The effect of GnRH analog treatment on BMI in children treated for precocious puberty: a systematic review and meta-analysis.

INTRODUCTION: The purpose of the present meta-analysis was to systematically evaluate the effect of GnRHa treatment on the BMI of children with precocious puberty after GnRHa treatment as compared to before, and to analyze the effect of GnRHa treatment on the body composition of children with precocious puberty at different BMIs by classifying into normal body mass, overweight, and obese groups according to BMI at the time of initial diagnosis. CONTENT: A meta-analysis was performed using Stata 12.0 software by searching PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP database), and Wan fang database for relevant literature on standard deviation score of body mass index (BMI-SDS) after GnRHa treatment as compared to before in children with precocious puberty. SUMMARY: A total of eight studies were included with a total sample size of 715 cases, and the results of meta-analysis showed that BMI-SDS increased in children with precocious puberty after GnRHa treatment as compared to before starting [(weighted mean difference (WMD)=0.23, 95 % CI: 0.14-0.33, p=0.000)] and also increased in children with normal body mass [(WMD=0.37, 95 % CI: 0.28-0.46, p=0.000)], and there was no significant change in BMI-SDS in children in the overweight or obese group [(WMD=0.01, 95 % CI: -0.08-0.10, p=0.775)]. OUTLOOK: Overall, there was an observed increase in BMI-SDS at the conclusion of GnRHa treatment in children with precocious puberty. Additionally, it was found that the effect of GnRHa treatment on body composition varied among children with different BMI status. Clinicians should emphasize the promotion of a healthy lifestyle and personalized dietary management for children.

SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization.

The function of SLC7A11 in the process of ferroptosis is well-established, as it regulates the synthesis of glutathione (GSH), thereby influencing tumor development along with drug resistance in non-small cell lung cancer (NSCLC). However, the determinants governing SLC7A11's membrane trafficking and localization remain unknown. Our study identified SPTBN2 as a ferroptosis suppressor, enhancing NSCLC cells resistance to ferroptosis inducers. Mechanistically, SPTBN2, through its CH domain, interacted with SLC7A11 and connected it with the motor protein Arp1, thus facilitating the membrane localization of SLC7A11 - a prerequisite for its role as System Xc-, which mediates cystine uptake and GSH synthesis. Consequently, SPTBN2 suppressed ferroptosis through preserving the functional activity of System Xc- on the membrane. Moreover, Inhibiting SPTBN2 increased the sensitivity of NSCLC cells to cisplatin through ferroptosis induction, both in vitro and in vivo. Using Abrine as a potential SPTBN2 inhibitor, its efficacy in promoting ferroptosis and sensitizing NSCLC cells to cisplatin was validated. Collectively, SPTBN2 is a potential therapeutic target for addressing ferroptosis dysfunction and cisplatin resistance in NSCLC.

Efficacy and safety of Chinese patent medicine Xiao Yao San in polycystic ovary syndrome: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Polycystic ovary syndrome (PCOS) is one of the most common endocrine-metabolic disorders in women of reproductive age worldwide. Previous studies using randomized controlled trials (RCTs) have revealed that Xiao Yao San (XYS), a classic Chinese patent medicine formula, can effectively treat PCOS. However, the entire evidence has yet to be systematically summarized. AIM OF THE STUDY: The aim of this systematic review and meta-analysis of clinical trials was to assess the effect of XYS for the treatment of PCOS. MATERIALS AND METHODS: 7 databases were thoroughly reviewed for RCTs published from inception to July 2022, assessing the effect of XYS in treating PCOS, including Cochrane Library, PubMed, Embase, Wan Fang Database, Chinese Biomedical Database, China National Knowledge Infrastructure, and China Science and Technology Journal Database. Outcome measures included ovulation rate, pregnancy rate, hormonal levels, and glycemic parameters. Either a random-effects model or a fixed-effect models was used to pool data. Pooled effect sizes were reported as odds ratios (ORs) or standardized mean differences (SMDs) with their 95% confidence intervals (CIs). RESULTS: A total of 9 trials including 736 PCOS patients met the selection criteria. Our results indicate that XYS plus conventional medicines for PCOS significantly improved ovulation rate (OR = 2.45, 95% CI = 1.94 to 3.08, P < 0.001) and pregnancy rate (OR = 2.65, 95% CI = 1.87 to 3.75, P < 0.001), meanwhile decreased levels of fasting insulin (FINS) (SMD = - 0.46, 95% CI: 0.65 to - 0.27, P < 0.001) and homeostatic model assessment for insulin resistance (HOMA-IR) (SMD = - 0.65, 95% CI = - 0.93 to - 0.37, P < 0.001). XYS plus conventional medicines for PCOS did not have a significant impact on levels of total testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and fasting plasma glucose (FPG). No serious adverse reactions were observed. CONCLUSION: XYS combined with conventional medicines can improve ovulation and pregnancy rates, decrease FINS and HOMA-IR in PCOS patients, indicating that XYS treatment may be used as a promising adjuvant therapy to the conventional medicines of PCOS. However, due to significant heterogeneity and methodological shortcomings, these results should be interpreted with great caution. Larger, higher quality RCTs are needed to rigorously assess the effect of XYS as a complementary therapy in managing PCOS.

LncRNA HHIP-AS1 suppresses lung squamous cell carcinoma by stabilizing HHIP mRNA.

AIMS: Lung squamous cell carcinoma (LUSC) causes over 400,000 deaths annually, yet it lacks targeted therapy. A major antagonist of Hedgehog pathway, HHIP (Hedgehog Interacting Protein) plays an important role in LUSC; however, the regulatory mechanism remains unclear. Long non-coding RNA HHIP-AS1 plays suppressive or promotive roles in different cancers, but its role in LUSC remains unknown. This manuscript is to investigate regulatory mechanism of HHIP and the role of HHIP-AS1 in LUSC. MAIN METHODS: Precision-cut lung slices (PCLS) from human LUSC samples are cultured to mimic LUSC growth. Overexpression and knockdown in multiple LUSC cell lines and PCLS are achieved by lentivirus infection. Transcriptome profile and lung cancer activity are evaluated by RNA-sequencing, immunostaining and CCK8 assay etc. KEY FINDINGS: HHIP is regulated independently of Hh pathway in LUSC. Additionally, downregulation of HHIP-AS1 is associated with poor prognosis. Consistently, HHIP-AS1 inhibits LUSC growth by suppressing cell proliferation and migration. Transcriptome profiling of HHIP-AS1 knockdown (KD) cells uncovered HHIP downregulation. Interestingly, a comparison between the transcriptomes of HHIP-AS1 KD or HHIP KD cells manifested high similarity. Subsequently it's confirmed that HHIP-AS1 regulates HHIP in LUSC cells. Notably, HHIP-AS1 regulation on LUSC growth is achieved through stabilizing HHIP mRNA rather than regulating MIR-153-3P/PCDHGA9 or MIR-425-5P/DNYC1I2. Finally, it's confirmed in PCLS from human LUSC samples that HHIP-AS1 suppresses LUSC via regulating HHIP mRNA. SIGNIFICANCE: This study uncovers HHIP-AS1 as a novel tumor suppressor in LUSC and provides new insights into the molecular regulation of LUSC, which will help developing new therapeutic strategies.

Icariin attenuates the tumor growth by targeting miR-1-3p/TNKS2/Wnt/ß-catenin signaling axis in ovarian cancer.

Purpose: Despite various therapy advances, ovarian cancer remains an incurable disease for which survival rates have only modestly improved. Natural products are important sources of anti-cancer lead compounds. Icariin exhibited broad anti-cancer efficacy. However, the mechanism of icariin against ovarian cancer is poorly elucidated. Methods: Cell viability was detected to evaluate the effect of icariin on SKOV-3 cells. The cell cycle and apoptosis were analyzed. The transcript of SKOV-3 cells was profiled by RNA-seq. GSEA and DEGs analyses were performed to interpret gene expression data. Western blot and TOP/FOP flash assay were applied to detect Wnt/ß-catenin signaling. MiRDB database and dual-luciferase reporter assay was applied to study the regulation of miR-1-3p on TNKS2. Anti-tumor efficacy of icariin was evaluated by xenograft mouse model. Immunohistochemistry was performed with antibodies against Ki67. Results: Icariin significantly suppressed the proliferation of SKOV-3 cells. Furthermore, icariin stalled cell cycle and induced apoptosis by blocking TNKS2/Wnt/ß-catenin pathway through upregulating the level of miR-1-3p. Finally, icariin dramatically suppressed tumor growth in vivo. Conclusions: In this study, we demonstrated for the first time that icariin significantly attenuated the growth of ovarian tumor in xenograft mouse model. Furthermore, we systematically revealed that icariin attenuates the tumor progression by suppressing TNKS2/Wnt/ß-catenin signaling via upregulating the level of miR-1-3p in ovarian cancer with transcriptome analysis.

Proapoptotic Effect of Icariin on Human Ovarian Cancer Cells via the NF-[Formula: see text]B/PI3K-AKT Signaling Pathway: A Network Pharmacology-Directed Experimental Investigation.

Based on network pharmacology tools and public bioinformatics databases, the pharmacodynamic target and key mechanism of icariin (ICA) in the treatment of ovarian cancer (OC) were identified and experimentally verified. Our previous research showed that TNF, MMP9, STAT3, PIK3CA, ERBB2, MTOR, IL2, PTGS2, KDR and F2 are important targets of ICA in the treatment of OC. TNF, as a hub gene in tumor tissues, was associated with poor prognosis. ICA acted on OC mainly through the biological functions of various kinases, and the pathway with the highest accuracy ([Formula: see text]-value) was PI3K. Meanwhile, we observed a close upstream and downstream relationship between NF-[Formula: see text]B and the Pl3K-AKT pathway. This study further verified the mechanism of ICA in promoting apoptosis of SKOV3 cells through the NF-[Formula: see text]B signaling pathway and the tandem relationship between NF-[Formula: see text]B and the Pl3K-AKT pathway. The assay results demonstrated that ICA can promote the apoptosis of SKOV3 cells as indicated by the proapoptotic markers Bax, Bcl-xl and Caspase-3 and the key factors of the NF-[Formula: see text]B signaling pathway (NF-[Formula: see text]Bp65, p-NF-[Formula: see text]Bp65, p-I[Formula: see text]B[Formula: see text] and I[Formula: see text]B[Formula: see text]. ICA can block the classical NF-[Formula: see text]B pathway by inhibiting I[Formula: see text]B[Formula: see text] phosphorylation and consequently blocking the activation of the NF-[Formula: see text]B pathway in SKOV3 cells. ICA can also promote apoptosis by blocking the activation of the NF-[Formula: see text]B pathway in SKOV3 cells via inhibition of NF-[Formula: see text]Bp65 nuclear translocation. After using a PI3K pathway inhibitor, we further discovered that ICA may reduce AKT signal transduction by inhibiting the level of Akt phosphorylation, resulting in a loss of PI3K/Akt-dependent activation of the NF-[Formula: see text]B pathway.

In silico analysis identifies neuropilin-1 as a potential therapeutic target for SARS-Cov-2 infected lung cancer patients.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), and is highly contagious and pathogenic. TMPRSS2 and Neuropilin-1, the key components that facilitate SARS-CoV-2 infection, are potential targets for treatment of COVID-19. Here we performed a comprehensive analysis on NRP1 and TMPRSS2 in lung to provide information for treating comorbidity of COVID-19 with lung cancer. NRP1 is widely expressed across all the human tissues while TMPRSS2 is expressed in a restricted pattern. High level of NRP1 associates with worse prognosis in multiple cancers, while high level of TMPRSS2 is associated with better survival of Lung Adenocarcinoma (LUAD). Moreover, NRP1 positively correlates with the oncogenic Cancer Associated Fibroblast (CAF), macrophage and endothelial cells infiltration, negatively correlates with infiltration of CD8+ T cell, the tumor killer cell in Lung Squamous cell carcinoma (LUSC). TMPRSS2 shows negative correlation with the oncogenic events in LUAD. RNA-seq data show that NRP1 level is slightly decreased in peripheral blood of ICU admitted COVID-19 patients, unaltered in lung, while TMPRSS2 level is significantly decreased in lung of COVID-19 patients. Our analysis suggests NRP1 as a potential therapeutic target, while sets an alert on targeting TMPRSS2 for treating comorbidity of COVID-19 and lung cancers.

Clinical features and development of Sepsis in Klebsiella pneumoniae infected liver abscess patients: a retrospective analysis of 135 cases.

BACKGROUND: Klebsiella pneumoniae is a primary pathogen of pyogenic liver abscess (PLA). However, little data are available on combination with sepsis. In this study, we aimed to evaluate the clinical characteristics and prognostic differences of PLA patients with sepsis. METHODS: This retrospective cohort study was conducted to investigate 135 patients with confirmed Klebsiella pneumoniae-caused liver abscesses (KPLA) from a tertiary teaching hospital, from 2013 to 2019. The patients were divided into two groups, KPLA with sepsis and KPLA without sepsis. The demographic characteristics, clinical features as well as laboratory and microbiologic findings were analyzed. RESULTS: A total of 135 patients with KPLA were analyzed. The mean age of patients was 60.9 ± 12.7 years, and the percentage of men was 59.3%. Among them, 37/135 (27.4%) of patients had sepsis and the mortality rate was 1.5%. The most common symptom was fever (91.1%). KPLA patients with sepsis had a significantly higher proportion of frailty, diarrhea, fatty liver, chronic renal insufficiency, and hepatic dysfunction compared to KPLA patients without sepsis (p < 0.05). Antibiotic therapy and percutaneous drainage were most frequently therapeutic strategy. Furthermore, the incidences of sepsis shock and acute respiratory distress syndrome were higher in the sepsis group compared to the non-sepsis group. As for metastatic infections, the lung was the most common site. In addition, KPLA patients with sepsis showed respiratory symptoms in 11 patients, endophthalmitis in 4 patients, and meningitis in 1 patient. CONCLUSION: Our findings emphasize that KPLA patients combined with or without sepsis have different clinical features, but KPLA patients with sepsis have higher rates of complications and metastatic infections. Taken together, further surveillance and control of septic spread is essential for KPLA patients.

Study on the regulatory mechanism and experimental verification of icariin for the treatment of ovarian cancer based on network pharmacology.

ETHNOPHARMACOLOGICAL RELEVANCE: Herba Epimedii (Berberidaceae) has the advantages of "nourishing the kidney and reinforcing the Yang". Many species in this genus have long been used in traditional Chinese medicine (TCM) and have been used as anticancer drugs in traditional Chinese herbal medicine formulations. Icariin, a major flavonoid glycoside extracted from Epimedium brevicornum Maxim, has been widely proven to exert an inhibitory effect on ovarian cancer (OC), and icariin can induce apoptosis and inhibit invasion and migration. However, the underlying mechanism remains unclear, so further research is necessary to verify its traditional use. AIM OF THE STUDY: This study aimed to explore the regulatory mechanism of icariin in the biological network and signalling pathway of OC through network pharmacology and cytological experiments. METHODS: Public databases and R × 3.6.2 software were adopted to predict the potential targets, construct the protein-protein interaction (PPI) network, and perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. After the network pharmacological analysis, cytological experiments, real-time quantitative PCR (qPCR) and Western blot (WB) analyses were used to verify the key signalling pathway. RESULTS: The targets related to treatment were TNF, MMP9, STAT3, PIK3CA, ERBB2, MTOR, IL2, PTGS2, KDR, and F2. GO and KEGG enrichment analyses indicated that various kinases and the PI3K/AKT signalling pathway were the most enriched molecules and pathways. Icariin inhibited OC SKOV3 cell proliferation, migration and invasion in vitro and promoted apoptosis by inhibiting the PI3K/AKT signalling pathway. CONCLUSION: Icariin promotes apoptosis and suppresses SKOV3 cell activities through the PI3K-Akt signalling pathway. This research not only provides a theoretical and experimental basis for more in-depth studies but also offers an efficient method for the rational utilization of a series of icariin flavonoids as anti-tumour drugs.

The prognostic relevance and expression of progranulin in adult patients with acute myeloid leukemia.

Progranulin (PGRN) is a secreted protein that can regulate cell cycle progression, cell motility, and tumorigenesis. The PGRN expression in hematological malignancies is limited to multiple myeloma, but its expression and survival prognostic role in acute myeloid leukemia (AML) is still controversial.To evaluate the PGRN expression and estimate its survival prognostic role in AML patients.In this study, all patients were divided into three groups, which included 38 newly diagnosed adult AML patients, 33 complete remissions (CR-AML) patients, and 60 healthy control (HC) patients. The endpoints were relapse-free survival (RFS) and overall survival (OS). We investigated plasma PGRN levels by using enzyme-linked immunosorbent assay.Plasma PGRN levels in AML patients were higher than that in CR-AML and HC groups. After two chemo cycles, 16 patients had complete remission (CR). The level of plasma PGRN in non-CR patients compared to CR patients was obviously different (median 44.19 vs 21.10 ng/mL) (P = .025). In non-M3 (French-American-British classification) patients, 70% (21/30) patients relapsed in 1 year and 80% (24/80) patients died in the observed time. Using the value (median 19.95) as a "cut-off" value, we have divided non-M3 patients into low- and high-PGRN expression groups. High-PGRN expression patients had a poorer RFS with a median of 5.4 months (95% CI 3.7-7.1) and low-PGRN expression patients had a good RFS with a median of 8.9 months (95% CI 6.3-11.5; P = .027). In the survival analyses, high-PGRN expression of AML patients had shorter OS than low-PGRN expression of AML patients (6.2 vs 20.5 months, P = .008).PGRN is overexpressed in AML, which is a convenient and independent prognostic marker that is measured easily in AML patients.

Rutaecarpine Suppresses Proliferation and Promotes Apoptosis of Human Pulmonary Artery Smooth Muscle Cells in Hypoxia Possibly Through HIF-1α-Dependent Pathways.

PURPOSE: The aim of this study is to investigate the potential roles of Rutaecarpine (Rut) in hypoxia-induced human pulmonary artery smooth muscle cells (HPASMCs) model. METHODS: HPASMCs were cultured with or without hypoxia followed by Rut administration. Cytotoxicity and cell proliferation were assessed by CCK-8 and Cell counting method. Flow cytometry was used for the measurement of cell apoptosis rates. The mRNA expression of hypoxia-induced factor (HIF)-1α and protein levels of HIF-1α, p53, p21, erythropoietin, and vascular endothelial growth factor were determined by quantitative real-time polymerase chain reaction and Western blot, respectively. RESULTS: Rut inhibited the proliferation of HPASMCs with IC50 value of 43.5 µmol·L. Hypoxia significantly increased proliferation and decreased apoptosis in HPASMCs, whereas Rut rescued this phenomenon at the appropriate concentration. Meanwhile, Rut effectively decreased the protein and mRNA expressions of HIF-1α. Knockdown of HIF-1α expression by small interfering RNA (siRNA) significantly enhanced the proapoptotic effect rather than antiproliferation effect of Rut in HPASMCs. Moreover, Rut simultaneously reduced proliferating cell nuclear antigen protein expression, whereas increased p53 and p21 protein levels. However, no significant difference was observed in the protein levels of vascular endothelial growth factor and erythropoietin. CONCLUSIONS: Our results demonstrated that Rut exerted protective effects on HPASMCs against hypoxia partly through the HIF-1α-dependent signaling pathway.