IL-33 aggravates extranodal NK/T cell lymphoma aggressiveness and angiogenesis by activating the Wnt/ß-catenin signaling pathway.

Extranodal NK/T cell lymphoma (ENKTCL) is an extremely aggressive form of lymphoma and lacks of specific diagnostic markers. The study intended to unearth the role of interleukin-33 (IL-33) in ENKTCL. RT-qPCR was conducted to assess mRNA levels of ENKTCL tissues and cells, while western blot assay was performed for evaluating protein levels. Plate cloning experiment and transwell assay were employed to measure aggressiveness of ENKTCL. Tube formation assay was executed to determine the angiogenesis ability. Mice ENKTCL xenograft model was designed to probe the impacts of IL-33 in vivo. IL-33 and suppression of tumorigenicity 2 receptor (ST2, receptor of IL-33) were enhanced in ENKTCL. IL-33 inhibition suppressed viability, migration, and invasion of ENKTCL cells. Moreover, IL-33 knockdown restricted angiogenesis in human umbilical vein endothelial cells (HUVECs). Furthermore, Wnt/ß-catenin pathway associated proteins (ß-catenin, c-myc, and cyclin D1) were downregulated by loss of IL-33. However, these impacts were overturned by Wnt/ß-catenin signaling agonist lithium chloride (LiCl). Additionally, IL-33 silencing exerted anti-tumor effect via Wnt/ß-catenin pathway in vivo. Silencing of IL-33 inhibited ENKTCL tumorigenesis and angiogenesis by inactivating Wnt/ß-catenin signaling pathway. As such, IL-33 might be a prospective treatment target for ENKTCL.

Mechanism Research of DHEA Treatment Improving Diminished Ovarian Reserve by Attenuating the AMPK-SIRT1 Signaling and Mitophagy.

This study aims to investigate the effect and mechanism of dehydroepiandrosterone (DHEA) on diminished ovarian reserve (DOR) by modulating the AMPK-SIRT1 signaling and mitophagy in rats. Three-month-old female Sprague-Dawley (SD) rats were randomized and injected intraperitoneally with sesame oil as the control or deoxyvinylcyclohexene (VCD) to induce DOR. The VCD-injected rats were randomized and injected subcutaneously with vehicle as the model group or with DHEA for 21 days as the DHEA group. After being identified in proestrus, rat blood samples were collected to prepare serum samples, and their ovarian tissues were dissected. Compared with the controls, significantly lower serum estradiol (E2), anti-Müllerian hormone (AMH), and inhibin B (IHNB) and higher follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were detected in the model group (DOR rats). The model group of rats displayed an increase in follicular atresia and a decrease in ovarian volume and the number of growing follicles and corpus luteum, accompanied by increased frequency of oocyte apoptosis and reduced levels of mitochondrial function. Furthermore, significantly higher levels of the AMPK-SIRT1 signaling and mitophagy were observed in the ovaries of rats in the model group. In contrast, treatment with DHEA significantly ameliorated the hormone disorder and morphological changes in the ovaries, reduced the frequency of apoptotic oocytes, and improved mitochondrial function in the ovaries of DOR rats. Mechanistically, DHEA treatment significantly attenuated the AMPK-SIRT1 signaling and mitophagy in the ovaries of DOR rats. DHEA treatment reduced the severity of DOR and enhanced ovarian reserve function by attenuating the AMPK-SIRT1 signaling and mitophagy in the ovaries of rats.

The Network Pharmacology Analysis of Tonifying Yang Formula for the Treatment of Diminished Ovarian Reserve.

Background: Diminished ovarian reserve (DOR) can lead to amenorrhea, infertility, and even the development of premature ovarian insufficiency, severely affecting the quality of life for women. Therefore, it is important to determine the main components of Tonifying Yang Formula, analyze the active substances and effective targets for treating DOR using Tonifying Yang Formula, and explore its potential mechanisms of action. Objective: The study is aim to determine the main components of Tonifying Yang Formula, analyze the active substances and effective targets for treating DOR using Tonifying Yang Formula, and explore its potential molecular mechanisms of action, providing important theoretical basis for clinical application. Methods: The main active components of Tonifying Yang Formula and their potential therapeutic targets for DOR were searched using the Chinese Medicine Systems Pharmacology Database and Analysis Platform, BATMAN-TCM, GeneCards, OMIM, and Uniprot databases. The protein-protein interaction network of shared targets between drugs and diseases was constructed using the STRING database. The shared targets of drugs and diseases were subjected to GO analysis and KEGG pathway enrichment analysis using the DAVID database. AutoDock Vina was used to perform molecular docking between the active substances and key targets of the drug to validate their interaction activities. Results: The key chemical components in the Tonifying Yang Formula for DOR treatment include quercetin, luteolin, beta-sitosterol, stigmasterol, and kaempferol. The 164 key targets for treating DOR with Tonifying Yang Formula included AKT1, TNF, JUN, TP53, IL6, IL1B, EGFR, VEGFA, INS, and CASP3, among others. GO enrichment analysis revealed that the Tonifying Yang Formula mainly regulates gene expression positively, negatively regulates the apoptotic process, and affects signal transduction. KEGG pathway enrichment analysis showed that Tonifying Yang Formula is mainly involved in cancer-related pathways, the AGE-RAGE signaling pathway in diabetic complications, prostate cancer, lipid and atherosclerosis, fluid shear stress and atherosclerosis, and the IL-17 signaling pathway. Molecular docking results indicated that the core components of the Tonifying Yang Formula had higher docking energies and stable binding with targets such as AKT1, IL6, JUN, TNF, and TP53. This study selected the PI3K/AKT signaling pathway for validation. Through experimental research, we found that Tonifying Yang Formula could improve ovarian reserve function by activating the PI3K/AKT signaling pathway. Conclusions: The potential mechanism of Tonifying Yang Formula therapy for DOR may be related to the influence of Chinese herbal compounds on pathways such as AKT1, IL6, JUN, TNF, and TP53, regulating the proliferation and apoptosis of ovarian granulosa cells, maintaining the function of the ovarian corpus luteum, regulating the secretion of related hormones, and alleviating ovarian tissue inflammation.

Glaucocalyxin A attenuates carbon tetrachloride-induced liver fibrosis and improves the associated gut microbiota imbalance.

Liver fibrosis refers to the pathophysiological process of dysplasia on the connective tissue of the liver, caused by a variety of pathogenic factors. Glaucocalyxin A (GLA) has anticoagulation, antibacterial, anti-inflammation, antioxidant and antitumour properties. However, whether GLA ameliorates liver fibrosis or not is still unclear. In this study, a liver fibrosis model was established using male C57BL/6 mice. The mice were treated with 5 and 10 mg/kg GLA via intraperitoneal injection, respectively. The ones that were treated with 5 mg/kg OCA were used as the positive control group. The levels of liver function, liver fibrosis biomarkers and liver pathological changes were then evaluated. We also explored the effects of GLA on inflammatory response and liver cell apoptosis. In addition, we investigated the gut microbiota mechanisms of GLA on liver fibrosis. The results from this study that GLA could significantly decrease the level of liver function (AST, ALT, TBA) and liver fibrosis (HA, LN, PC-III, IV-C). On the other hand, a significant decrease in inflammation levels (IL-1ß, TNF-α) were also noted. GLA also improves CCl4-induced pathological liver injuries and collagen deposition, in addition to decreasing apoptosis levels. In addition, an increase in the ratio of Bacteroidetes and Firmicutes in liver disease was also observed. GLA also improves the gut microbiota. In conclusion, GLA attenuates CCl4-induced liver fibrosis and improves the associated gut microbiota imbalance.

Treatment of Polycystic Ovary Syndrome-Related Infertility Using a Combination of Compound Xuanju Capsules and Hormones: A Meta-Analysis.

Objective: Our aim was to perform a meta-analysis to compare the therapeutic effects of compound Xuanju capsules combined with hormone therapy vs hormone therapy alone in polycystic ovary syndrome (PCOS)-related infertility. Methods: Electronic databases including PubMed, The Cochrane Library, Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang Data and VIP database were manually searched. The quality of included studies was evaluated based on Cochrane Systematic Review standards, and the valid data were extracted for meta-analysis using RevMan 5.3 software (Cochrane Review). Results: A total of 14 randomized controlled trials (RCTs) including 1249 patients were included in the study. Meta-analysis showed that patients in the compound Xuanju capsule + hormone therapy group had higher estradiol (E2) levels and overall rates of effective treatment than patients in the hormone therapy alone group. Moreover, they exhibited lower levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), as well as lower Kupperman scores, than the hormone therapy alone group. Conclusions: The combination of compound Xuanju capsules and hormone therapy is more effective than hormone therapy alone in the treatment of PCOS-related infertility. However, the quality of current studies is low, and high-quality clinical trials are warranted.

Treatment of Circadian Disorder with Premature Ovarian Insufficiency With the Nourishing Yin and Tonifying Yang Sequential Method with Femoston.

Objective: The clinical effects of the nourishing Yin and tonifying Yang sequential method with Femoston was explored in treating circadian disorder with premature ovarian insufficiency (POI). Method: We enrolled 600 patients with circadian disorder and POI in a prospective study and divided the patients into 2 groups: an experimental and a control group. Both groups were treated with Femoston and the experimental group also received nourishing Yin and tonifying Yang sequential method. We observed the overall response rate, Kupperman Index, number of adverse events, and the levels of prostaglandin E2 (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), total cholesterol (TC), triglycerices (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), as well as peak systolic velocity (PSV), pulsatility index (PI), resistance index (RI), maximum ovarian diameter (MOD) and antral follicle count (AFC). Results: The experimental group also exhibited elevated TC, TG, LDL-C, MOD and AFC after treatment, whereas the control group did not. Compared with the control group, the experimental group had a higher overall response rate, E2, FSH, LH, HDL-C, PSV, MOD, AFC, a lower Kupperman Index, TC, TG, LDL-C, PI, RI and number of adverse events. Conclusions: In patients with circadian disorder with POI, the nourishing Yin and tonifying Yang sequential method with Femoston improved ovarian function, blood supply to the ovaries and sex hormone levels and lowered blood lipids with acceptable safety parameters.

Clinical efficacy of cisplatin, dexamethasone, gemcitabine and pegaspargase (DDGP) in the initial treatment of advanced stage (stage III-IV) extranodal NK/T-cell lymphoma, and its correlation with Epstein-Barr virus.

Objective: To evaluate the clinical efficacy and safety of the DDGP regimen in treating extranodal NK/T-cell lymphoma and investigate the correlation between Epstein-Barr virus (EBV)-DNA variation after treatment and the clinical efficacy of NK/T-cell lymphoma. Methods: Sixty-four patients with extranodal NK/T-cell lymphoma received DDGP regimen-based chemotherapy. Short-term and long-term clinical efficacy and adverse reactions were observed. The relationship between EBV-DNA changes before and after therapy and clinical efficacy was investigated. Results: After the DDGP regimen was used as the initial treatment, the short-term clinical efficacy included 39 complete remission (CR) (60.94%), 12 partial remission (PR) (18.75%), 2 stable disease (SD) (3.13%) and 11 progressive disease (PD) (17.18%). Objective response rate (ORR) was 79.69% and 82.82% for disease control rate (DCR). 3-year progression-free survival (PFS) was 62.00% and 3-year overall survive (OS) was 74.90%. Hemocytopenia was the predominant adverse effect. Between EBV-DNA positive group and its negative counterpart, a significant difference was noted in OS (P=0.046), but no difference in ORR, DCR or PFS was observed. In the EBV-DNA positive group, ORR, DCR, PFS and OS were higher for patients whose EBV-DNA copy number decreased within a normal range than patients remained positive (93.33% versus 61.53%, P=0.041 for ORR; 93.33% versus 61.53%, P=0.041 for DCR, P=0.003 for PFS, P=0.017 for OS). The main adverse reactions included bone marrow suppression, gastrointestinal reaction and coagulation dysfunction, which were mitigated and treated after expectant or dose-decrement treatment. Conclusion: DDGP regimen can significantly improve the clinical prognosis of NK/T-cell lymphoma patients with tolerable adverse reactions. The variation in EBV-DNA is correlated with clinical efficacy and prognosis, which provides a theoretical basis for NK/T-cell lymphoma therapy. Clinical trial: In November 2011, this clinical trial was registered on the website: www.ClinicalTrials.gov (No. NCT01501149).

Efficacy of dose-adjusted EPOCH plus rituximab/R-CHOP regimens and the prognosis analysis in patients with MYC, BCL2/BCL6 gene copy number gain lymphoma and double-hit lymphoma: results from a single institution retrospective clinical study.

PURPOSE: To compare the efficacy of rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-DA-EPOCH) with traditional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimens in double-hit lymphoma (DHL) and gene copy number gain (CNG) lymphoma and to contrast the prognosis of these two disease types. METHODS: We retrospectively examined 127 cases of newly diagnosed diffuse large B-cell lymphoma (DLBCL), and used fluorescence in situ hybridization (FISH) to detect genetic abnormalities in MYC, BCL2, and BCL6. RESULTS: In the two schemes, the 2-year progression-free survival (PFS) was higher for R-DA-EPOCH group than for R-CHOP (79.8% vs 57.5%, P=0.002), this advantage was also reflected in 2-year overall survival (OS) (81.6% vs 58.5%, P=0.002). In double CNG patients, R-DA-EPOCH regimen was significantly better than R-CHOP (P=0.007 for PFS, P=0.010 for OS), and R-DA-EPOCH has the same advantage in DHL patients (P=0.001 for PFS, P=0.047 for OS). For the two disease types, the PFS for DHL was inferior to that for double CNG (52.9% vs 72.4%, P=0.008), while the OS was not significantly different (P=0.050). Subgroup analysis showed that the PFS for double CNG with MYC and BCL2 was superior to that for DHL with MYC and BCL2 (P=0.043), this trend is also seen in double CNG and DHL with MYC and BCL6 (P=0.036). However, the OS was not significantly different between the two subgroups. Multivariate analyses showed that in DLBCL patients with genetic abnormality detected by FISH, the treatment and disease types were independent prognostic factors. The adverse reaction rates were similar in R-DA-EPOCH and R-CHOP (P>0.05). CONCLUSION: Our retrospective study shows that DHL has a poorer prognosis than double CNG. Based on its improved lifetime and good tolerance, R-DA-EPOCH is a promising regimen for DHL or double CNG, which is expected to become the first-line treatment for high-risk DLBCL types based on more clinical research.

Regulation of the MAPK signaling pathway by miR-421-5p in rats under light pollution.

The present study aimed to explore the difference in the expression profiles of ovarian microRNA sequences in rats in a light pollution environment and rats in a normal light environment. Rats in the control group were exposed to 12­h light/dark cycles, while rats in the model group were continuously exposed to 24­h light. The ovaries were extracted from the two groups of rats, and Illumina HiSeq 2500 high­throughput sequencing technology was used to detect the differences in microRNA (miRNA) expression among the two groups. Fluorescence quantitative reverse transcription­polymerase chain reaction was used to verify the differential expression of miRNA. The present study was designed to experimentally validate the interaction between miR­421­5p and mitogen­activated protein kinase (MAPK) 7 by using the dual­luciferase reporter system, and to explore the expression of proteins in the MAPK signaling pathway with a lentiviral vector­mediated small hairpin RNA interference against microRNA­421­5p. The expression of 45 miRNAs was significantly different. In total, 13 miRNAs were upregulated, of which 5 miRNA sequences were known and 8 were predicted. Furthermore, 32 miRNAs were downregulated, of which 11 miRNA sequences were known and 21 were predicted. The results of the luciferase reporter assay confirmed the targeting association between miR­421­5p and MAPK7. The expression levels of MAPK and genes in its downstream signaling pathways, including c­Fos, CREB and c­Myc, were downregulated when miR­421­5p was overexpressed and upregulated when miR­421­5p was silenced. The differential expression of miRNAs may serve an important role in the development of the ovary in a light pollution environment. miR­421­5p may regulate ovarian growth and development by targeting the MAPK signaling pathway in light polluted rat ovaries.

Design, synthesis and biological evaluation of phthalimide-alkylamine derivatives as balanced multifunctional cholinesterase and monoamine oxidase-B inhibitors for the treatment of Alzheimer's disease.

A series of novel phthalimide-alkylamine derivatives were synthesized and evaluated as multi-functions inhibitors for the treatment of Alzheimer's disease (AD). The results showed that compound TM-9 could be regarded as a balanced multi-targets active molecule. It exhibited potent and balanced inhibitory activities against ChE and MAO-B (huAChE, huBuChE, and huMAO-B with IC50 values of 1.2µM, 3.8µM and 2.6 µM, respectively) with low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-9 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Interestingly, compound TM-9 abided by Lipinski's rule of five. Furthermore, our investigation proved that TM-9 indicated weak cytotoxicity, and it could cross the blood-brain barrier (BBB) in vitro. The results suggest that compound TM-9, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.

Design, synthesis and biological evaluation of 2-acetyl-5-O-(amino-alkyl)phenol derivatives as multifunctional agents for the treatment of Alzheimer's disease.

A series of 2-acetyl-5-O-(amino-alkyl)phenol derivatives was designed, synthesized and evaluated as multi-function inhibitors for the treatment of Alzheimer's disease (AD). The results revealed that compound TM-3 indicated selective AChE inhibitory potency (eeAChE, IC50 = 0.69 µM, selective index (SI) = 32.7). Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-3 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. And TM-3 was also a highly selective MAO-B inhibitor (IC50 = 6.8 µM). Moreover, TM-3 could act as antioxidant (ORAC value was 1.5eq) and neuroprotectant, as well as a selective metal chelating agent. More interestingly, compound TM-3 could cross the blood-brain barrier (BBB) in vitro and abided by Lipinski's rule of five. Therefore, compound TM-3, a promising multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against AD.

Effectiveness of co-treatment with traditional Chinese medicine and letrozole for polycystic ovary syndrome: a meta-analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is an endocrine disease that affects gynecological health. Treatment of PCOS remains a big challenge for clinicians. OBJECTIVE: This meta-analysis was developed to compare the efficacy of co-treatment with traditional Chinese medicine (TCM) and letrozole against letrozole monotherapy in the treatment of PCOS. SEARCH STRATEGY: Randomized controlled trials (RCTs) were electronically retrieved from PubMed, Cochrane Library, China Biomedical Literature Database, China National Knowledge Infrastructure and Wanfang Data; related papers that were not available electronically were manually checked. All papers were assessed according to the Cochrane Handbook for Systematic Reviews of Interventions and the valid data were analyzed using Revman software (The Cochrane Collaboration, Copenhagen, Denmark). INCLUSION CRITERIA: We included RCTs that compared co-treatment with TCM and letrozole against letrozole monotherapy in women with PCOS, which was defined by anovulation, biochemical or clinical hyperandrogenemia and polycystic ovaries. We included trials from all sources. DATA EXTRACTION AND ANALYSIS: Two independent reviewers extracted data, and evaluated study quality according to the Cochrane Handbook for Systematic Reviews of Interventions criteria for RCT, including issues of patient randomization, blinding and bias. RESULTS: Eight RCTs, involving a total of 537 patients, were included in the present study. The meta-analysis showed that the cycle ovulation rate, the pregnancy rate and the total effective rate of symptom treatment were higher in treatments combining TCM with letrozole, compared with letrozole monotherapy. Although the rate of luteinizing hormone (LH)/follicle-stimulating hormone (FSH) and the body mass index of the group receiving combined therapy were lower than in letrozole monotherapy, no statistical difference was found in the LH and FSH level between the two groups. CONCLUSION: Available evidence showed that co-treatment with TCM and letrozole was more effective than letrozole monotherapy in the treatment of PCOS.