OBJECTIVES: To summarize the clinical manifestations and genetic characteristics of creatine deficiency syndrome (CDS) caused by GAMT gene mutations. METHODS: A retrospective analysis was conducted on the clinical and genetic data of two children diagnosed with GAMT deficiency-type CDS at the Children's Medical Center of Xiangya Hospital, Central South University, from December 2020 to December 2024. RESULTS: The two patients presented with symptoms in infancy, and both had compound heterozygous mutations in the GAMT gene. Case 1 exhibited seizures and intellectual disability, while Case 2 had intellectual disability and attention-deficit hyperactivity disorder. Magnetic resonance spectroscopy of cranial MRI in both patients indicated reduced creatine peaks. After creatine treatment, seizures in Case 1 were controlled, but both patients continued to experience intellectual disabilities and behavioral issues. As of December 2024, a total of 21 cases have been reported in China (including this study), and 115 cases have been reported abroad. All patients exhibited developmental delay or intellectual disabilities, with 66.9% (91/136) experiencing seizures, 33.8% (46/136) presenting with motor disorders, and 36.8% (50/136) having behavioral problems. Seventy-five percent (102/136) of patients received creatine treatment, leading to significant improvements in seizures and motor disorders, although cognitive improvement was not substantial. CONCLUSIONS GAMT deficiency-type CDS is rare and presents with nonspecific clinical features. Timely diagnosis facilitates targeted treatment, which can partially improve prognosis.
Child ; Female ; Humans ; Male ; Creatine/deficiency* ; Guanidinoacetate N-Methyltransferase/deficiency* ; Intellectual Disability/genetics* ; Mutation ; Retrospective Studies ; Rhabdomyolysis/genetics* ; Language Development Disorders ; Movement Disorders/congenital*

OBJECTIVES: To assess the preliminary efficacy and safety of a dose-intensified C5VD regimen (cisplatin, 5-fluorouracil, vincristine, and doxorubicin) in children with locally advanced hepatoblastoma. METHODS: This prospective study enrolled 24 children with newly diagnosed, locally advanced hepatoblastoma who received the dose-intensified C5VD regimen at Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, and Shanghai Children's Hospital between January 2020 and December 2023. Clinical characteristics, treatment outcomes, and chemotherapy-related toxicities were analyzed. RESULTS: Of the 24 patients, 13 were male and 11 were female, with a median age at diagnosis of 18.7 months (range: 3.5-79.4 months). All patients achieved complete macroscopic resection of hepatic lesions without liver transplantation. Serum alpha-fetoprotein levels decreased significantly after two chemotherapy cycles. During a median follow-up of 38.4 months (range: 15.8-50.7 months), all patients maintained continuous complete remission, with 3-year event-free survival and overall survival rates of 100%. Across 144 chemotherapy cycles, the incidence rates of grade 3-4 neutropenia, thrombocytopenia, and infections were 97%, 77%, and 71%, respectively; no treatment-related deaths occurred. Notably, 5 patients (21%) developed Brock grade ≥3 hearing loss, of whom 1 required a hearing aid. CONCLUSIONS The dose-intensified C5VD regimen demonstrates significant efficacy with an overall favorable safety profile in the treatment of newly diagnosed, locally advanced pediatric hepatoblastoma. Grade 3-4 myelosuppression and infection are the predominant toxicities. However, high‑dose cisplatin-induced ototoxicity remains a concern, highlighting the need for improved otoprotective strategies.
Humans ; Hepatoblastoma/pathology* ; Male ; Female ; Infant ; Liver Neoplasms/pathology* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use* ; Child, Preschool ; Prospective Studies ; Doxorubicin/adverse effects* ; Child ; Cisplatin/adverse effects* ; Vincristine/adverse effects* ; Fluorouracil/adverse effects*

Aim To explore the mechanism of rhein in the treatment of IgA nephropathy in rats by impro-ving spleen immune function based on mTORC1 path-way.Methods Thirty-two SD rats were randomly di-vided into control group,model group(IgAN),rhein group(RH)and rapamycin group.The deposition of IgA in mesangial region and pathological changes of spleen and kidney were observed,and the ratio of Th/Ts in spleen was determined by immunohistochemical method.The protein expressions of p-mTOR,p-p70S6k,TGF-β1 and TNF-α in spleen were detected by Western blot.Results Compared with the control group,IgAN group significantly increased urinary sludge red blood cell count,24 hour urinary total pro-tein,serum creatinine,blood urea nitrogen,serum IgA,Th/Ts,p-mtor,p-P70S6K and spleen TNF-αprotein expression levels(P＜0.01),and spleen TGF-β1 protein expression(P＜0.05).IgA deposi-tion in mesangial area of the kidney increased signifi-cantly,and pathological changes were observed in spleen and kidney.Compared with IgAN group,urine sludge red blood cell count,serum IgA,Th/Ts,p-mTOR,p-P70S6K and TNF-α protein expression lev-els in RH and RAPA groups were significantly reduced(P＜0.01).24 hour urinary total protein,blood urea nitrogen,serum creatinine and spleen TGF-β1 protein decreased(P＜0.05),the deposition of IgA in the mesangial region of the kidney decreased,and the pathological changes of spleen and kidney were allevia-ted.There was no significant difference between RH group and RAPA group.Conclusions RH can allevi-ate IgA nephropathy by inhibiting the activity of m-TORC1 pathway in the spleen of IgA nephropathy rats,thereby inhibiting the differentiation of splenic lympho-cytes and reducing the secretion of IgA.

Aim To explore the mechanism of rhein in the treatment of IgA nephropathy in rats by impro-ving spleen immune function based on mTORC1 path-way.Methods Thirty-two SD rats were randomly di-vided into control group,model group(IgAN),rhein group(RH)and rapamycin group.The deposition of IgA in mesangial region and pathological changes of spleen and kidney were observed,and the ratio of Th/Ts in spleen was determined by immunohistochemical method.The protein expressions of p-mTOR,p-p70S6k,TGF-β1 and TNF-α in spleen were detected by Western blot.Results Compared with the control group,IgAN group significantly increased urinary sludge red blood cell count,24 hour urinary total pro-tein,serum creatinine,blood urea nitrogen,serum IgA,Th/Ts,p-mtor,p-P70S6K and spleen TNF-αprotein expression levels(P＜0.01),and spleen TGF-β1 protein expression(P＜0.05).IgA deposi-tion in mesangial area of the kidney increased signifi-cantly,and pathological changes were observed in spleen and kidney.Compared with IgAN group,urine sludge red blood cell count,serum IgA,Th/Ts,p-mTOR,p-P70S6K and TNF-α protein expression lev-els in RH and RAPA groups were significantly reduced(P＜0.01).24 hour urinary total protein,blood urea nitrogen,serum creatinine and spleen TGF-β1 protein decreased(P＜0.05),the deposition of IgA in the mesangial region of the kidney decreased,and the pathological changes of spleen and kidney were allevia-ted.There was no significant difference between RH group and RAPA group.Conclusions RH can allevi-ate IgA nephropathy by inhibiting the activity of m-TORC1 pathway in the spleen of IgA nephropathy rats,thereby inhibiting the differentiation of splenic lympho-cytes and reducing the secretion of IgA.

Objective To develop the functions and optimize the automatic monitoring module for arrhythmias of the adverse drug event active surveillance and assessment system-Ⅱ,in order to continuously improve the performance,enhance the monitoring efficiency,and explore the ways to optimize the module.Methods Expand and optimize the functions of the module,increase the customized configuration,and determine the optimal setting conditions;compare the optimized test data with the results of the evaluation studies on the automatic monitoring of drug-induced arrhythmias in large samples of medicated population previously,and verify the optimization extent as well as the accuracy of the module.Results In the new module optimized according to the characteristics of the monitoring population,the function of"mandatory medical order keywords"was added,and it was determined that the inclusion of 6 electrocardiogram examination-related medical order keywords with a frequency of not less than 2 occurrences was the optimal configuration condition for the optimization of the module;combining the results of the previous automatic monitoring and evaluation researches,the system functions were verified and compared under the conditions of using the whole drugs and 2 kinds of single drug.While there was no loss of true positive cases,the number of cases with system alarms decreased by 30.75％,80.13％and 90.82％,respectively,compared with that before the optimization of the module,and the positive predictive value was significantly improved.Conclusion After the function expansion and optimization,the automatic monitoring module of drug-induced arrhythmias significantly reduces the labor cost of case evaluation and keeps the accuracy of monitoring results constant;the new module can better adapt to the demands of different automatic monitoring modes and operates stably,which is more generalizable and flexible,and provides a new way of considering for the research and development of automatic monitoring modules.

Objective To investigate the effect of catalpol(CAT)on necrotic apoptosis in acute myocardial infarction(AMI)rats.Methods Rat AMI model was constructed by ligating the anterior descending branch of the left coronary artery.Sixty SPF grade SD male rats were randomly grouped into sham surgery group(Sham group),AMI model group(Model group),low-dose CAT group(CAT-L group,30 mg·kg-1 CAT),high-dose CAT group(CAT-H group,60 mg·kg-1 CAT),and high-dose CAT+RIP1 activator recombinant RIP1 group(CAT-H+rRIP1 group,60 mg·kg-1 CAT+8 μg·kg-1 rRIP1),12 in each group.CAT was administered by gavage once a day for a total of 4 weeks.Recombinant RIP1 was administered via tail vein injection and the next day for a total of 4 weeks.Sham group and Model group were given equal amounts of physiological saline by gavage and tail vein injection,respectively.The CAT-L group and CAT-H group were injected with physiological saline via the tail vein the next day while receiving gastric lavage.TUNEL staining was applied to observe the apoptosis of rat cardiomyocytes.Western Blot was applied to detect the expression of RIP1/RIP3/MLKL signaling pathway related proteins in rat myocardial tissue.Results The apoptosis rates of myocardial cells in the sham group,model group,CAT-L group,CAT-H group,and CAT-H+rRIP1 group were(4.23±0.63)％,(33.48±3.94)％,(13.50±1.86)％,and(29.62±3.08)％,respectively;the expression levels of RIP1 protein in myocardial tissue were 0.21±0.02,0.86±0.09,0.43±0.04,and 0.72±0.07,respectively;the expression levels of RIP3 protein were 0.30±0.03,0.94±0.09,0.49±0.05,and 0.83±0.08,respectively;the phosphorylation levels of MLKL protein were 0.35±0.04,1.13±0.11,0.64±0.06,and 0.97±0.10,respectively.The above indexes in Model group were compared with those in Sham group,and those in CAT-H group were compared with those in Model group and CAT-H+rRIP1 group,and the differences were statistically significant(all P＜0.05).Conclusion CAT may inhibit necrotic apoptosis of myocardial cells in AMI rats by down-regulating the RIP1/RIP3/MLKL signaling pathway.

Parabacteroides distasonis is a gram-negative bacterium initially isolated from a clinical specimen in the 1930s. The strain was re-classified to form the new genus Parabacteroides in 2006. P. distasonis can regulate intestinal barrier function and plays a key role in immune response and metabolic regulation of bodies. Traditional Chinese medicine(TCM) is closely related to the intestinal microbiota. Polysaccharides, saponins, and other ingredients of TCM can treat diseases by interacting with P. distasonis, but the specific mechanisms underlying these processes are still unclear, requiring further exploration. This study reviewed the roles and related mechanisms of P. distasonis in inflammatory-immune diseases, metabolic diseases, cardiovascular disease, neuropsychiatric diseases, cancer, and other diseases and summarized the relevant research results of TCM to prevent and treat diseases by regulating P. distasonis. This study provides a reference for subsequent exploration of P. distasonis and research on the interaction between TCM and intestinal microbiota.
Humans ; Gastrointestinal Microbiome/drug effects* ; Medicine, Chinese Traditional ; Animals ; Bacteroidetes ; Drugs, Chinese Herbal/pharmacology*

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and dyslipidemia. Carvacrol (CAR) has demonstrated the potential to mitigate dyslipidemia. This study aims to investigate whether CAR can modulate blood glucose and lipid levels in a T2DM rat model by regulating short-chain fatty acids (SCFAs) and the GPR41/43 pathway. The T2DM rat model was induced by a high-fat diet combined with low-dose streptozocin injection and treated with oral CAR and/or mixed antibiotics. Fasting blood glucose, oral glucose tolerance, and insulin tolerance tests were assessed. Serum lipid parameters, hepatic and renal function indicators, tissue morphology, and SCFAs were measured. In vitro, high glucose (HG)-induced IEC-6 cells were treated with CAR, and optimal CAR concentration was determined. HG-induced IEC-6 cells were treated with SCFAs or/and GPR41/43 agonists. CAR significantly reduced blood lipid and glucose levels, improved tissue damage, and increased SCFA levels in feces and GPR41/43 expression in colonic tissues of T2DM rats. CAR also attenuated HG-induced apoptosis of IEC-6 cells and enhanced GPR41/43 expression.Overall, these findings suggest that CAR alleviates blood lipid and glucose abnormalities in T2DM rats by modulating SCFAs and the GPR41/43 pathway.

Aim To investigate the mechanisms of Chaijin JieYu Anshen formula modulating the depres-sive behaviors and the synaptic plasticity of hippocam-pal neurons in insomnia-concomitant depression rats based on the histone deacetylase 5(HDAC5)/myocyte enhancer factor 2C(MEF2C)pathway.Methods A rat model of insomnia-concomitant depression was es-tablished by PCPA injection combined with chronic un-predictable mild stress(CUMS),and the experiment was divided into the control group,the model group,the high,medium and low dose group of Chaijin JieYu Anshen formula,and the positive drug group.The de-pression of rats was evaluated by sugar-water prefer-ence test,open field test and morris water maze.The levels of 5-hydroxytryptamine(5-HT)and dopamine(DA)in serum were measured by enzyme linked im-munosorbent assay(ELISA).The pathological damage of hippocampal neurons was observed by HE staining and Nissl staining.The damage of dendritic spines of hippocampal neurons was observed by Golgi staining,and the levels of HDAC5,MEF2C,postsynaptic densi-ty-95(PSD-95)and synaptophysin 1(SYN1)in hip-pocampus were measured by Western blot,immunohis-tochemistry and immunofluorescence.Results Com-pared with the model group,the Chaijin JieYu Anshen formula could increase the sugar-water preference rate of the model rats,reduce the immobility time in the open field experiment,increase the total activity dis-tance,shorten the evasion latency in the localization navigation experiment,and prolong the residence time in the quadrant where the platform was located in the space exploration experiment(P＜0.05,P＜0.01).Moreover,the Chaijin JieYu Anshen formula improved the hippocampal neuron and dendritic spine damage and increase the dendritic branch length and dendritic spine density of hippocampal neurons(P＜0.01,P＜0.01),restore the serum levels of 5-HT and DA in insomnia-concomitant depression rats(P＜0.05,P＜0.01),down-regulate the HDAC5 protein,and up-regulate the expression of MEF2C,PSD-95,and SYN1 protein(P＜0.05,P＜0.01 or P＜0.001).Conclusions Chaijin JieYu Anshen formula may alle-viate the depression-like behavior of model rats by re-ducing the expression of HDAC5 protein,thus deregu-lating the inhibition of transcription factor MEF2C,promoting the expression of PSD-95 and SNY1 protein,and exerting a protective effect on hippocampal neurons and synapses.

Based on the CX3C chemokine ligand 1(CX3CL1)-CX3C chemokine receptor 1(CX3CR1) axis, this study explored the potential mechanism by which Zuogui Jiangtang Jieyu Formula(ZGJTJY) improved neuroinflammation and enhanced neuroprotective effect in a rat model of diabetes mellitus complicated with depression(DD). The DD rat model was established by feeding a high-fat diet combined with streptozotocin(STZ) intraperitoneal injection for four weeks and chronic unpredictable mild stress(CUMS) combined with isolated cage rearing for five weeks. The rats were divided into a control group, a model group, a positive control group, an inhibitor group, and a ZGJTJY group. The open field test and forced swimming test were used to assess the depression-like behaviors of the rats. Enzyme-linked immunosorbent assay(ELISA) was performed to measure the expression levels of the pro-inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in plasma. Immunofluorescence staining was used to detect the expression of ionized calcium-binding adapter molecule 1(Iba1), postsynaptic density protein-95(PSD95), and synapsin-1(SYN1) in the hippocampus. Hematoxylin-eosin(HE) staining, Nissl staining, and TdT-mediated dUTP nick end labeling(TUNEL) fluorescence staining were performed to assess hippocampal neuronal damage. Western blot was used to measure the expression levels of CX3CL1, CX3CR1, A2A adenosine receptor(A2AR), glutamate receptor 2A(NR2A), glutamate receptor 2B(NR2B), and brain-derived neurotrophic factor(BDNF) in the hippocampus. Compared with the model group, the ZGJTJY group showed improved depression-like behaviors in DD rats, enhanced neuroprotective effect, increased expression of PSD95, SYN1, and BDNF(P<0.01), and decreased expression of Iba1, IL-1β, and TNF-α(P<0.01), as well as the expression of CX3CL1, CX3CR1, A2AR, NR2A, and NR2B(P<0.01). These results suggest that ZGJTJY may exert its neuroprotective effect by inhibiting the CX3CL1-CX3CR1 axis and activation of hippocampal microglia, thereby improving neuroinflammation and abnormal activation of N-methyl-D-aspartate receptor(NMDAR) subunits, and ultimately enhancing the expression of synaptic-related proteins PSD95, SYN1, and BDNF in the hippocampus.
Rats ; Animals ; Depression/drug therapy* ; Brain-Derived Neurotrophic Factor ; Neuroprotective Agents ; Tumor Necrosis Factor-alpha/metabolism* ; Neuroinflammatory Diseases ; Diabetes Mellitus ; Receptors, Glutamate ; CX3C Chemokine Receptor 1/genetics*