Bu-Shen-Ning-Xin decoction ameliorates premature ovarian insufficiency by suppressing oxidative stress through rno_circRNA_012284/rno_miR-760-3p/HBEGF pathway.

BACKGROUND: POI (premature ovarian insufficiency) refers to premature and rapid decline of ovarian reserve function in women before the age of 40, which can be manifested as menstrual disorders, endocrine abnormalities and low fertility. Bu-Shen-Ning-Xin decoction (BSNXD) has been found to have therapeutic effects on POI. Nevertheless, how it exerts therapeutic effects remains elusive. PURPOSE: This research aims to clarify the pharmacological mechanisms of BSNXD. METHODS: We applied Ultra Performance Liquid Chromatography (UPLC) to identify the main components of BSNXD.4-vinylcyclohexene diepoxide(VCD)was used to induce POI models. ELISA detected the serum level of hormones. H&E staining evaluated the morphology of ovarian tissues.CircRNA and mRNA expression profiles in the ovaries of both POI rats and those treated with BSNXD were detected. Then, dysregulated circRNAs and mRNAs that were potentially altered by BSNXD were screened. Network pharmacology analysis was performed to identify drug targets of BSNXD active ingredients. A circRNA-miRNA-mRNA network and an oxidative stress(OS)-related subnetwork were constructed. Expression of rno_circRNA_012284, rno_miR-760-3p, and HBEGF(Heparin-binding epidermal growth factor-like growth factor) was measured by RT-PCR and their binding were verified by dual-luciferase reporter assays. ROS was measured through DCFH-DA fluorescence probes. The HBEGF target was selected for molecular docking with key active ingredients.Surface plasmon resonance(SPR) was applied to verify the binding ability and affinity between components and HBEGF. RESULTS: UPLC analysis indicated that 6 chemical compounds including berberine, paeoniflorin, morroniside,gallic acid, loganin, baicalin were identified.Elevated FSH and LH levels, suppressed E2 and AMH levels in the serum, and inhibited follicles and corpus luteums in the ovarian tissues of VCD-induced rats were notably reversed by BSNXD.In total, 992 up- and 1135 down-regulated circRNAs, and 205 up- and 243 down-regulated mRNAs were found in POI rat ovaries following BSNXD administration. Furthermore, 198 drug targets of BSNXD were identified. An OS-related and BSNXD-targeted ceRNA subnetwork composed of rno_circRNA_012284/rno_miR-760-3p/HBEGF was established. rno_circRNA_012284 and HBEGF were up-regulated and rno_miR-760-3p was down-regulated in POI ovarian granulosa cells (OGCs) after BSNXD administration. rno_circRNA_012284 was a sponge of rno_miR-760-3p to elevate HBEGF expression. Moreover, rno_circRNA_012284 overexpression alleviated POI-induced excessive ROS generation in ovarian granulosa cells, while rno_circRNA_012284 inhibition exerted the opposite effect. Finally,molecular docking speculated active ingredients of each herb acted on HBEGF to reduce the OS. SPR tests showed that Berberine,Baicalein,Quercetin,Pachymic acid,Paeoniflorin exhibited satisfying affinity with HBEGF protein. CONCLUSION: This study demonstrates that BSNXD ameliorates POI partly by attenuating OS in ovarian granulosa cells via rno_circRNA_012284/rno_miR-760-3p/HBEGF axis, uncovering the pharmacological mechanisms of BSNXD in alleviating POI.

Genetic polymorphisms and their correlation with dyslipidemia in Chinese patients diagnosed with diabetes mellitus.

BACKGROUND: Dyslipidemia is a common complication in patients with diabetes mellitus (DM) that increases the risk of cardiovascular disease. Genetic polymorphisms have been implicated in the development of dyslipidemia. AIM: To investigate the association between polymorphisms of candidate genes involved in lipid metabolism and dyslipidemia in Chinese patients with DM. METHODS: A cross-sectional study was conducted on 1098 Chinese patients with DM recruited from multiple healthcare centers. Demographic and clinical data were collected, and dyslipidemia was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Genomic DNA was extracted from blood samples and genotyping for selected polymorphisms of candidate genes (APOE, LPL, CETP, and others) was performed using PCR and DNA sequencing techniques. Statistical analyses were performed using logistic regression models adjusted for potential confounding factors. RESULTS: The study population consisted of 578 males (52.6%) and 520 females (47.4%), with a mean age of 58.4 ± 12.2 years. The prevalence of dyslipidemia was 64.8%. Significant associations were found between dyslipidemia and the APOE rs7412 T/T, APOE rs429358 C/C, LPL rs328 G/G, and CETP rs708272 G/G genotypes after adjusting for covariates. Subgroup analyses showed generally consistent associations across subgroups, although some variations in effect sizes were observed. CONCLUSION: This study identified significant associations between genetic polymorphisms of APOE, LPL, and CETP genes and dyslipidemia in Chinese patients with DM.

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.

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.

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.

Rapid production of kilogram-scale graphene nanoribbons with tunable interlayer spacing for an array of renewable energy.

Graphene nanoribbons (GNRs) are widely recognized as intriguing building blocks for high-performance electronics and catalysis owing to their unique width-dependent bandgap and ample lone pair electrons on both sides of GNR, respectively, over the graphene nanosheet counterpart. However, it remains challenging to mass-produce kilogram-scale GNRs to render their practical applications. More importantly, the ability to intercalate nanofillers of interest within GNR enables in-situ large-scale dispersion and retains structural stability and properties of nanofillers for enhanced energy conversion and storage. This, however, has yet to be largely explored. Herein, we report a rapid, low-cost freezing-rolling-capillary compression strategy to yield GNRs at a kilogram scale with tunable interlayer spacing for situating a set of functional nanomaterials for electrochemical energy conversion and storage. Specifically, GNRs are created by sequential freezing, rolling, and capillary compression of large-sized graphene oxide nanosheets in liquid nitrogen, followed by pyrolysis. The interlayer spacing of GNRs can be conveniently regulated by tuning the amount of nanofillers of different dimensions added. As such, heteroatoms; metal single atoms; and 0D, 1D, and 2D nanomaterials can be readily in-situ intercalated into the GNR matrix, producing a rich variety of functional nanofiller-dispersed GNR nanocomposites. They manifest promising performance in electrocatalysis, battery, and supercapacitor due to excellent electronic conductivity, catalytic activity, and structural stability of the resulting GNR nanocomposites. The freezing-rolling-capillary compression strategy is facile, robust, and generalizable. It renders the creation of versatile GNR-derived nanocomposites with adjustable interlay spacing of GNR, thereby underpinning future advances in electronics and clean energy applications.

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.

Influence of impact velocity and impact attack angle of bullets on damage of human tissue surrogate -- ballistic gelatin.

PURPOSE: Terminal performance of a bullet in human body is critical for the treatment of gunshot injury and optimization of bullet design. The effects of the impact velocity (v0) and the impact attack angle (δ0) of the bullet on its terminal performance was investigated, using a new evaluation method (called expansion method) based on the expansion of cracks and the permanent cavity wall in ballistic gelatin. METHODS: Ballistic gelatin was used to simulate human body. The 7.62 mm × 39 mm rifle bullets with different v0 (600-760 m/s) and δ0 (0°-6°) were fired into the gelatin blocks. The gelatin block was cut into slices of about 20 mm thickness. The cracks and the permanent cavity on each slice were obtained manually. The damaged gelatin was determined using two methods: expanding the permanent cavity but ignoring the cracks, and expanding both the permanent cavity and the cracks. The relations between the damaged gelatin and v0 and δ0 were obtained using linear fitting method. RESULTS: According to the distribution of the damaged gelatin along the penetration depth, the damaged gelatin block could be divided into two parts: the less damaged part and the severely damaged part. The length of the less damaged part depends mostly on δ0; while the average damaged area of this part depends on both δ0 as well as v0. The cracks contributed significantly to the total volume of damaged gelatin, particularly when the expansion was larger than 1.9 mm. The total damaged gelatin increases with v0, δ0 and the expansion extent. The average length of equivalent cracks grew with v0 and δ0 when considering the cracks, and decreased with v0 when ignoring the cracks. CONCLUSION: The expansion method is suitable to investigate the influence of different factors of bullets on their terminal performance. The characteristics of the damaged gelatin have a linear relationship with the initial attack angle (δ0) and the initial velocity (v0) of the bullet.

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.

Detection and Phylogenetic Analysis of a Novel Tick-Borne Virus in Yunnan and Guizhou Provinces, Southwestern China.

Dabieshan tick virus (DTV) is a novel tick-borne virus with the potential to infect both animals and humans. It has been confirmed that DTV is widely distributed in Shandong and Zhejiang Provinces. In this study, a total of 389 ticks were sampled from Honghe city of Yunnan Province and Bijie city of Guizhou Province, and then divided into 148 pools according to the location and species. QRT-PCR and nested PCR were performed to confirm the presence of DTV. The results showed a minimum infection rate of 2.43% (5/206) in Yunnan Province and 3.28% (6/183) in Guizhou Province, respectively. Interestingly, DTV was identified in Rhipicephalusmicroplus for the first time besides Haemaphysalis longicornis. Phylogenetic analysis showed that DTV from Yunnan and Guizhou Provinces shared over 94% identity with isolates derived from Hubei and Shandong Provinces, and DTV was relatively conservative in evolutionary dynamics. These findings provide molecular evidence of Dabieshan tick virus in different species of ticks from unrecognized endemic regions and suggest that DTV may be widely prevalent in southwestern China.

The effect of dipeptidyl peptidase IV on disease-associated microglia phenotypic transformation in epilepsy.

BACKGROUND: Accumulating evidence suggests that disease-associated microglia (DAM), a recently discovered subset of microglia, plays a protective role in neurological diseases. Targeting DAM phenotypic transformation may provide new therapeutic options. However, the relationship between DAM and epilepsy remains unknown. METHODS: Analysis of public RNA-sequencing data revealed predisposing factors (such as dipeptidyl peptidase IV; DPP4) for epilepsy related to DAM conversion. Anti-epileptic effect was assessed by electroencephalogram recordings and immunohistochemistry in a kainic acid (KA)-induced mouse model of epilepsy. The phenotype, morphology and function of microglia were assessed by qPCR, western blotting and microscopic imaging. RESULTS: Our results demonstrated that DPP4 participated in DAM conversion and epilepsy. The treatment of sitagliptin (a DPP4 inhibitor) attenuated KA-induced epilepsy and promoted the expression of DAM markers (Itgax and Axl) in both mouse epilepsy model in vivo and microglial inflammatory model in vitro. With sitagliptin treatment, microglial cells did not display an inflammatory activation state (enlarged cell bodies). Furthermore, these microglia exhibited complicated intersections, longer processes and wider coverage of parenchyma. In addition, sitagliptin reduced the activation of NF-κB signaling pathway and inhibited the expression of iNOS, IL-1ß, IL-6 and the proinflammatory DAM subset gene CD44. CONCLUSION: The present results highlight that the DPP4 inhibitor sitagliptin can attenuate epilepsy and promote DAM phenotypic transformation. These DAM exhibit unique morphological features, greater migration ability and better surveillance capability. The possible underlying mechanism is that sitagliptin can reduce the activation of NF-κB signaling pathway and suppress the inflammatory response mediated by microglia. Thus, we propose DPP4 may act as an attractive direction for DAM research and a potential therapeutic target for epilepsy.

UAV assisted landing guided by UV LEDs.

Ultraviolet (UV) light communication has several advantages, including strong anti-interference ability, all-weather operation, and covert communications. In this paper, we built a landing assistance system for an unmanned aerial vehicle (UAV). In addition, we derived the formula of Lambertian power for UV LED. This formula is compared to the traditional line-of-sight (LOS) UV power formula in consideration of not only the area of the receiving aperture, but also the divergence angle of the UV LED. The simulation results show that with the increase of the receiver angle, the larger the divergence angle of the UV LED, the faster the UV power attenuation. When the receiver is not in the direction of the light source normal and the angle is fixed, there will be an optimal Lambertian order to make the receiver receive the maximum optical power at this angle. Finally, we did a set of outdoor experiments, which verified the correctness of the theoretical results.

The Mediating Effect of Alexithymia on the Relationship Between Schizotypal Traits and Sleep Problems Among College Students.

A body of research has investigated the relationship between alexithymia and sleep problems, as well as the relationship between schizophrenia and alexithymia. However, there have been few studies on the relationships between the three. The current study explored the relationship between schizotypal traits and sleep problems among college students, and the potential role of alexithymia as a mediator of this relationship. The participants were all first-year students at a medical university in Guangdong province, China. A total of 2,626 college students participated. They were asked to complete a questionnaire that incorporated the Schizotypal Personality Questionnaire (SPQ), the Toronto Alexithymia Scale (TAS-20), and the Insomnia Severity Index (ISI). The results revealed a relatively high percentage of students with mild insomnia (74.8%) and a smaller percentage with moderate to severe insomnia (7.9%). Correlation analysis revealed that both the TAS-20 and ISI scores had significant positive correlations with the SPQ score (p < 0.01). There was also a significant positive correlation between the TAS-20 and ISI scores (p < 0.01). The ISI score was significantly influenced by the SPQ score in a direct way, and increased considerably with increases in the TAS-20 score, indicating the importance of alexithymia as a mediator. The mediation model was tested via regression analysis and the bias-corrected bootstrap method, and these results further confirmed the role of alexithymia as a mediator.

Effectiveness of Cotreatment with Kuntai Capsule and Climen for Premature Ovarian Failure: A Meta-Analysis.

OBJECTIVE: To compare the treatment efficacy of Kuntai capsule with Climen only in the therapy of premature ovarian failure. METHODS: Randomized controlled trials were electronically retrieved from PubMed, Cochrane Library, Web of science, CBM, CNKI, Wanfang, and Weipu database. In addition, some related papers were manually checked. All papers were assessed according to the Cochrane Handbook for Systematic Reviews of Interventions, and the effective data were analyzed by Revman 5.3 Software. RESULTS: 11 randomized control trials involving 1068 patients were included. Results of meta-analysis showed that E2 (estrogen), the total therapeutic effective rate of the group of Kuntai capsule, and hormone were higher than hormone only. The LH (luteinizing hormone), FSH (follicle-stimulating hormone), and Kupperman score of the group of Kuntai capsule and Climen were lower than Climen only. CONCLUSION: Available evidence shows that Kuntai capsule with Climen is more effective than Climen in the therapy of premature ovarian failure. Nowadays, the quality of the research studies is low. More large-scaled randomized trials will need to be carried out.

Micro RNAs and the biological clock: a target for diseases associated with a loss of circadian regulation.

BACKGROUND: Circadian clocks are self-sustaining oscillators that coordinate behavior and physiology over a 24 hour period, achieving time-dependent homeostasis with the external environment. The molecular clocks driving circadian rhythmic changes are based on intertwined transcriptional/translational feedback loops that combine with a range of environmental and metabolic stimuli to generate daily internal programing. Understanding how biological rhythms are generated throughout the body and the reasons for their dysregulation can provide avenues for temporally directed therapeutics. SUMMARY: In recent years, microRNAs have been shown to play important roles in the regulation of the circadian clock, particularly in Drosophila, but also in some small animal and human studies. This review will summarize our current understanding of the role of miRNAs during clock regulation, with a particular focus on the control of clock regulated gene expression.

The Chemosensory Pleasure Scale: A New Assessment for Measuring Hedonic Smell and Taste Capacities.

Anhedonia, or the inability to experience pleasure, is a key clinical feature of many mental disorders such as depression and schizophrenia. Although various valid measurements of anhedonia and pleasure experience exist, no scales exist that quantify smell and taste pleasure experiences. The Chemosensory Pleasure Scale (CPS) was therefore designed to assess the hedonic capacity for smell and taste pleasure. We examined the reliability and validity of the CPS in our study. First, we conducted exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) to identify and examine the structure of the CPS. Second, the CPS's validity and test-retest stability were investigated. The CPS was correlated with other measurements of anhedonia and pleasure experience. Furthermore, the empirical validity of CPS was also examined in our study. The results indicated that the CPS is a reliable and valid measure for assessing an individual's hedonic capacity for smell and taste pleasure in nonclinical samples. Further application of the CPS for various populations is also discussed herein, especially for patients with mental disorders such as depression, schizophrenia, and autism.

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.