Oxidative stress is a pivotal factor in the onset and progression of diabetic kidney disease （DKD）， and it plays an essential role in the prevention and treatment of DKD. The "Gaozhuo" pathogenesis posits that DKD is characterized by the invasion of Gaozhuo and damage to the kidney collaterals， with the underlying cause being the insufficiency of spleen Qi and the internal formation of Gaozhuo， which provides valuable guidance on oxidative stress. The insufficiency of spleen Qi and the internal formation of Gaozhuo represent a dynamic， evolving process. Gaozhuo invades the kidney collaterals， impairs kidney Qi， and progressively leads to the congealing and stagnation of Gaozhuo and blood， ultimately resulting in the failure of both the spleen and kidneys. The damage caused by Gaozhuo to the kidney collaterals and kidney Qi is analogous to the organ and functional damage of the kidneys induced by excessive reactive oxygen species and oxidative stress. Damage to the kidney collaterals means organic injuries to the glomeruli， renal tubules， and renal interstitium， and the depletion of kidney Qi refers to damage to glomerular filtration and renal tubular reabsorption. The congealing and stagnation of Gaozhuo and blood in the kidney collaterals is similar to oxidative stress-induced thickening of the glomerular basement membrane and fibrosis. The interaction between spleen and kidney Qi deficiency and the congealing and stagnation of Gaozhuo and blood creates a vicious cycle that exacerbates the condition， ultimately evolving into the failure of both the spleen and kidneys. The failure of the spleen and kidneys is analogous to renal failure， and its extreme manifestation is end-stage renal disease and uremia. The treatment of oxidative stress in DKD with traditional Chinese medicine （TCM） is based on the principles of strengthening the spleen and tonifying the kidneys， and dispelling turbidity and removing blood stasis. According to the syndrome type， it is recommended to use methods such as strengthening the spleen and tonifying Qi while dispelling dampness and removing turbidity， strengthening the spleen and tonifying the kidneys while dispelling dampness and removing turbidity， strengthening the spleen and tonifying the kidneys while dispelling turbidity and removing blood stasis， or consolidating the spleen and kidneys while clearing away turbidity and blood stasis.

Diabetic cardiomyopathy （DCM） is one of the most common complications of diabetes mellitus and is a major threat to global health. As a key mechanism in the occurrence and progression of DCM， the inflammatory response persists throughout the entire course of the DCM. The Gaozhuo theory suggests that the basic pathogenesis of inflammatory injury in DCM is the Qi deficiency of spleen and kidney and Gaozhuo invasion， and divides the pathological process into three phases： Gaozhuo invasion， turbid heat damage to the channels， and turbid blood stasis and heat junction. Among them， the Qi deficiency of spleen and kidney and the endogenous formation of Gaozhuo represent the process of inflammatory factor formation induced by glucose metabolism disorders. Turbid heat damage to the channels refers to the process of myocardial inflammatory injury mediated by inflammatory factors， and turbid blood stasis and heat junction are the process of myocardial injury developing toward myocardial fibrosis and ventricular remodeling. As the disease continues to progress， it eventually develops into a depletion of the heart Yang， leading to the ultimate regression of heart failure. According to the theory of Gaozhuo， traditional Chinese medicine （TCM） should regulate inflammatory injury in DCM by strengthening the spleen and tonifying the kidney to address the root cause， and resolving dampness and lowering turbidity to treat the symptoms. If the turbidity has been stored for a long time and turns into heat， strengthening the spleen and tonifying the kidney， and clearing heat and resolving turbidity should be the therapy. If the turbidity， stasis， and heat are knotted in the heart and collaterals， strengthening the spleen and tonifying the kidney， and resolving stasis and lowering turbidity should be the therapy. TCM compounds and monomers can regulate the inflammatory response in DCM. TCM compounds can be divided into the categories for benefiting Qi to resolve turbidity， benefiting Qi and clearing heat to resolve turbidity， and benefiting Qi and activating blood to reduce turbidity. The compounds can inhibit upstream signals of inflammation and expression of inflammatory factors， improve the inflammatory damage to myocardium and blood vessels， myocardial fibrosis， and cardiac systole and diastole， and thus slow down the onset and progression of DCM.

Retinal microcirculatory disorder is a key factor in the occurrence and development of diabetic retinopathy （DR）， and also an important link in the prevention and treatment of DR. The theory of "Gaozhuo" holds that the microcirculatory disorder in DR is based on the deficiency of spleen Qi and is characterized by the obstruction caused by "Gaozhuo" and blood stasis. The deficiency of spleen Qi is an essential precondition for the endogenous formation and accumulation of Gaozhuo， while Gaozhuo invasion is the direct cause of microcirculatory disorders in DR. The deficiency of spleen Qi and the endogenous formation of Gaozhuo mean the process in which glucose metabolism dysfunction induces an excessive production of inflammatory factors and lipid metabolites. The obstruction caused by "Gaozhuo" and blood stasis is the direct pathogenesis of microcirculatory disorders in DR， encompassing two stages： Gaozhuo obstruction and turbidity and stasis stagnation. Gaozhuo obstruction and turbidity and stasis stagnation represent the process in which inflammatory factors and lipid metabolites damage the retinal microcirculation and induce thrombosis， thus mediating microcirculatory disorders. Turbidity and stasis stagnation and blood extravasation outside the vessels reveal the progression to microvascular rupture and hemorrhage resulting from the microcirculatory disorders. According to the pathogenesis evolution of the theory of "Gaozhuo"， microcirculatory disorders in DR can be divided into deficiency of spleen Qi with Gaozhuo obstruction， deficiency of spleen Qi with turbidity and stasis stagnation， and turbidity and stasis stagnation with blood extravasation outside the vessels. Clinically， treatment principles should focus on strengthening the spleen and benefiting Qi， resolving turbidity， and dispersing stasis. Different syndrome patterns should be addressed with tailored therapies， such as enhancing the spleen and benefiting Qi while regulating Qi and reducing turbidity， strengthening the spleen and benefiting Qi while resolving turbidity and dispelling stasis， and strengthening the spleen and resolving turbidity while removing stasis and stopping bleeding. Representative prescriptions include modified Wendantang， modified Buyang Huanwutang， modified Danggui Buxuetang， Zhuixue Mingmu decoction， Tangmuqing， Shengqing Jiangzhuo Tongluo Mingmu prescription， Danhong Huayu decoction， and Yiqi Yangyin Huoxue Lishui formula.

Non-alcoholic fatty liver disease （NAFLD） is one of the most common complications of type 2 diabetes mellitus （T2DM）， and hepatic stellate cell （HSC） activation is the key link in the progression of NAFLD to liver fibrosis. According to the theory of "Gaozhuo"， spleen deficiency and Qi stagnation， along with Gaozhuo invasion， are the causes of NAFLD progression to liver fibrosis， which reveals the pathogenesis essence of HSC activation in traditional Chinese medicine （TCM）. Among them， spleen deficiency and Qi stagnation are the root causes of the endogenous formation of Gaozhuo. Spleen deficiency indicates the insulin sensitivity decrease and glucose metabolism disorders， and Qi stagnation means the dysregulation of hepatic glucose and lipid metabolism， which creates the preconditions for HSC activation. Gaozhuo invasion is the direct cause of HSC activation， including three stages： Internal retention of Gaozhuo， turbidity and stasis stagnation， and toxic stasis and consolidation. Internal retention of Gaozhuo refers to the abnormal metabolism and deposition of hepatic lipids， as well as the microcirculatory disorders. Turbidity and stasis stagnation is the process by which lipotoxicity stimulates the transformation of HSC into myofibroblast （MFB）， and toxic stasis and consolidation represent the secretion of a large amount of extracellular matrix （ECM） by MFB to promote the fibrosis. According to the theory of Gaozhuo and the activation process of HSC， syndromes for T2DM combined with NAFLD can be classified into spleen deficiency and Qi stagnation with internal retention of Gaozhuo， spleen Qi deficiency with turbidity and stasis stagnation， and spleen Qi deficiency with toxic stasis and consolidation. Clinically， the treatment principle is to strengthen the spleen and promote Qi， resolve turbidity， and eliminate blood stasis. Both TCM compounds and monomers can effectively inhibit the HSC activation. TCM compounds can be classified into categories for regulating spleen and harmonizing liver， resolving turbidity and removing stasis， and detoxifying and removing stasis. They mainly work by improving lipid metabolism， reducing lipid accumulation in the liver， alleviating inflammatory and oxidative stress responses， inhibiting the activation and proliferation of HSC， and reducing ECM deposition， thereby delaying the progression of liver fibrosis.

Based on the etiology and clinical diagnostic criteria of type 2 diabetes mellitus （T2DM）， identification and typing of treatment from the perspective of traditional Chinese and western medicine， the criteria for evaluating the clinical compatibility of traditional Chinese and western medicine in animal models of T2DM were set up. The literature was reviewed to sort out and analyze the existing commonly used modeling methods， summarize the mechanism， compare the advantages and disadvantages， and calculate the consistency between the animal model and the clinical symptoms， syndromes， and indicators from the perspective of traditional Chinese and western medicine. The authors found that spontaneous animal models and high-fat diets combined with multiple low-dose streptozotocin （STZ） induction models were more in line with modern medical pathogenesis of T2DM. However， it fails to form some special syndromes required for traditional Chinese medicine （TCM） research. In addition， there are many methods of combining the etiology and pathogenesis of TCM， which can be divided into three categories： intervention carried out by drug administration， behavioral stimulation， or environmental changes according to TCM， or use of hormones according to clinical evidence and combination of the two methods mentioned above. All of them can successfully establish different types of animal models. However， different methods of establishing syndrome models have their own advantages and disadvantages， and there is no unified standard for the stability and evaluation of syndrome models. As for the clinical consistency criteria of traditional Chinese and western medicine established in this paper， the animal model with 100% consistency has not been calculated due to the conditions of incomplete symptoms and syndromes described in the studies and different selection indicators. Consequently， the establishment of a simple， easy-to-use， and affordable T2DM animal model with both traditional Chinese and western medicine disease characteristics and the improvement of the Chinese and western medicine evaluation system for different evidence types are of great significance for the future development of TCM research on T2DM.

Based on the etiology and clinical diagnostic criteria of type 2 diabetes mellitus （T2DM）， identification and typing of treatment from the perspective of traditional Chinese and western medicine， the criteria for evaluating the clinical compatibility of traditional Chinese and western medicine in animal models of T2DM were set up. The literature was reviewed to sort out and analyze the existing commonly used modeling methods， summarize the mechanism， compare the advantages and disadvantages， and calculate the consistency between the animal model and the clinical symptoms， syndromes， and indicators from the perspective of traditional Chinese and western medicine. The authors found that spontaneous animal models and high-fat diets combined with multiple low-dose streptozotocin （STZ） induction models were more in line with modern medical pathogenesis of T2DM. However， it fails to form some special syndromes required for traditional Chinese medicine （TCM） research. In addition， there are many methods of combining the etiology and pathogenesis of TCM， which can be divided into three categories： intervention carried out by drug administration， behavioral stimulation， or environmental changes according to TCM， or use of hormones according to clinical evidence and combination of the two methods mentioned above. All of them can successfully establish different types of animal models. However， different methods of establishing syndrome models have their own advantages and disadvantages， and there is no unified standard for the stability and evaluation of syndrome models. As for the clinical consistency criteria of traditional Chinese and western medicine established in this paper， the animal model with 100% consistency has not been calculated due to the conditions of incomplete symptoms and syndromes described in the studies and different selection indicators. Consequently， the establishment of a simple， easy-to-use， and affordable T2DM animal model with both traditional Chinese and western medicine disease characteristics and the improvement of the Chinese and western medicine evaluation system for different evidence types are of great significance for the future development of TCM research on T2DM.

INTRODUCTION: Lecanemab has shown promise in treating early Alzheimer's disease (AD), but its safety and efficacy in Chinese populations remain unexplored. This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment (MCI) or mild AD. METHODS: In this single-arm, real-world study, participants with MCI due to AD or mild AD received biweekly intravenous lecanemab (10 mg/kg). The study was conducted at Hainan Branch, Ruijin Hospital Shanghai Jiao Tong University School of Medicine. Patient enrollment and baseline assessments commenced in November 2023. Safety assessments included monitoring for amyloid-related imaging abnormalities (ARIA) and other adverse events. Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales (mini-mental state examination [MMSE], montreal cognitive assessment [MoCA], clinical dementia rating-sum of boxes [CDR-SB]), plasma biomarker analysis, and advanced neuroimaging. RESULTS: A total of 64 patients were enrolled in this ongoing real-world study. Safety analysis revealed predominantly mild adverse events, with infusion-related reactions (20.3%, 13/64) being the most common. Of these, 69.2% (9/13) occurred during the initial infusion and 84.6% (11/13) did not recur. ARIA-H (microhemorrhages/superficial siderosis) and ARIA-E (edema/effusion) were observed in 9.4% (6/64) and 3.1% (2/64) of participants, respectively, with only two symptomatic cases (one ARIA-E presenting with headache and one ARIA-H with visual disturbances). After 6 months of treatment, cognitive scores remained stable compared to baseline (MMSE: 22.33 ± 5.58 vs . 21.27 ± 4.30, P = 0.733; MoCA: 16.38 ± 6.67 vs . 15.90 ± 4.78, P = 0.785; CDR-SB: 2.30 ± 1.65 vs . 3.16 ± 1.72, P = 0.357), while significantly increasing plasma amyloid-β 42 (Aβ42) (+21.42%) and Aβ40 (+23.53%) levels compared to baseline. CONCLUSIONS: Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD. Cognitive stability and biomarker changes over 6 months suggest potential efficacy, though high dropout rates and absence of a control group warrant cautious interpretation. These findings provide preliminary real-world evidence for lecanemab's use in China, supporting further investigation in larger controlled studies. REGISTRATION ClinicalTrials.gov , NCT07034222.
Humans ; Alzheimer Disease/drug therapy* ; Male ; Female ; Aged ; Middle Aged ; Cognitive Dysfunction/drug therapy* ; Aged, 80 and over ; Amyloid beta-Peptides/metabolism* ; Biomarkers ; East Asian People

Nonobstructive azoospermia (NOA), one of the most severe types of male infertility, etiology often remains unclear in most cases. Therefore, this study aimed to detect four biallelic detrimental variants (0.5%) in the minichromosome maintenance domain containing 2 ( MCMDC2 ) genes in 768 NOA patients by whole-exome sequencing (WES). Hematoxylin and eosin (H&E) demonstrated that MCMDC2 deleterious variants caused meiotic arrest in three patients (c.1360G>T, c.1956G>T, and c.685C>T) and hypospermatogenesis in one patient (c.94G>T), as further confirmed through immunofluorescence (IF) staining. The single-cell RNA sequencing data indicated that MCMDC2 was substantially expressed during spermatogenesis. The variants were confirmed as deleterious and responsible for patient infertility through bioinformatics and in vitro experimental analyses. The results revealed four MCMDC2 variants related to NOA, which contributes to the current perception of the function of MCMDC2 in male fertility and presents new perspectives on the genetic etiology of NOA.
Humans ; Male ; Azoospermia/genetics* ; Meiosis/genetics* ; Spermatogenesis/genetics* ; Adult ; Exome Sequencing ; Microtubule-Associated Proteins/genetics* ; Alleles ; Infertility, Male/genetics*

OBJECTIVE: To investigate the effect of 5-hydroxytryptamine (5-HT) on the proliferation, apoptosis and colony-forming unit-megakaryocyte (CFU-MK) of Meg-01 cells and its possible mechanisms. METHODS: The uptake and metabolism of 5-HT in Meg-01 cells were analysed by reverse-phase high-performance liquid chromatography (RP-HPLC) with electrochemical detection. The expression of 5-HT2B receptor (5-HT2BR) in megakaryocytes was detected by immunofluorescence staining. The cell proliferation and viability were measured by MTT and Trypan blue staining after Meg-01 cells were single-cultured or co-cultured with different concentrations of 5-HT/5-HT2BR inhibitor Ketanserin for 48 h. Meg-01 cells were incubated with 5-HT/ Ketanserin for 72 h, then the flow cytometry was used to detect early apoptosis of the cells and the activity of caspase-3. Using CFU-MK assay to investigate the effect of 5-HT on the differentiation of megakaryocytes. RESULTS: 5-HT could be uptaken by Meg-01 cells, and metabolized into 5-hydroxyindoleacetic acid (5-HIAA). The expression of 5-HT2BR on megakaryocytes could be detected after immunofluorescence staining. 5-HT could promote the proliferation of Meg-01 cells at a dose-dependent manner (r =0.82), with the most significant effect observed at a concentration of 200 nmol/L (P < 0.001). Trypan blue staining also indicated that 200 nmol/L 5-HT had the most significant effect on the viability of Meg-01 cells (P < 0.05). The proliferation of Meg-01 cells treated with 5-HT was increased compared with the untreated control (P < 0.001), while the combination of 5-HT with ketanserin downregulated this effect. 5-HT significantly reduced the early apoptosis rate (P < 0.001) and caspase-3 activity (P < 0.05) of Meg-01 cells, while addition of ketanserin significantly increased the early apoptosis rate of Meg-01 cells (P < 0.001) and caspase-3 activity also increased to some extent. 5-HT promoted the formation of CFU-MK in bone marrow cells in a dose-dependent manner (r =0.89). The addition of ketanserin reduced the promoting effect of 5-HT on CFU-MK formation (P < 0.01). CONCLUSION There may be monoamine oxidase present in megakaryocytes, which can metabolize and decompose 5-HT into 5-HIAA. 5-HT may promote the proliferation and differentiation of megakaryocytes through 5-HT2BR. Besides, 5-HT can also reduce the apoptosis of megakaryocytes, and its anti-apoptotic effect may be mediated by 5-HT2BR and caspase-3 pathways.
Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Megakaryocytes/metabolism* ; Serotonin/pharmacology* ; Humans ; Receptor, Serotonin, 5-HT2B/metabolism* ; Caspase 3/metabolism* ; Cell Differentiation