Objective: To evaluate the efficacy and safety of ruxolitinib combined with low-dose hormone for patients with acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Thirty patients with aGVHD after allo-HSCT admitted to the Department of Hematology of the General Hospital of Western Theater Command from November 2021 to November 2024 were retrospectively analyzed. All patients were treated with low-dose hormone (methylprednisolone 0.3-1 mg kg -d ) combined with ruxolitinib 5-10 mg d . The efficacy and adverse reactions were observed during the follow-up period to analyze the survival outcomes of the patients. Results: A total of 30 patients with aGVHD after allo-HSCT were included in this study, consisting of 15 (50%) males and 15 (50%) females with a median age of 34 year-old (ranging from 14 to 62). Classification by disease type: there were 18 cases of acute myeloid leukemia, 4 cases of acute lymphoblastic leukemia, 4 cases of aplastic anemia, and 4 cases of myelodysplastic syndrome. Classification by aGVHD severity: there were 27 cases (90%) of Ⅱ-Ⅳ degree aGVHD and 11 cases (36.7%) of Ⅲ-Ⅳ degree aGVHD. Ruxolitinib in combination with low-dose glucocorticoid treatment yield responses in 28 (93.3%) patients, of which 27 (90%) achieved complete remission (CR), while 1 (3.3%) showed partial remission (PR). One patient (3.3%) had no response (NR), and 1 patient (3.3%) exhibited progressed disease (PD). Overall survival (OS) at 1 year of transplantation was 73.9% (95%CI 49.5% to 87.7%), progression-free survival (PFS) was 93.3% (95%CI 75.9% to 98.3%), non-relapse mortality (NRM) was 20.6% (95%CI 7.9% to 47.4%), and median survival time was 27.6 months. Conclusion: Ruxolitinib combined with low-dose hormones is safe and effective in the treatment of aGVHD after allo-HSCT.

ObjectiveTo observe the clinical efficacy of the Yiqi Yangyin Huoxue prescription （YYHP） in the treatment of cathartic colon （CC） and its effects on fecal short-chain fatty acids （SCFAs）， and to explore the correlations among CC severity indicators and between these indicators and patient history. MethodsAccording to the inclusion and exclusion criteria， 98 patients meeting the diagnostic criteria of both traditional Chinese and Western medicine for CC with the syndrome of Qi-Yin deficiency complicated by blood stasis were randomly assigned to an observation group and a control group. The observation group received YYHP granules， while the control group received lactulose. Both medications were administered twice daily， one sachet each time， half an hour after breakfast and dinner， with a treatment course of 8 weeks. The primary constipation symptom score， Patient Assessment of Constipation Quality of Life （PAC-QOL） score， and TCM syndrome score were assessed before and after treatment and at the 8^th week after the end of treatment. The overall clinical effective rate， as well as the efficacy attenuation index and degree， were evaluated. Fecal SCFA levels were measured using gas chromatography-mass spectrometry （GC-MS）. Spearman correlation analysis was performed to explore the correlations among CC severity indicators and between these indicators and patient history. ResultsThe overall clinical effective rate in the observation group （95.83%） was higher than that in the control group （78.72%） （P<0.05）. After treatment， the total scores for primary constipation symptoms， PAC-QOL， and TCM syndromes decreased in both groups （P<0.05）， with more significant reductions in the observation group （P<0.05）. The severity of all primary constipation symptoms was alleviated in both groups （P<0.05）. In terms of "excessive straining and difficult defecation"， "anal heaviness， incomplete evacuation， and bloating sensation"， "abdominal distension"， and "defecation frequency"， the observation group showed better efficacy than the control group （P<0.05）. Scores of the four PAC-QOL dimensions and the scores and severity of primary and secondary TCM symptoms were reduced in both groups （P<0.05）， with more significant reductions in the observation group （P<0.05）. After treatment， acetic acid， propionic acid， butyric acid， and total SCFAs in the observation group increased significantly （P<0.05）. The efficacy attenuation index and degree in the observation group were lower than those in the control group （P<0.05）. No severe adverse reactions occurred in either group， and there was no statistically significant difference in the incidence of adverse reactions between the two groups. Positive correlations of varying degrees were observed among the total scores of primary constipation symptoms， PAC-QOL， and TCM syndromes， as well as between these scores and the history of stimulant laxative use， disease duration， and age. ConclusionYYHP can effectively alleviate the primary constipation symptoms in CC patients， improve quality of life， and ameliorate TCM syndromes， with good safety. It also has the advantage of a lower rebound degree after drug withdrawal， and its mechanism may be related to increasing fecal SCFA levels. Long-term abuse of stimulant laxatives may aggravate the severity of CC and prolong the disease course.

Purpose: In this study, the neural communication patterns between hypothalamic structures and cortical areas in girls diagnosed with central precocious puberty (CPP) were explored. Endocrine profiles were incorporated to clarify the pathophysiological interactions between cerebral networks and hormonal regulation. The hypothalamus was designated as the key focus area for connectivity analysis. Methods: Fifty-seven girls (37 CPP, 20 non-CPP) were recruited from the Pediatric Development Clinic at the Second Affiliated Hospital of Anhui Medical University. The collected data included demographic information, gonadotropin-releasing hormone stimulation tests, and magnetic resonance imaging scans. Hypothalamic functional connectivity (FC) was analyzed using predefined region of interest coordinates, and correlations between hormone levels and FC values were assessed. Results: Compared to the non-CPP group, the CPP group exhibited elevated baseline follicle-stimulating hormone (FSH), baseline luteinizing hormone (LH), peak FSH, peak LH, and peak LH/FSH ratios. Patients with CPP exhibited enhanced neural synchronization linking the right lateral hypothalamic effector zone to the right superior frontal gyrus (displaying a borderline significant correlation with peak LH concentrations), concurrent with diminished functional coupling of the right lateral hypothalamic efferent to the right fusiform/supramarginal gyri. The left lateral hypothalamic projections demonstrated amplified connectivity with the right cuneus. No FC differences were observed in the medial hypothalamus. Conclusion Abnormal lateral hypothalamus FC patterns were identified in CPP girls and were particularly linked to peak LH levels. The findings offer novel insights into the neuroendocrine mechanisms underlying CPP.

Objective:To investigate the effects of metformin on esophageal squamous cell carcinoma cell growth, migration and angiogenesis by regulating the expression of ALKBH3.Methods:Human esophageal cancer TE-1 cells were treated with different concentrations (0, 0.5, 1.0, 2.0, 4.0, 8.0 mmol/L) of metformin, and they were divided into a blank control group, low- (0.5 mmol/L), medium- (1.0 mmol/L), and high- (2.0 mmol/L) concentration metformin groups, a metformin (2.0 mmol/L) +pcDNA-NC group, and a metformin (2.0 mmol/L) +pcDNA-ALKBH3 group. The cell viability was determined by the CCK-8 method. The cell proliferation ability was detected by the clone formation assay. The cell migration and invasion abilities were examined by the Transwell assay. The cell apoptosis was detected by flow cytometry. The tube formation ability of cells was detected by the angiogenesis assay. A xenograft tumor model was constructed using 4- to 6-week-old male BALB/c thymus-less nude mice, which were divided into a model control group, a metformin group, a metformin+pcDNA-NC group, and a metformin+pcDNA-ALKBH3 group using a random number table method, and with six in each group. And the volume and weight of the tumor were measured. The protein expression levels of apoptosis-related proteins Bcl-2, Bax, ALKBH3 and vascular endothelial growth factor A (VEGF-A) were detected by Western blotting. The expression of CD31 protein was detected by immunohistochemistry.Results:After treating TE-1 cells with 0, 0.5, 1.0, 2.0, 4.0, and 8.0 mmol/L metformin for 48 hours, the cell viability was (100.00±0.00) %, (90.31±5.23) %, (81.25±8.65) %, (63.52±6.80) %, (54.64±5.35) %, and (31.48±4.21) %, respectively, with a statistically significant difference ( F=98.11, P<0.001). There were statistically significant differences in cell viability between 0.5, 1.0, 2.0, 4.0, 8.0 mmol/L and 0 mmol/L (all P<0.05). The IC 50 of metformin for TE-1 cells was 4.46 mmol/L. The numbers of colony formations of TE-1 cells in the blank control group, low-, medium-, and high-concentration metformin groups, metformin+pcDNA-NC group, and metformin+pcDNA-ALKBH3 group were 153.15±13.55, 134.80±11.62, 116.24±10.43, 93.17±8.85, 89.39±8.46, 110.26±7.21, respectively, with a statistically significant difference ( F=34.28, P<0.001); the numbers of colony formations of TE-1 cells in the metformin groups at different concentrations decreased significantly with the increase in metformin concentration (both P<0.05); compared with the metformin+pcDNA-NC group, the number of colony formations of cells in the metformin+pcDNA-ALKBH3 group increased ( P<0.05). The numbers of migration of TE-1 cells of 6 groups were 152.13±13.40, 133.85±10.72, 115.28±8.64, 91.16±7.89, 85.39±7.23, 116.85±8.36, the numbers of invasion were 135.22±10.77, 112.07±9.53, 86.30±7.45, 69.53±6.74, 65.81±5.65, 79.80±6.32, respectively, with statistically significant differences ( F=41.35, P<0.001; F=69.06, P<0.001); the numbers of migrated and invaded cells in the metformin groups at different concentrations decreased significantly with the increase in metformin concentration (all P<0.05); compared with the metformin+pcDNA-NC group, the numbers of migrated and invaded cells in the metformin+pcDNA-ALKBH3 group increased significantly (both P<0.05). The apoptosis rates of TE-1 cells in 6 groups were (3.22±1.13) %, (13.82±1.90) %, (22.67±2.53) %, (29.18±3.24) %, (26.84±2.75) %, and (16.36±1.63) %, respectively, with a statistically significant difference ( F=103.66, P<0.001); the apoptosis rates of cells in the metformin groups at different concentrations gradually increased with the increase in metformin concentration (both P<0.05); compared with the metformin+pcDNA-NC group, the apoptosis rate of cells in the metformin+pcDNA-ALKBH3 group was relatively lower ( P<0.05). The tubular structure of cells in blank control group was intact, and there were different degrees of damage to the tubular structure of cells in the low-, medium-, high- concentration metformin groups, the degree of damage to the tubular structure of cells in the metformin+pcDNA-ALKBH3 group was reduced. The numbers of cellular tubular structures of TE-1 cells in the 6 groups were 38.35±3.20, 27.15±2.64, 15.92±3.14, 7.39±1.50, 8.61±1.37, and 29.33±4.20, respectively, with a statistically significant difference ( F=113.92, P<0.001); the number of cellular tubular structures in the low-, medium-, and high- concentration metformin groups gradually decreased (both P<0.05); the number of cellular tubular structures in the metformin+pcDNA-ALKBH3 group was more than that in the metformin+pcDNA-NC group ( P<0.05). There were statistically significant differences in the protein expressions of Bcl-2, Bax, ALKBH3, and VEGF-A in TE-1 cells among 6 groups ( F=56.36, P<0.001; F=57.26, P<0.001; F=159.30, P<0.001; F=132.89, P<0.001); compared with the blank control group, the protein expressions of Bcl-2, ALKBH3, and VEGF-A in the metformin groups at different concentrations decreased, while the protein expression of Bax increased (all P<0.05); compared with the metformin+pcDNA-NC group, the protein expressions of Bcl-2, ALKBH3, and VEGF-A in the metformin+pcDNA-ALKBH3 group increased, and the expression level of Bax decreased (all P<0.05). The weights of tumors in the model control group, metformin group, metformin+pcDNA-NC group, and metformin+pcDNA-ALKBH3 group were (1.16±0.12), (0.46±0.05), (0.50±0.06), (1.19±0.14) g, the volumes of tumors were (878.36±108.93), (413.59±50.23), (439.78±51.39), (793.75±96.98) mm 3, with statistically significant differences ( F=96.61, P<0.001; F=51.90, P<0.001); the weight of tumors were lower and the volume of tumors were smaller in the metformin group than those in the model control group (both P<0.05), the weight of tumors were higher and the volume of tumors were bigger in the metformin+pcDNA-ALKBH3 group than those in the metformin group and the metformin+pcDNA-NC group (all P<0.05). CD31 was mainly distributed in the cytoplasm and cell membrane of tumor cells. There were statistically significant differences in the positive rates of CD31 and the protein expression levels of VEGF-A in transplanted tumor tissues among 4 groups ( F=7.12, P=0.002; F=48.81, P<0.001); the positive rate of CD31 and the protein expression level of VEGF-A in the metformin group were lower than those in the model control group; the positive rate of CD31 and the protein expression level of VEGF-A in the metformin+pcDNA-ALKBH3 group were higher than those in the metformin group and the metformin+pcDNA-NC group (all P<0.05) . Conclusions:Metformin may inhibit the proliferation, migration, and tumor angiogenesis of esophageal squamous cell carcinoma by reducing ALKBH3 expression.

Objective To analyze the correlation between tongue image features and the risk levels of disease in patients with idiopathic membranous nephropathy(IMN).Methods Based on IMN clinical research electronic data acquisition system,a cross-sectional study method was used to analyze the clinical diagnosis and treatment data of 135 IMN patients from Guangdong Provincial Hospital of Chinese Medicine.The patients were grouped according to the risk levels of disease,and then the correlation between the risk levels of disease and tongue image features was analyzed.During the description of tongue image features,TB is for tongue body,TC is for tongue coating,L is for luminance,a is for red-green axis,G is for the value of green,B is for the value of blue,and AUT is for the value of autocorrelation.Results The comparison of tongue image feature indicators of patients with different risk levels of IMN showed that:(1)the higher the level of disease risk of IMN patients,the greater the values of TB-L,TB-G and TB-B(P<0.05 or P<0.01).The values of tongue image indicator TB-a and TC-a of the patients with different risk levels of IMN were shown in decreasing sequence:low-risk group>high-risk group>middle-risk group>extremely-high-risk group(P<0.05).(2)Linear regression analysis showed that TB-L,TB-G,and TB-B were significantly increased in the high-risk group compared with those in the middle-and low-risk groups(P<0.05 or P<0.01),whereas there were no significant differences between the middle-risk group and low-risk group(P>0.05).(3)The results of correlation analysis showed that there was a positive correlation among most of the tongue image feature indicators(including TB-L,TB-G,TB-B,TB-AUT,TC-L,TC-G,and TC-B,etc.)and the risk level of disease,while TB-a was negatively correlated with the risk level of disease,and the differences were all statistically significant(P<0.05 or P<0.01).(4)All patients were treated with Chinese medicine and/or Chinese patent medicine,and 46.7%of patients were given hormones and immunosuppressants,and there was no statistically significant difference in the the use of hormones and immunosuppressants among various groups(P=0.637).Conclusion There is a correlation between the tongue image features of IMN patients and the risk level of disease,and the results will provide an objective reference for the assessment of illness state and traditional Chinese medicine(TCM)syndrome differentiation of IMN patients.With reference to the changes in the tongue image features,the illness state can be precisely identified,which is more accurate than the inspection of four diagnostic methods of TCM.

Graves'ophthalmopathy(GO)is a specific autoimmune disease occurring in orbital tissues and is closely related to hyperthyroidism caused by Graves'disease(GD).Its disabling and disfiguring features significantly impact the quality of life of patients.The exact mechanism of GO still remains to be fully elucidated.In recent years,gene sequencing and medical microbiology studies have shown that changes in the gut microbiota may play a role in the development and progression of GO,with gut dysbiosis altering immune system regulatory signals and causing immune damage to organs.Clarifying the correlation between gut microbiota and GO helps to understand the disease's pathogenic mechanism and provides a theoretical basis for the diagnosis and treatment of GO.This review summarizes the impact of gut microbiota dysbiosis in the pathogenesis of GO and promising therapeutic approaches,including research progress in aspects such as gut microbiota experiments,case studies,pathogenesis,and treatment strategies.

Objective To investigate the association between high-density lipoprotein cholesterol(HDL-C)levels and all-cause and cause-specific mortality in the elderly population,and to determine the optimal HDL-C concentration range associated with the lowest mortality risk.Methods This prospective cohort study included 16,632 elderly individuals aged≥60 years from the National Health and Nutrition Examination Survey(NHANES)between 1999 and 2018.Participants were divided into 5 groups based on HDL-C levels:<40 mg/dl group(n=2933),40-49 mg/dl group(n=4602),50-59 mg/dl group(n=3824),60-79 mg/dl group(n=3988),and≥80 mg/dl group(n=1285).Mortality data were obtained by linking records with the National Death Index(NDI).Cox proportional hazards regression and restricted cubic spline curves were used to analyze the association between HDL-C and mortality risk.Subgroup and sensitivity analyses were conducted.Results Multivariable-adjusted Cox models showed that,compared with 50-59 mg/dl HDL-C group,HDL-C<40 mg/dl group had significantly higher risks of all-cause mortality(HR=1.17,95%CI 1.05-1.31,P=0.006),cardiovascular mortality(HR=1.32,95%CI 1.08-1.58,P=0.001),and non-cardiovascular mortality(HR=1.14,95%CI 1.02-1.27,P=0.013).HDL-C≥80 mg/dl group had significantly higher risks of all-cause mortality(HR=1.18,95%CI 1.03-1.35,P=0.027)and non-cardiovascular mortality(HR=1.23,95%CI 1.03-1.46,P=0.029),but no significant effect on cardiovascular mortality(HR=1.07,95%CI 0.88-1.28,P=0.492).Restricted cubic spline curves revealed U-shaped associations between HDL-C and all-cause/non-cardiovascular mortality,and an inverse J-shaped association with cardiovascular mortality.These patterns were consistent in both elderly men and women.The HDL-C levels associated with the lowest risk were 56 mg/dl(95%CI 53-59 mg/dl)for all-cause mortality,54 mg/dl(95%CI 51-57 mg/dl)for cardiovascular mortality,and 59 mg/dl(95%CI 56-62 mg/dl)for non-cardiovascular mortality.Subgroup analyses showed no significant effect modifications.Sensitivity analyses confirmed the primary findings.Conclusions In the elderly population,extremely high HDL-C levels increase the risks of all-cause mortality and non-cardiovascular mortality,but do not elevate cardiovascular mortality.The risk of all-cause mortality is the lowest at an HDL-C concentration of 56 mg/dl.

BACKGROUND: Increasing evidence indicates that oxidative stress and interferon γ (IFNγ)-driven cellular immune responses are responsible for the pathogenesis of vitiligo. However, the connection between oxidative stress and the local production of IFNγ in early vitiligo remains unexplored. The aim of this study was to identify the mechanism underlying the production of IFNγ by mast cells and its impact on vitiligo pathogenesis. METHODS: Skin specimens from the central, marginal, and perilesional skin areas of active vitiligo lesions were collected to characterize changes of mast cells, CD8 + T cells, and IFNγ-producing cells. Cell supernatants from hydrogen peroxide (H 2 O 2 )-treated keratinocytes (KCs) were harvested to measure levels of soluble stem cell factor (sSCF) and matrix metalloproteinase (MMP)-9. A murine vitiligo model was established using Mas-related G protein-coupled receptor-B2 (MrgB2, mouse ortholog of human MrgX2) conditional knockout (MrgB2 -/- ) mice to investigate IFNγ production and inflammatory cell infiltrations in tail skin following the challenge with tyrosinase-related protein (Tyrp)-2 180 peptide. Potential interactions between the Tyrp-2 180 peptide and MrgX2 were predicted using molecular docking. The siRNAs targeting MrgX2 and the calcineurin inhibitor FK506 were also used to examine the signaling pathways involved in mast cell activation. RESULTS: IFNγ-producing mast cells were closely aligned with the recruitment of CD8 + T cells in the early phase of vitiligo skin. sSCF released by KCs through stress-enhanced MMP9-dependent proteolytic cleavage recruited mast cells into sites of inflamed skin (Perilesion vs . lesion, 13.00 ± 4.00/high-power fields [HPF] vs . 26.60 ± 5.72/HPF, P <0.05). Moreover, IFNγ-producing mast cells were also observed in mouse tail skin following challenge with Tyrp-2 180 (0 h vs . 48 h post-recall, 0/HPF vs . 3.80 ± 1.92/HPF, P <0.05). The IFNγ + mast cell and CD8 + T cell counts were lower in the skin of MrgB2 -/- mice than in those of wild-type mice (WT vs . KO 48 h post-recall, 4.20 ± 0.84/HPF vs . 0.80 ± 0.84/HPF, P <0.05). CONCLUSION Mast cells activated by MrgX2 serve as a local IFNγ producer that bridges between innate and adaptive immune responses against MCs in early vitiligo. Targeting MrgX2-mediated mast cell activation may represent a new strategy for treating vitiligo.
Vitiligo/metabolism* ; Mast Cells/immunology* ; Animals ; Interferon-gamma/metabolism* ; Mice ; Humans ; Melanocytes/metabolism* ; Receptors, G-Protein-Coupled/genetics* ; Mice, Knockout ; Mice, Inbred C57BL ; Male ; Female ; Matrix Metalloproteinase 9/metabolism* ; Stem Cell Factor/metabolism*

In this study, Saccharomyces cerevisiae R0 was used as the chassis cell to synthesize oleanolic acid from scratch through the heterologous expression of β-amyrin synthase(β-AS) from Glycyrrhiza uralensis, cytochrome P450 enzyme CYP716A154 from Catharanthus roseus, and cytochrome P450 reductase AtCPR from Arabidopsis thaliana. The engineered strain R1 achieved shake flask titres of 5.19 mg·L~(-1). By overexpressing enzymes in the pentose phosphate pathway(PPP)(ZWF1, GND1, TKL1, and TAL), the NADH kinase gene in the mitochondrial matrix(POS5), truncated 3-hydroxy-3-methylglutaryl-CoA reductase(tPgHMGR1) from Panax ginseng, and farnesyl diphosphate synthase gene(SmFPS) from Salvia miltiorrhiza, the precursor supply and intracellular reduced nicotinamide adenine dinucleotide phosphate(NADPH) supply were enhanced, resulting in an 11.4-fold increase in squalene yield and a 3.6-fold increase in oleanolic acid yield. Subsequently, increasing the copy number of the heterologous genes tPgHMGR1, β-AS, CYP716A154, and AtCPR promoted the metabolic flow towards the final product, oleanolic acid, and increased the yield by three times. Shake flask fermentation data showed that, by increasing the copy number, precursor supply, and intracellular NADPH supply, the final engineered strain R3 could achieve an oleanolic acid yield of 53.96 mg·L~(-1), which was 10 times higher than that of the control strain R1. This study not only laid the foundation for the green biosynthesis of oleanolic acid but also provided a reference for metabolic engineering research on other pentacyclic triterpenoids in S. cerevisiae.
Oleanolic Acid/biosynthesis* ; Saccharomyces cerevisiae/metabolism* ; Industrial Microbiology ; Microorganisms, Genetically-Modified/metabolism* ; Plants/enzymology* ; Fermentation ; Metabolic Engineering

Medical institutions, with their clinical practice foundation and abundant human use experience data, have become important carriers for the inheritance and innovation of traditional Chinese medicine(TCM) and the "cradles" of the preparation of new TCM. To effectively promote the transformation of new TCM originating from the TCM clinical practice in medical institutions and establish an effective evaluation index system for the transformation of new TCM conforming to the characteristics of TCM, consensus experts adopted the literature research, questionnaire survey, Delphi method, etc. By focusing on the policy and technical evaluation of new TCM originating from the TCM clinical practice in medical institutions, a comprehensive evaluation from the dimensions of drug safety, efficacy, feasibility, and characteristic advantages was conducted, thus forming a comprehensive evaluation system with four primary indicators and 37 secondary indicators. The expert consensus reached aims to encourage medical institutions at all levels to continuously improve the high-quality research and development and transformation of new TCM originating from the TCM clinical practice in medical institutions and targeted at clinical needs, so as to provide a decision-making basis for the preparation, selection, cultivation, and transformation of new TCM for medical institutions, improve the development efficiency of new TCM, and precisely respond to the public medication needs.
Medicine, Chinese Traditional/standards* ; Humans ; Consensus ; Drugs, Chinese Herbal/therapeutic use* ; Surveys and Questionnaires