This study aims to investigate the antipyretic effects and mechanisms of ethanol extracts from Arisaematis Rhizoma fermented with bile from different sources on a rat model of fever induced by a dry-yeast suspension. The rat model of fever was established by subcutaneous injection of 20% dry-yeast suspension into the rat back. The levels of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), interleukin-6(IL-6) in the serum, as well as prostaglandin E_2(PGE_2) and cyclic adenosine monophosphate(cAMP) in the hypothalamus, were determined by ELISA. Metabolomics analysis was then performed on serum and hypothalamus samples based on UPLC-Q-TOF MS to explore the potential biomarkers and metabolic pathways. The results showed that the body temperatures of rats significantly rose 4 h after modeling. After oral administration of high-dose ethanol extracts of Arisaematis Rhizoma fermented with bovine bile(NCH) and porcine bile(ZCH), the body temperatures of rats declined(P<0.05), and the NCH group showed better antipyretic effect than the ZCH group. Additionally, compared with the model group, the NCH and ZCH groups showed lowered levels of IL-1β, IL-6, TNF-α, PGE_2, and cAMP(P<0.01). The results of serum and hypothalamus metabolomics analysis indicated that both NCH and ZCH exerted antipyretic effects by regulating phenylalanine metabolism, sphingolipid metabolism, arachidonic acid metabolism, and steroid hormone biosynthesis. Collectively, both NCH and ZCH can play an obvious antipyretic role in the rat model of dry yeast-induced fever, and the underlying mechanism might be closely associated with inhibiting inflammation and regulating metabolic disorders. Moreover, NCH demonstrates better antipyretic effect.
Animals ; Rats ; Male ; Fermentation ; Rats, Sprague-Dawley ; Rhizome/metabolism* ; Drugs, Chinese Herbal/chemistry* ; Bile/chemistry* ; Antipyretics/chemistry* ; Fever/metabolism* ; Cattle ; Swine ; Tumor Necrosis Factor-alpha/metabolism* ; Ethanol/chemistry* ; Interleukin-6/blood* ; Interleukin-1beta/blood*

Based on the high-fat diet-induced hyperlipidemia rat model, this study aimed to evaluate the lipid-lowering effect of Arisaema Cum Bile and explore its mechanisms, providing experimental evidence for its clinical application. Biochemical analysis was used to detect serum levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), high-density lipoprotein cholesterol(HDL-C), low-density lipoprotein cholesterol(LDL-C), triglycerides(TG), and total cholesterol(TC) to assess the lipid-lowering activity of Arisaema Cum Bile. Additionally, 16S rDNA sequencing and metabolomics techniques were employed to jointly elucidate the lipid-lowering mechanisms of Arisaema Cum Bile. The experimental results showed that high-dose Arisaema Cum Bile(PBA-H) significantly reduced serum ALT, AST, LDL-C, TG, and TC levels(P<0.01), and significantly increased HDL-C levels(P<0.01). The effect was similar to that of fenofibrate, with no significant difference. Furthermore, Arisaema Cum Bile significantly alleviated hepatocyte ballooning and mitigated fatty degeneration in liver tissues. As indicated by 16S rDNA sequencing results, PBA-H significantly enhanced both alpha and beta diversity of the gut microbiota in the model rats, notably increasing the relative abundance of Akkermansia and Subdoligranulum species(P<0.01). Liver metabolomics analysis revealed that PBA-H primarily regulated pathways involved in arachidonic acid metabolism, vitamin B_6 metabolism, and steroid biosynthesis. In summary, Arisaema Cum Bile significantly improved abnormal blood lipid levels and liver pathology induced by a high-fat diet, regulated hepatic metabolic disorders, and improved the abundance and structural composition of gut microbiota, thereby exerting its lipid-lowering effect. The findings of this study provide experimental evidence for the clinical application of Arisaema Cum Bile and the treatment of hyperlipidemia.
Animals ; Gastrointestinal Microbiome/drug effects* ; Rats ; Male ; Metabolomics ; Hyperlipidemias/microbiology* ; Drugs, Chinese Herbal/administration & dosage* ; Rats, Sprague-Dawley ; Hypolipidemic Agents/pharmacology* ; Liver/metabolism* ; Humans ; Alanine Transaminase/metabolism* ; Triglycerides/metabolism* ; Aspartate Aminotransferases/metabolism*

Objective:To explore the efficacy and safety of cryopreservation-free integrated autologous hematopoietic stem cell transplantation (HSCT) model for patients with multiple myeloma.Methods:A total of 96 patients with newly diagnosed multiple myeloma (NDMM) between July 31, 2020, and December 31, 2022, were retrospectively analyzed, of which 41 patients in the observation group received integrated non-cryopreserved transplantation mode. After hematopoietic stem cells were mobilized and collected, melphalan was started immediately for pre-transplant conditioning, and non-cryopreserved grafts from the medical blood transfusion refrigerator were directly injected intravenously into the patient within 24-48 h after the melphalan conditioning. The control group consisted of 55 patients who received traditional transplantation mode. After hematopoietic stem cells were collected, stem cell cryopreservation was performed in liquid nitrogen, and then the transplant plans were started at the right time. All patients received mobilization of autologous hematopoietic stem cells using the G-CSF combined with the plerixafor.Results:① A total of 34 patients (82.9% ) with VGPR plus CR in the observation group were significantly higher than 33 patients (60.0% ) in the control group ( P=0.016). ②Compared with the control group, the incidence of grade 1 oral mucosal inflammation was higher in the observation group ( P<0.001) ; however, the incidence of grades 2 and 3 oral mucosal inflammation was lower ( P=0.004, P=0.048), and neither group experienced grade 4 or above oral mucosal inflammation. The incidence of grade 1 diarrhea was higher in the observation group ( P=0.002), whereas the incidence of grade 3 diarrhea was lower ( P=0.007). No statistically significant difference was observed in the incidence of grade 4 diarrhea ( P=0.506), and neither group experienced grade 5 diarrhea. ③ The incidence of bacterial infection in the observation group was lower than that in the control group (34.1% vs 65.5%, P=0.002), whereas no statistically significant difference was observed in the incidence of fungal infection (29.3% vs 31.4%, P=0.863) and viral infection (4.88% vs 3.64%, P=0.831). ④No statistically significant difference was observed in the implantation time of granulocytes and platelets between the observation and control groups [10 (8-20) days vs 11 (8-17) days, P=0.501; 13 (10-21) days vs 15 (10-20) days, P=0.245]. ⑤ All patients did not receive lenalidomide treatment 100 days post-transplantation. At 30 days post-transplantation, the CTL, NK, and Th cell counts in the observation group were lower than those in the control group ( P<0.001, P=0.002, P=0.049), and the NKT cell counts were higher than those in the control group ( P=0.024). At 100 days post-transplantation, the CTL, NKT, and Th cell counts in the observation group were higher than those in the control group ( P=0.025, P=0.011, P=0.007), and no statistically significant difference in NK cell counts was observed between the two groups ( P=0.396). ⑥ The median follow-up was 18 (4-33) months. The overall 2-year survival rates of the observation and control groups post-transplantation were 91.5% and 78.2%, respectively ( P=0.337). The recurrence-free survival rates were 85.3% and 77.6%, respectively ( P=0.386), and the cumulative recurrence rates were 9.8% and 16.9%, respectively ( P=0.373) . Conclusion:In NDMM, the cryopreservation-free integrated autologous HSCT model can achieve similar therapeutic effects as traditional transplantation models, with lower rates of severe mucosal inflammation and infection compared with traditional transplantation models.

Objective:To explore the clinical characteristics and prognoses of severe autoimmune glial fibrillary acidic protein astrocytopathy (GFAP-A).Methods:A retrospective analysis was performed. The clinical data of 12 patients with severe GFAP-A admitted to Department of Neurology, Guangdong 999 Brain Hospital from January 2018 to June 2023 were collected, including demography, clinical manifestations, MRI features, laboratory examination results (such as antibodies), treatments and prognoses.Results:Among the 12 patients, 9 were male and 3 were female, with an average onset age of (46.58±17.53) years. Primary symptoms included headache, limb weakness, limb numbness, mental disorder, epileptic seizure, and urinary and defecation disorder; 9 patients had fever before onset. With aggravated severe GFAP-A, 12 patients had impaired consciousness, 12 had respiratory failure, 6 had unstable blood pressure and heart rate, and 2 had status epilepticus. Cranial MRI indicated abnormal lesions in all 12 patients, including 10 with brainstem involvement (7 had involved medulla oblongata); 10 showed soft meningeal enhancement. In 8 patients received MRI of the whole spinal cord, 7 had abnormal spinal cord lesions; point-like enhancement of the whole spinal meninges was observed in 6 of the 7 patients. All 12 patients had positive cerebrospinal fluid GFAP-IgG, and 3 patients also had positive serum GFAP-IgG. All patients accepted glucocorticoids and immunoglobulin immunotherapy, and 1 patient was supplemented with mycophenolate mofetil; 8 patients had good prognosis, and 4 patients died. Pulmonary infection, hyponatremia, hypoproteinemia, and deep vein thrombosis were the common complications.Conclusion:Patients with severe GFAP-A mainly manifest as meningoencephalitis and meningoencephalomyelitis, and are likely involved medulla oblongata, enjoying rapid clinical progression; even with early immunotherapy, high mortality rate is still noted.

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

AIM: To explore the clinical efficacy of different anti-vascular endothelial growth factor(VEGF)drugs in the treatment of diabetic macular edema(DME), and analyze their relationship with optical coherence tomography(OCT)classification.METHODS: A total of 45 DME patients treated with ranibizumab(admitted to our hospital from February 2020 to February 2022)were selected as the ranibizumab group, and 45 DME patients treated with conbercept during the same period were selected as the conbercept group. The ranibizumab group was treated with retinal photocoagulation combined with ranibizumab, and the conbercept group was treated with retinal photocoagulation combined with conbercept. The improvement of symptoms(improvement time of macular edema, time of retinal thickness returning to normal, disappearance time of neovascularization and absorption time of fundus hemorrhage), levels of serum interleukin-6(IL-6)and VEGF, central macular thickness(CMT), best corrected visual acuity(BCVA), and complications were compared between the two groups, and the relationship between their clinical efficacy and different OCT types were analyzed.RESULTS: There was no significant difference in the improvement time of macular edema, time of retinal thickness returning to normal, disappearance time of neovascularization and absorption time of fundus hemorrhage between the two groups(P>0.05); After treatment, the values of IL-6, VEGF and BCVA in the two groups were significantly lower than those before treatment(P<0.01), but there was no significant difference between the two groups(P>0.05); compared with before treatment, CMT was significantly decreased in both groups after treatment(P<0.05), and compared with ranibizumab group, the CMT was significantly decreased in the conbercept group(P<0.01); there was no significant difference in the incidence of complications between two groups(P>0.05); there were significant differences in the total effective rate among patients with serous retinal detachment(SRD), cystoid macular edema(CME)and diffuse retinal thickening(DRT; P<0.05), among which DRT had the highest total effective rate and SRD had the lowest total effective rate.CONCLUSION: Both conbercept and ranibizumab in the treatment of DME can effectively improve the clinical symptoms of patients and reduce the inflammatory response, but conbercept can better reduce the level of CMT, and has better treatment effect on DRT-type DME patients.

Parvalbumin interneurons belong to the major types of GABAergic interneurons. Although the distribution and pathological alterations of parvalbumin interneuron somata have been widely studied, the distribution and vulnerability of the neurites and fibers extending from parvalbumin interneurons have not been detailly interrogated. Through the Cre recombinase-reporter system, we visualized parvalbumin-positive fibers and thoroughly investigated their spatial distribution in the mouse brain. We found that parvalbumin fibers are widely distributed in the brain with specific morphological characteristics in different regions, among which the cortex and thalamus exhibited the most intense parvalbumin signals. In regions such as the striatum and optic tract, even long-range thick parvalbumin projections were detected. Furthermore, in mouse models of temporal lobe epilepsy and Parkinson's disease, parvalbumin fibers suffered both massive and subtle morphological alterations. Our study provides an overview of parvalbumin fibers in the brain and emphasizes the potential pathological implications of parvalbumin fiber alterations.
Mice ; Animals ; Epilepsy, Temporal Lobe/pathology* ; Parvalbumins/metabolism* ; Parkinson Disease/pathology* ; Neurons/metabolism* ; Interneurons/physiology* ; Disease Models, Animal ; Brain/pathology*

AIM: To explore the relationship between the changes of serum circFTO and microRNA-141-3p(miR-141-3p)levels and the different disease stages of diabetes retinopathy.METHODS: A total of 198 patients with type 2 diabetes admitted to our hospital from October 2019 to November 2022 were collected as the study subjects, the patients were grouped into non diabetes retinopathy(NDR)group(70 cases), non proliferative diabetes retinopathy(NPDR)group(66 cases)and proliferative diabetes retinopathy(PDR)group(62 cases)according to different stages; meantime, 67 volunteers with normal physical examination results were collected as the control group. The levels of serum circFTO and miR-141-3p were detected by real-time fluorescent quantitative PCR(qRT-PCR); Pearson correlation analysis was used to examine the correlation between the serum circFTO, miR-141-3p and various indicators in patients with diabetes retinopathy; multivariate Logistic regression analysis was applied to explore the influencing factors of diabetes retinopathy.RESULTS: CircFTO, systolic blood pressure(SBP), and diastolic blood pressure(DBP)in PDR group were higher than those in control group, NDR group and NPDR group, while miR-141-3p and high-density lipoprotein cholesterol(HDL-C)were lower than those in control group, NDR group and NPDR group(P<0.05). Fasting blood glucose(FPG)and glycosylated hemoglobin(HbA1c)in NDR group, NPDR group and PDR group were higher than those in the control group(all P<0.05). The course of disease in PDR group was longer than that in NDR group and NPDR group(P<0.05). Serum circFTO in patients with diabetes retinopathy was positively correlated with SBP, DBP, FPG, HbA1c, and miR-141-3p was negatively correlated with SBP, DBP, FPG, HbA1c(all P<0.05). CircFTO was a risk factor for diabetes retinopathy, and miR-141-3p was a protective factor for diabetes retinopathy(P<0.05).CONCLUSION: Serum circFTO is obviously increased and miR-141-3p is obviously decreased in patients with diabetes retinopathy, both of them are closely related to disease stage, and are expected to become important indicators for evaluating disease progress.

Objective To study the invasive histopathological features of papillary thyroid carcinoma(PTC)with tall cell variant(TCV).Methods A retrospective analysis of 19 170 cases of PTC in Ruijin Hospital,Shanghai Jiao Tong University School of Medicine from January 2018 to May 2023 was performed to analyze and the clinicopathological features between TCV-PTC group and classic PTC(cPTC)group.Results Pathological results showed 1 380 cases in TCV-PTC group and 15 578 cases in cPTC group.TCV-PTC had higher proportion and(or)mean value in patients'age,extraglandular invasion,nerve invasion,vascular invasion,maximum diameter of cancer focus,multifocality,lymph node metastasis and BRAF mutation,but the proportion of patients with coexistent Hashimoto's thyroiditis was lower than cPTC,and all results had significant difference(P<0.05).Conclusions Compared with the cPTC,TCV-PTC has stronger local invasive characteristics and lymph node metastasis rate,which provides the basis for the subsequent clinical treatment.