Through a comprehensive analysis combining network pharmacology prediction and transcriptomics, this study systematically explained the multi-target mechanism of Cyanotis arachnoidea(CA) Gel in improving melasma. A melasma model was induced in female SD rats by progesterone injection combined with ultraviolet B(UVB) irradiation for 40 consecutive days, while the blank control group was only fed routinely. After successful model establishment, the rats were randomly divided into five groups and administered different doses of CA ethanol extract gel(high, medium, and low doses) or arbutin Gel(positive control), which were applied once daily for 28 consecutive days. Subsequently, the levels of superoxide dismutase(SOD), malondialdehyde(MDA), and tyrosinase(TYR) in the skin, serum, and liver tissues were measured. Hematoxylin-eosin(HE) staining and Masson-Fontana staining were used to observe the pathological changes in the tissues. Network pharmacology combined with transcriptomics was employed to identify core targets and pathways, and the differential gene expression was validated by quantitative real-time PCR(qPCR). Pharmacodynamic experiments showed that CA Gel significantly increased SOD activity and decreased MDA and TYR levels in the skin, serum, and liver of model rats. It also improved epidermal thickening, inflammatory infiltration, collagen loss, and melanin deposition. Network pharmacology analysis showed that CA mainly regulated core targets such as signal transducer and activator of transcription 3(STAT3), epidermal growth factor receptor(EGFR), and interleukin-6(IL-6), and modulated the phosphatidylinositol 3-kinase(PI3K)-protein kinase B(AKT) and interleukin-17(IL-17) signaling pathways. Transcriptomic analysis showed that CA Gel significantly downregulated the gene expression of heat shock protein 90β family member 1(Hsp90b1), heat shock protein 90α family member 1(Hsp90aa1), and the key steroid synthesis enzyme cytochrome P450 family 17 subfamily A member 1(Cyp17a1), while upregulating thioredoxin 1(Txn1). qPCR results confirmed that CA Gel regulated oxidative stress and inflammatory response by inhibiting the IL-17 signaling pathway and steroid hormone synthesis. This study, for the first time, reveals the molecular mechanism of CA Gel in improving melasma through multi-target synergistic regulation of oxidative stress, inflammatory response, and hormone metabolism pathways, providing a scientific basis for the treatment of pigmentation diseases with traditional Chinese medicine.
Animals ; Rats ; Female ; Rats, Sprague-Dawley ; Network Pharmacology ; Drugs, Chinese Herbal/administration & dosage* ; Melanosis/metabolism* ; Transcriptome/drug effects* ; Humans ; Superoxide Dismutase/genetics* ; Signal Transduction/drug effects* ; Malondialdehyde/metabolism*

Objective:To analyze the relationship between microRNA-21(miR-21)expression and the risk of very early relapse post-induction chemotherapy in children with acute lymphoblastic leukemia(ALL).Methods:A total of 110 newly diagnosed children with ALL admitted to Huanggang Central Hospital from March 2020 to September 2022 were included.All patients received induction chemotherapy according to the CCLG-2008 protocol.The patients who achieved complete response(CR)after induction chemotherapy were followed up for 18 months,with very early relapse as the endpoint event.Then the patients were divided into a relapse group and a non-relapse group.Cox regression was used to analyze the influencing factors of very early relapse after induction chemotherapy in children with ALL.ROC curve and decision curve were used to evaluate the predictive value of peripheral blood miR-21 for very early relapse after induction chemotherapy in children with ALL.Restricted cubic splines were used to analyze the dose-response relationship between peripheral blood miR-21 and very early relapse after induction chemotherapy in children with ALL.Results:A total of 102 children with ALL achieved CR after induction chemotherapy,among whom 24 cases(23.53％)experienced very early relapse,with a median relapse time of 14 months.The proportions of patients with high-risk stratification at initial diagnosis,extramedullary infiltration,and minimal residual disease(MRD)positivity were significantly higher in the relapse group than those in the non-relapse group;The absolute lymphocyte count(ALC)in peripheral blood was significantly lower,while the expression levels of miR-21 and lactate dehydrogenase(LDH)were significantly higher in the relapse group compared with the non-relapse group(all P＜0.05).Cox regression analysis showed that very early relapse after induction chemotherapy in children with ALL was associated with medium risk and high risk at initial diagnosis,extramedullary infiltration,decreased ALC in peripheral blood,MRD positivity,as well as high expression levels of miR-21 and LDH(all P＜0.05).ROC curve analysis indicated that the area under the curve(AUC)of peripheral blood miR-21 for predicting very early relapse after induction chemotherapy in children with ALL was 0.800,with an optimal cutoff value of 4.830.Restricted cubic spline analysis revealed that there was a non-linear dose-response relationship between peripheral blood miR-21 and the risk of very early relapse after induction chemotherapy in children with ALL.When the expression level of peripheral blood miR-21 exceeded 4.830,the risk of very early relapse increased with the elevation of miR-21 expression.Decision curve analysis demonstrated that combining peripheral blood miR-21 with other risk factors enhanced the predictive performance for the risk of very early relapse after induction chemotherapy in children with ALL.Conclusion:Very early relapse after induction chemotherapy in children with ALL is associated with elevated expression of miR-21 in peripheral blood,and high expression of miR-21 may increase the risk of very early relapse.Detecting miR-21 before induction chemotherapy has predictive significance for very early relapse in children with ALL,and combining it with other risk factors can improve the predictive efficacy.

Objective:To analyze the relationship between microRNA-21(miR-21)expression and the risk of very early relapse post-induction chemotherapy in children with acute lymphoblastic leukemia(ALL).Methods:A total of 110 newly diagnosed children with ALL admitted to Huanggang Central Hospital from March 2020 to September 2022 were included.All patients received induction chemotherapy according to the CCLG-2008 protocol.The patients who achieved complete response(CR)after induction chemotherapy were followed up for 18 months,with very early relapse as the endpoint event.Then the patients were divided into a relapse group and a non-relapse group.Cox regression was used to analyze the influencing factors of very early relapse after induction chemotherapy in children with ALL.ROC curve and decision curve were used to evaluate the predictive value of peripheral blood miR-21 for very early relapse after induction chemotherapy in children with ALL.Restricted cubic splines were used to analyze the dose-response relationship between peripheral blood miR-21 and very early relapse after induction chemotherapy in children with ALL.Results:A total of 102 children with ALL achieved CR after induction chemotherapy,among whom 24 cases(23.53％)experienced very early relapse,with a median relapse time of 14 months.The proportions of patients with high-risk stratification at initial diagnosis,extramedullary infiltration,and minimal residual disease(MRD)positivity were significantly higher in the relapse group than those in the non-relapse group;The absolute lymphocyte count(ALC)in peripheral blood was significantly lower,while the expression levels of miR-21 and lactate dehydrogenase(LDH)were significantly higher in the relapse group compared with the non-relapse group(all P＜0.05).Cox regression analysis showed that very early relapse after induction chemotherapy in children with ALL was associated with medium risk and high risk at initial diagnosis,extramedullary infiltration,decreased ALC in peripheral blood,MRD positivity,as well as high expression levels of miR-21 and LDH(all P＜0.05).ROC curve analysis indicated that the area under the curve(AUC)of peripheral blood miR-21 for predicting very early relapse after induction chemotherapy in children with ALL was 0.800,with an optimal cutoff value of 4.830.Restricted cubic spline analysis revealed that there was a non-linear dose-response relationship between peripheral blood miR-21 and the risk of very early relapse after induction chemotherapy in children with ALL.When the expression level of peripheral blood miR-21 exceeded 4.830,the risk of very early relapse increased with the elevation of miR-21 expression.Decision curve analysis demonstrated that combining peripheral blood miR-21 with other risk factors enhanced the predictive performance for the risk of very early relapse after induction chemotherapy in children with ALL.Conclusion:Very early relapse after induction chemotherapy in children with ALL is associated with elevated expression of miR-21 in peripheral blood,and high expression of miR-21 may increase the risk of very early relapse.Detecting miR-21 before induction chemotherapy has predictive significance for very early relapse in children with ALL,and combining it with other risk factors can improve the predictive efficacy.

OBJECTIVE: To compare the therapeutic effect between Hunyuan moxibustion and oral western medication on diarrhea-predominant irritable bowel syndrome（IBS-D）of spleen and kidney yang deficiency. METHODS: Sixty patients with IBS-D of spleen and kidney yang deficiency were randomly divided into a Hunyuan moxibustion group and a western medication group, 30 cases each group. The Hunyuan moxibustion group was treated with Hunyuan moxibustion at Guanyuan（CV 4），40 min each time, once a day; in the western medication group，loperamide hydrochloride capsules (2 mg each time, 3 times a day) and bacillus licheniformis live capsules (0.5 g each time, 3 times a day) were given orally.Both groups were treated for 20 days. The scores of irritable bowel syndrome（IBS）symptom severity scale（IBS-SSS）, IBS quality of life scale (IBS-QOL) and TCM symptom grading quantitative were observed before and after treatment, and the clinical efficacy and safety were evaluated in the two groups. RESULTS: After treatment，each item scores and total scores of IBS-SSS in the two groups were lower than those before treatment（P<0.05）, and the total scores of IBS-QOL were higher than those before treatment (P<0.05)；each item score and total score of IBS-SSS in the Hunyuan moxibustion group were lower than those in the western medication group (P<0.05), and the total score of IBS-QOL in the Hunyuan moxibustion group was higher than that in the western medication group (P<0.05).After treatment, each item score and total score of TCM symptom grading quantitative in the Hunyuan moxibustion group were lower than those before treatment (P<0.05), the abdominal pain, diarrhea, lack of appetite scores and total score in the western medication group were lower than those before treatment (P<0.05)；and the abdominal pain, soreness and weakness of waist and knees, fear to cold and cold limbs scores and total score in the Hunyuan moxibustion group were lower than those in the western medication group (P<0.05).The total effective rate was 90.0%（27/30）in the Hunyuan moxibustion group, which was higher than 73.3%（22/30）in the western medication group (P<0.05). No adverse reactions occurred in both groups during treatment. CONCLUSION Hunyuan moxibustion can effectively improve the symptom severity and quality of life in patients with IBS-D of spleen and kidney yang deficiency, especially in improving the symptoms of abdominal pain, soreness and weakness of waist and knees, fear to cold and cold limbs.Its therapeutic effect is superior to western medication.
Humans ; Spleen ; Irritable Bowel Syndrome/therapy* ; Quality of Life ; Capsules ; Moxibustion ; Yang Deficiency/therapy* ; Kidney ; Abdominal Pain/therapy* ; Diarrhea/therapy*

Background/Aims: Chronic hepatitis B (CHB) and fatty liver (FL) often co-exist, but natural history data of this dual condition (CHB-FL) are sparse. Via a systematic review, conventional meta-analysis (MA) and individual patient-level data MA (IPDMA), we compared liver-related outcomes and mortality between CHB-FL and CHB-no FL patients. Methods: We searched 4 databases from inception to December 2021 and pooled study-level estimates using a random- effects model for conventional MA. For IPDMA, we evaluated outcomes after balancing the two study groups with inverse probability treatment weighting (IPTW) on age, sex, cirrhosis, diabetes, ALT, HBeAg, HBV DNA, and antiviral treatment. Results: We screened 2,157 articles and included 19 eligible studies (17,955 patients: 11,908 CHB-no FL; 6,047 CHB-FL) in conventional MA, which found severe heterogeneity (I2=88–95%) and no significant differences in HCC, cirrhosis, mortality, or HBsAg seroclearance incidence (P=0.27–0.93). IPDMA included 13,262 patients: 8,625 CHB-no FL and 4,637 CHB-FL patients who differed in several characteristics. The IPTW cohort included 6,955 CHB-no FL and 3,346 CHB-FL well-matched patients. CHB-FL patients (vs. CHB-no FL) had significantly lower HCC, cirrhosis, mortality and higher HBsAg seroclearance incidence (all p≤0.002), with consistent results in subgroups. CHB-FL diagnosed by liver biopsy had a higher 10-year cumulative HCC incidence than CHB-FL diagnosed with non-invasive methods (63.6% vs. 4.3%, p<0.0001). Conclusions IPDMA data with well-matched CHB patient groups showed that FL (vs. no FL) was associated with significantly lower HCC, cirrhosis, and mortality risk and higher HBsAg seroclearance probability.

Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.

OBJECTIVES: To investigate the clinical treatment outcomes and the changes of the outcomes over time in extremely preterm twins in Guangdong Province, China. METHODS: A retrospective analysis was performed for 269 pairs of extremely preterm twins with a gestational age of <28 weeks who were admitted to the department of neonatology in 26 grade A tertiary hospitals in Guangdong Province from January 2008 to December 2017. According to the admission time, they were divided into two groups: 2008-2012 and 2013-2017. Besides, each pair of twins was divided into the heavier infant and the lighter infant subgroups according to birth weight. The perinatal data of mothers and hospitalization data of neonates were collected. The survival rate of twins and the incidence rate of complications were compared between the 2008-2012 and 2013-2017 groups. RESULTS: Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of severe asphyxia and smaller head circumference at birth (P<0.05). The mortality rates of both of the twins, the heavier infant of the twins, and the lighter infant of the twins were lower in the 2013-2017 group compared with the 2008-2012 group (P<0.05). Compared with the 2008-2012 group, the 2013-2017 group (both the heavier infant and lighter infant subgroups) had lower incidence rates of pulmonary hemorrhage, patent ductus arteriosus (PDA), periventricular-intraventricular hemorrhage (P-IVH), and neonatal respiratory distress syndrome (NRDS) and a higher incidence rate of bronchopulmonary dysplasia (P<0.05). CONCLUSIONS There is a significant increase in the survival rate over time in extremely preterm twins with a gestational age of <28 weeks in the 26 grade A tertiary hospitals in Guangdong Province. The incidences of severe asphyxia, pulmonary hemorrhage, PDA, P-IVH, and NRDS decrease in both the heavier and lighter infants of the twins, but the incidence of bronchopulmonary dysplasia increases. With the improvement of diagnosis and treatment, the multidisciplinary collaboration between different fields of fetal medicine including prenatal diagnosis, obstetrics, and neonatology is needed in the future to jointly develop management strategies for twin pregnancy.
Bronchopulmonary Dysplasia/epidemiology* ; Female ; Gestational Age ; Humans ; Infant ; Infant, Extremely Premature ; Infant, Newborn ; Pregnancy ; Respiratory Distress Syndrome, Newborn/epidemiology* ; Retrospective Studies ; Treatment Outcome

Background: and Purpose Recent studies suggested an increased incidence of cerebral venous thrombosis (CVT) during the coronavirus disease 2019 (COVID-19) pandemic. We evaluated the volume of CVT hospitalization and in-hospital mortality during the 1st year of the COVID-19 pandemic compared to the preceding year. Methods: We conducted a cross-sectional retrospective study of 171 stroke centers from 49 countries. We recorded COVID-19 admission volumes, CVT hospitalization, and CVT in-hospital mortality from January 1, 2019, to May 31, 2021. CVT diagnoses were identified by International Classification of Disease-10 (ICD-10) codes or stroke databases. We additionally sought to compare the same metrics in the first 5 months of 2021 compared to the corresponding months in 2019 and 2020 (ClinicalTrials.gov Identifier: NCT04934020). Results: There were 2,313 CVT admissions across the 1-year pre-pandemic (2019) and pandemic year (2020); no differences in CVT volume or CVT mortality were observed. During the first 5 months of 2021, there was an increase in CVT volumes compared to 2019 (27.5%; 95% confidence interval [CI], 24.2 to 32.0; P<0.0001) and 2020 (41.4%; 95% CI, 37.0 to 46.0; P<0.0001). A COVID-19 diagnosis was present in 7.6% (132/1,738) of CVT hospitalizations. CVT was present in 0.04% (103/292,080) of COVID-19 hospitalizations. During the first pandemic year, CVT mortality was higher in patients who were COVID positive compared to COVID negative patients (8/53 [15.0%] vs. 41/910 [4.5%], P=0.004). There was an increase in CVT mortality during the first 5 months of pandemic years 2020 and 2021 compared to the first 5 months of the pre-pandemic year 2019 (2019 vs. 2020: 2.26% vs. 4.74%, P=0.05; 2019 vs. 2021: 2.26% vs. 4.99%, P=0.03). In the first 5 months of 2021, there were 26 cases of vaccine-induced immune thrombotic thrombocytopenia (VITT), resulting in six deaths. Conclusions During the 1st year of the COVID-19 pandemic, CVT hospitalization volume and CVT in-hospital mortality did not change compared to the prior year. COVID-19 diagnosis was associated with higher CVT in-hospital mortality. During the first 5 months of 2021, there was an increase in CVT hospitalization volume and increase in CVT-related mortality, partially attributable to VITT.

To evaluate whether the polygenic profile modifies the development of sporadic Alzheimer's disease (sAD) and pathological biomarkers in cerebrospinal fluid (CSF), 462 sAD patients and 463 age-matched cognitively normal (CN) controls were genotyped for 35 single-nucleotide polymorphisms (SNPs) that are significantly associated with sAD. Then, the alleles found to be associated with sAD were used to build polygenic risk score (PRS) models to represent the genetic risk. Receiver operating characteristic (ROC) analyses and the Cox proportional hazards model were used to evaluate the predictive value of PRS for the sAD risk and age at onset. We measured the CSF levels of Aβ42, Aβ42/Aβ40, total tau (T-tau), and phosphorylated tau (P-tau) in a subgroup (60 sAD and 200 CN participants), and analyzed their relationships with the PRSs. We found that 14 SNPs, including SNPs in the APOE, BIN1, CD33, EPHA1, SORL1, and TOMM40 genes, were associated with sAD risk in our cohort. The PRS models built with these SNPs showed potential for discriminating sAD patients from CN controls, and were able to predict the incidence rate of sAD and age at onset. Furthermore, the PRSs were correlated with the CSF levels of Aβ42, Aβ42/Aβ40, T-tau, and P-tau. Our study suggests that PRS models hold promise for assessing the genetic risk and development of AD. As genetic risk profiles vary among populations, large-scale genome-wide sequencing studies are urgently needed to identify the genetic risk loci of sAD in Chinese populations to build accurate PRS models for clinical practice.

Objective:To evaluate the association between the efficacy and safety of metformin and the influence of variants in SLC47A1 rs2289669 G>A polymorphism in the treatment of systemic lupus erythematosus (SLE).Methods:A multicenter, randomized, double-blind, placebo-controlled trial was conducted. Patients were consented at enrollment for blood donation for genotyping, and their peripheral blood were used to detect the distribution frequency of SLC47A1 mutations. The major or mild/moderate flares defined by modified safety lupus erythematosus national assessment (SELENA)-systemic lupus erythematosus disease activity index (SLEDAI) Flare Index (SFI) and adverse events were recorded at 12 months of follow-up. The correlation between efficacy/safety and genotype was analyzed. Student's t test and χ2 test was used to assess the continuous variables and categorical variables. Results:Between May 24, 2016, and Dec 13, 2017, a total of 31 patients in the metformin group and 35 in the placebo group were detected. There were no statistical significant differences in the clinical manifestations, SELENA-SLEDAI scores, and therapy of the participants at baseline. There was no significant difference in the frequency of AA genotype, GA genotype, and GG genotype of SLC47A1 rs2289669 distribution between the metformin group and the placebo group. In the metformin group, patients who flared had a lower frequency of A alleles than those non-flared [25%(4/16) vs 61%(28/46), χ2=6.116, P=0.019 8]; the flare rate was significantly lower in patients with AA genotype than in GG genotype [0%(0/8) vs 57%(4/7), χ2=6.234, P=0.012 5]. The infection rate was lower in the metformin group than that in the placebo group [38%(12/31) vs 69%(24/35), χ2=5.913, P=0.015 0], but there was no significant difference among different genotypes in the metformin group. Compared to GG geno-type, AA genotype showed a trend of decrease in infection rate[38%(3/8) vs 72%(5/7), χ2=1.727, P=0.188 8]. Conclusion:Metformin has a favorable safety profile and may reduce the frequency of flares in SLE patients with low-grade lupus disease activity. The metformin therapeutic efficacy in SLE is relevant to the SLC47A1 gene polymorphism. Patients of the AA genotype may benefit most from metformin than those of the GG and GA genotypes.