Diabetic retinopathy(DR)remains the leading cause of vision loss in patients with diabetes. Current anti-vascular endothelial growth factor(VEGF)therapies are limited by inadequate response in some patients and the necessity for repeated intravitreal injections, underscoring the urgent need for novel therapeutic targets. Angiopoietin-like protein 4(ANGPTL4), a multifunctional secreted protein, has emerged as a critical regulator in the pathogenesis and progression of DR, positioning it as a promising interventional target. This review systematically elaborates the biological characteristics of ANGPTL4, with a focus on its expression dynamics, molecular mechanisms, and regulatory networks rolesin the development of DR. Furthermore, the prospects of ANGPTL4-targeted therapeutic strategies are discussed, aiming to offer new insights and directions for understanding DR pathogenesis, advancing multi-target drug development, and improving clinical management.

ObjectiveHepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. The main risk factors associated with HCC include viral hepatitis (B and/or C), alcohol abuse, and metabolic dysfunction-associated steatotic liver disease (MASLD), which progressively advance to liver fibrosis, cirrhosis, and ultimately evolve into HCC. Surgical resection represents the most effective treatment for HCC, while recent advances in immunotherapy, including immune checkpoint inhibitors and adoptive cell therapies, have provided improved treatment prospects for patients with unresectable HCC. However, the complex metabolic heterogeneity of HCC limits the therapeutic efficacy. Metabolic intermediates acyl-CoA not only provide energy and substrates for numerous biochemical reactions but also serve as donors for protein lysine acylation, a major class of post-translational modification (PTM). Therefore, a deeper understanding of the molecular mechanisms underlying protein lysine acylation and hepatocarcinogenesis is urgently needed. MethodsThe levels of protein lysine acylation and silence information regulator 5 (SIRT5) expression levels in clinical HCC samples were analyzed by Western blot. Quantitative malonylome and succinylome of HCC samples were analyzed by antibody-based affinity enrichment coupled with tandem mass spectrometry. The proliferation of HCC cells was analyzed with Cell Counting Kit-8 (CCK-8) assays, the apoptosis was quantified by Annexin V-FITC/propidium iodide (PI) staining coupled with flow cytometry, and the ability of cells to migrate was assayed by Transwell assays. The enzymatic activity of glutathione S-transferase Mu 1 (GSTM1) was quantified. Transgenic mice with hepatic overexpression of SIRT5 were constructed using CRISPR-Cas9, and primary hepatocarcinogenesis was induced by administration of diethylnitrosamine. ResultsWestern blot analysis indicated that the expression level of SIRT5 was elevated in clinical samples from HCC patients, and the levels of lysine malonylation, glutarylation, and succinylation were significantly reduced in HCC tissues. Knockout of SIRT5 in MHCC-97H and MHCC-97L hepatoma cells suppressed cell proliferation, and increased the percentage of apoptotic cells significantly. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the differentially malonylome and succinylome of HCC samples revealed significant enrichment in two major classes of biological processes: core energy metabolism (e.g., glycolysis/gluconeogenesis, tricarboxylic acid metabolic process, fatty acid beta oxidation) and detoxification and oxidative stress response (e.g., response to toxic substance, chemical carcinogenesis, reactive oxygen species (ROS)). SIRT5 removes malonylation from lysine residues in GSTM1 and restores its detoxification activity, which is crucial for the survival of hepatocytes under stressed conditions. More importantly, in vivo experiment indicated that hepatic-specific overexpression of SIRT5 in mice accelerated diethylnitrosamine-induced liver fibrosis and hepatocarcinogenesis, indicating the critical role of SIRT5 in HCC progression. ConclusionThis study highlights the previously unrecognized SIRT5-GSTM1 axis as a key regulator in hepatocarcinogenesis, and suggests a potential target for the treatment of patients with HCC.

Background: Diabetic peripheral neuropathy (DPN) is a common chronic complication of diabetes mellitus that significantly impairs patients’ quality of life. Traditional Chinese medicine (TCM), as a major component of complementary and alternative medicine, has accumulated numerous effective formulas for the clinical management of DPN. However, systematic approaches for optimizing TCM formulas remain limited. Objective: To establish a pathway-oriented approach for TCM formula optimization and to evaluate the efficacy and mechanisms of the optimized formula in DPN. Methods: We developed 2 formula optimization algorithms that defined pathway-oriented herbal correlation (HC) and herbal contribution (HO) to screen and construct a new herbal formula, Qihongtongbi (QHTB), for treating Qi deficiency and blood stasis syndrome complicated with DPN. An animal experiment was subsequently conducted to evaluate the therapeutic effectiveness of QHTB. A total of 32 specific-pathogen-free male ob/ob mice (18–20 g) were randomly divided into 4 groups: model, Mudan Granules (MDG), QHTB low- and high-dose groups (n = 8). Ten male C57BL/6J mice (18–20 g) served as the control group. Metabolomics analysis was further employed to elucidate the biological mechanisms underlying the effects of QHTB. Results: Based on our previous study on TCM medication patterns for treating DPN, 22 candidate herbs were selected for formula optimization. The top 5 candidate herbs (total HC = 25.24 × 10 ) exhibited HC values comparable to those of MDG (total HC = 26.1 × 10 ). These herbs were Carthamus tinctorius L. (HC = 5.40 × 10 ), Astragalus mongholicus Bunge (HC = 5.23 × 10 ), Salvia miltiorrhiza Bunge (HC = 5.15 × 10 ), Commiphora myrrha (T. Nees) Engl. (HC = 5.02 × 10 ), and Glycyrrhiza glabra L. (HC = 4.44 × 10 ). HO analysis showed that the cumulative HO of these 5 herbs exceeded 50%. In vivo experiments demonstrated that, compared with the model group, QHTB significantly lowered blood glucose (P < 0.05), enhanced nerve conduction velocity (P < 0.01), improved nociceptive hypersensitivity (P < 0.01), and ameliorated sciatic nerve morphology, with efficacy comparable to MDG. Serum and fecal metabolomics further revealed that QHTB exerted multipathway regulatory effects, among which nicotinate and nicotinamide metabolism represented a key mechanism. Conclusion: In summary, this study provides a methodological reference for the systematic optimization of TCM formulas.

Childhood obesity is a chronic nutritional disorder caused by multiple factors that result in excessive total body fat and/or increased local fat content and abnormal fat distribution，sometimes accompanied by complications such as metabolic syndrome. The obesity caused by other factors excluding the secondary factors like genetics or metabolism is referred to as simple obesity. The incidence of childhood obesity in China is showing a trend toward younger ages and rapid growth，posing a serious threat to people's health and creating a heavy economic burden. Therefore，it is urgent to control and effectively intervene in childhood obesity. Traditional Chinese herbal medicine has long been a representative of internal treatment and shows effectiveness and advantages in the clinical treatment of childhood obesity. However，there is currently a lack of a comprehensive set of diagnostic and treatment standards，as well as evidence-based clinical practice. In order to improve clinical physicians' understanding of this disease and to promote the standardization and rationalization of herbal treatment，experts in clinical Chinese and Western medicine，nutrition，and methodology from across China were invited. On the basis of expert experience and current evidence，the Grading of Recommendations Assessment，Development，and Evaluation （GRADE） method was used to grade the evidence and recommendations. After two rounds of Delphi expert consultations，the guideline secretariat revised and refined the materials based on expert opinions. Ultimately，14 entries of expert consensus and recommendations were formulated，highlighting the advantages and characteristics of herbal treatment for childhood obesity，clarifying syndrome differentiation，medication，treatment cycles，and combination therapy plans for common clinical syndromes，thereby providing more treatment ideas in clinical practice and better leveraging therapeutic advantages.

Based on the traditional Chinese medicine （TCM） theories of body fluid metabolism and turbid phlegm obstructing the orifices， and drawing on recent advances in cerebrospinal fluid-interstitial fluid （CSF-ISF） exchange， glymphatic clearance， and extracellular matrix （ECM） regulation， this article discusses the possible scientific connotation of "invisible phlegm" from the perspectives of pathogenesis， clinical manifestations， and therapeutic implications. Impaired brain fluid exchange may lead to reduced clearance， the retention of metabolic wastes and pathological proteins. Abnormal ECM remodeling may further disrupt molecular diffusion and local microenvironmental homeostasis， resulting in a pathological process characterized by slowed fluid movement， reduced clearance， and abnormal retention. This process bears a certain functional resemblance to the TCM pathogenesis of impaired distribution of body fluids， endogenous formation of turbid phlegm and obstruction of the brain orifices， and may also be associated with manifestations such as a clouded sensation in the head， cognitive abnormalities， and emotional disturbances. On this basis， the potential effects of certain phlegm-dissolving Chinese medicines in improving brain clearance function and extracellular microenvironmental homeostasis warrant further investigation. We therefore propose that， the "invisible phlegm" of TCM in brain tissue may manifest as a pathological retention state characterized by restricted fluid exchange， impaired clearance function， and extracellular microenvironmental imbalance. This perspective may provide a new avenue for investigating TCM treatment of neurological and psychiatric disorders from the perspective of phlegm.

Based on the traditional Chinese medicine （TCM） theories of body fluid metabolism and turbid phlegm obstructing the orifices， and drawing on recent advances in cerebrospinal fluid-interstitial fluid （CSF-ISF） exchange， glymphatic clearance， and extracellular matrix （ECM） regulation， this article discusses the possible scientific connotation of "invisible phlegm" from the perspectives of pathogenesis， clinical manifestations， and therapeutic implications. Impaired brain fluid exchange may lead to reduced clearance， the retention of metabolic wastes and pathological proteins. Abnormal ECM remodeling may further disrupt molecular diffusion and local microenvironmental homeostasis， resulting in a pathological process characterized by slowed fluid movement， reduced clearance， and abnormal retention. This process bears a certain functional resemblance to the TCM pathogenesis of impaired distribution of body fluids， endogenous formation of turbid phlegm and obstruction of the brain orifices， and may also be associated with manifestations such as a clouded sensation in the head， cognitive abnormalities， and emotional disturbances. On this basis， the potential effects of certain phlegm-dissolving Chinese medicines in improving brain clearance function and extracellular microenvironmental homeostasis warrant further investigation. We therefore propose that， the "invisible phlegm" of TCM in brain tissue may manifest as a pathological retention state characterized by restricted fluid exchange， impaired clearance function， and extracellular microenvironmental imbalance. This perspective may provide a new avenue for investigating TCM treatment of neurological and psychiatric disorders from the perspective of phlegm.

Metabolic dysfunction-associated fatty liver disease （MAFLD） has become the most common chronic liver disease worldwide. Its pathological process is centered on the “two-hit” theory， with gut-liver axis dysregulation running through the entire disease course from steatosis to liver cirrhosis and even hepatocellular carcinoma， and it forms an extensive cross-system regulatory mechanism with the metabolic， cardiovascular， renal， and psychological and nervous systems through multi-dimensional pathways such as the “gut-liver-brain axis”， the “liver-kidney axis”， and the “liver-heart axis”. Disease progression is not limited to the liver itself， and it also involves functional imbalance of multiple organ systems throughout the body. This article systematically elaborates on the association mechanism of “liver pathological progression-multi-axis regulation-comorbidity occurrence” in MAFLD， proposes synergistic management strategies integrating early screening based on risk stratification， targeted intervention， and multidisciplinary diagnosis and treatment， and analyzes the limitations of current research and future development directions， in order to provide a theoretical basis and practical guidance for precise diagnosis and treatment and individualized management of MAFLD.

Objective To compare the benefits and drawbacks of primary patch expansion versus pericardial tube right ventricular-pulmonary artery connection in patients diagnosed with pulmonary atresia with ventricular septal defect (PA/VSD). Methods A retrospective study was conducted on patients diagnosed with PA/VSD who underwent primary right ventricular-pulmonary artery connection surgery at our center between 2010 and 2020. Patients were categorized into two groups based on the type of right ventricular-pulmonary artery connection: a pericardial tube group and a patch expansion group. Clinical data and imaging findings were compared between the two groups. Results A total of 51 patients were included in the study, comprising 31 males and 20 females, with a median age of 12.57 (4.57, 49.67) months. The pericardial tube group included 19 patients with a median age of 17.17 (7.33, 49.67) months, while the patch expansion group consisted of 32 patients with a median age of 8.58 (3.57, 52.72) months. In both groups, the diameter of pulmonary artery, McGoon index, and Nakata index significantly increased after treatment (P<0.001). However, the pericardial tube group exhibited a longer extracorporeal circulation time (P<0.001). The reoperation rate was notably high, with 74.51% of patients requiring further surgical intervention, including 26 (81.25%) patients in the patch expansion group and 12 (63.16%) patients in the pericardial tube group. No statistical differences were observed in long-term cure rates or mortality between the two groups (P＞0.005). Conclusion In patients with PA/VSD, both patch expansion and pericardial tube right ventricular-pulmonary artery connection serve as effective initial palliative treatment strategies that promote pulmonary vessel development and provide a favorable foundation for subsequent radical operations. However, compared to the pericardial tube approach, the patch expansion technique is simpler to perform and preserves some intrinsic potential for pulmonary artery development, making it the preferred procedure.

Metabolic-associated fatty liver disease (MAFLD) and osteoporosis (OP) are two very common metabolic diseases. A growing body of experimental evidence supports a pathophysiological link between MAFLD and OP. MAFLD is often associated with the development of OP. Rutaecarpine (RUT) is one of the main active components of Chinese medicine Euodiae Fructus. Our previous studies have demonstrated that RUT has lipid-lowering, anti-inflammatory and anti-atherosclerotic effects, and can improve the OP of rats. However, whether RUT can improve both fatty liver and OP symptoms of MAFLD mice at the same time remains to be investigated. In this study, we used C57BL/6 mice fed a high-fat diet (HFD) for 4 months to construct a MAFLD model, and gave the mice a low dose (5 mg·kg^-1) and a high dose (15 mg·kg^-1) of RUT by gavage for 4 weeks. The effects of RUT on liver steatosis and bone metabolism were then evaluated at the end of the experiment [this experiment was approved by the Experimental Animal Ethics Committee of Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences (approval number: IMB-20190124D₃03)]. The results showed that RUT treatment significantly reduced hepatic steatosis and lipid accumulation, and significantly reduced bone loss and promoted bone formation. In summary, this study shows that RUT has an effect of improving fatty liver and OP in MAFLD mice.

Background: Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Methods: Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ≤40 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ≥8 prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. Conclusion MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.