insulin sensitivity, suppressing inflammatory responses, improving vascular endothelial function, and inhibiting smooth muscle cell proliferation and migration. These mechanisms collectively reduce the risk of cardiovascular disease development. Thus, PPARα plays a pivotal role in various pathological processes via mechanisms such as lipid metabolism regulation, anti-inflammatory actions, and anti-apoptotic effects. PPARα is activated by binding to natural or synthetic lipophilic ligands, including endogenous fatty acids and their derivatives (e.g., linoleic acid, oleic acid, and arachidonic acid) as well as synthetic peroxisome proliferators. Upon ligand binding, PPARα activates the nuclear receptor retinoid X receptor (RXR), forming a PPARα-RXR heterodimer. This heterodimer, in conjunction with coactivators, undergoes further activation and subsequently binds to peroxisome proliferator response elements (PPREs), thereby regulating the transcription of target genes critical for lipid and glucose homeostasis. Key genes include fatty acid translocase (FAT/CD36), diacylglycerol acyltransferase (DGAT), carnitine palmitoyltransferase I (CPT1), and glucose transporter (GLUT), which are primarily involved in fatty acid uptake, storage, oxidation, and glucose utilization processes. Advancing research on PPARα as a therapeutic target for cardiovascular diseases has underscored its growing clinical significance. Currently, PPARα activators/agonists, such as fibrates (e.g., fenofibrate and bezafibrate) and thiazolidinediones, have been extensively studied in clinical trials for CVD prevention. Traditional PPARα agonists, including fenofibrate and bezafibrate, are widely used in clinical practice to treat hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. These fibrates enhance fatty acid metabolism in the liver and skeletal muscle by activating PPARα, and their cardioprotective effects have been validated in numerous clinical studies. Recent research highlights that fibrates improve insulin resistance, regulate lipid metabolism, correct energy metabolism imbalances, and inhibit the proliferation and migration of vascular smooth muscle and endothelial cells, thereby ameliorating pathological remodeling of the cardiovascular system and reducing blood pressure. Given the substantial attention to PPARα-targeted interventions in both basic research and clinical applications, activating PPARα may serve as a key therapeutic strategy for managing cardiovascular conditions such as myocardial hypertrophy, atherosclerosis, ischemic cardiomyopathy, myocardial infarction, diabetic cardiomyopathy, and heart failure. This review comprehensively examines the regulatory roles of PPARα in cardiovascular diseases and evaluates its clinical application value, aiming to provide a theoretical foundation for further development and utilization of PPARα-related therapies in CVD treatment.

Objective:To understand the current status and characteristics of clinical trials for oral diseases in China, for the purpose of providing a reference for the research and development of oral diseases in China.Methods:Retrieving the information on clinical trials related to oral diseases registered on the "Platforms for drug clinical trial registration and information" of the National Medical Products Administration from the date of the database establishment to December 31, 2024. The number of clinical trials, type of drugs, trial phases, indication, trial scope, design types were statistically analyzed.Results:As of December 31, 2024, a total of 578 drug clinical trials for oral disease were registered, accounting for 2.1% (578/27 905) of the clinical trials disclosed on the platform during the same period. Bioequivalence clinical trials accounted for the highest proportion [73.9% (427/578)], followed by Phase Ⅰ [9.0% (52/578)], Phase Ⅱ [8.0% (46/578)], and Phase Ⅲ [4.5% (26/578)]. The 578 clinical trials involved 149 types of trial drugs, mainly chemical drugs, among which 127 were developed by domestic pharmaceutical enterprises and 27 by international pharmaceutical enterprises (the five investigational drugs have undergone clinical trials by both domestic and international pharmaceutical companies). The project leader units of the 578 drug clinical trials were distributed in 27 provinces, autonomous regions, municipalities, and Hong Kong Special Administrative Region. Excluding 427 bioequivalence clinical trials, the project leader units of 151 new drug clinical trials showed a significant aggregation phenomenon, and only three specialized oral hospitals have served as project leader units for drug clinical trials.Conclusions:The number of drug clinical trials for oral disease in China has generally shown an increasing trend, but there are still problems such as small number of clinical trials, low proportion of investment in new drug development and international multicenter trials, concentrated indications of clinical trials and insufficient clinical trial experience in specialized oral medical institutions. Enhancing the enthusiasm and innovation capabilities of domestic pharmaceutical enterprises in the research and development of oral diseases drugs, exploring the advantages of traditional Chinese medicine/natural medicine resources for oral diseases, and establishing a clinical research system in specialized oral medical institutions are of great significance for the development of oral drugs.

Aim To investigate the possible mechanism of the myocardial protective effect of Danzhi Jiangtang capsules(DJC)on db/db mice based on NLRP3 in-flammasome-mediated pyroptosis.Methods The db/db mice were randomly divided into the model group,DJC low,medium,and high dose groups,and the met-formin group,and the db/m mice were taken as the blank group.The administration lasted for eightweeks.At the end of drug administration,blood glucose,blood lipids,cardiac enzymes and inflammatory factors were detected in each group of mice.HE and Masson stai-ning was performed to observe the morphology and fi-brosis of myocardial tissue.TUNEL staining was per-formed to detect apoptosis.RT-qPCR was performed to detect the mRNA expression of ANP,BNP and β-MHC,and Western blot was performed to detect the protein expression of NLRP3,ASC,caspase-1,cleaved-caspase-1,GSDMD and GSDMD-NT in myocardial tis-sue.Results DJC could alleviate myocardial patho-logical damage,reduce collagen deposition and apopto-sis,reduce the levels of blood glucose,blood lipid,myo-cardial enzyme and inflammatory factors in db/db mice.DJC could reduce the mRNA expressions of ANP,BNP and β-MHC,and the protein expressions of NLRP3,ASC,caspase-1,cleavedcaspase-1,GSDMD and GSDMD-NT in myocardial tissues.Conclusion DJC attenuates myocardial injury in db/db mice,prob-ably by inhibiting the activation of NLRP3 inflamma-somes,attenuating cardiomyocyte pyroptosis,and amel-iorating the inflammatory state.