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Qi Wang,1,2,* Wen-Na Li,3,* Wuxiyar Otkur,4 Yu Cui,1 Hui-Sheng Chen1,2 1Department of Neurology, General Hospital of Northern Theater Command, Shenyang, 110016, People’s Republic of China; 2Dalian Medical University, Dalian, People’s Republic of China; 3Department of Neurology, Tangshan Central Hospital, Tangshan, People’s Republic of China; 4School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui-Sheng Chen, Department of Neurology, General Hospital of Northern Theater Command, 83 Wen Hua Road, Shenyang, 110016, People’s Republic of China, Tel +86 024 28897511, Email chszh@aliyun.comBackground: We conducted a post-hoc analysis of the RICAMIS trial to investigate the effect of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) on the efficacy of remote ischemic conditioning treatment.Methods: In this post-hoc analysis, NLR, PLR, and SII were measured before randomization. Patients were divided into two groups based on their cut-off values: high vs low NLR, high vs low PLR, and high vs low SII groups. Each group was further subdivided into RIC and control groups. The primary endpoint was a poor outcome (mRS 2– 6 at 90 days). Differences in the primary endpoint between the RIC and control subgroups were compared, and the interactions of treatment assignment with NLR, PLR, and SII were evaluated.Results: A total of 1679 patients were included in the final analysis. Compared with the control group, RIC significantly improved functional outcomes regardless of the inflammation status. The improved probability of poor outcome in the RIC vs control group was numerically greater in the high vs low inflammation group (NLR, 7.8% vs 5.1%; PLR, 7% vs 6.5%; SII, 9% vs 5.3%). However, we did not find an interaction effect of an intervention (RIC or control) with different NLR, PLR, or SII on clinical outcomes (P > 0.05). In addition, the NLR and SII were independently associated with functional outcomes in all patients, regardless of whether they received RIC.Conclusion: Inflammation may not affect the efficacy of RIC in patients with acute moderate ischemic stroke, although a lower probability of poor outcome at 90 days was identified in patients with a high vs low inflammatory status.Keywords: neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, remote ischemic conditioning, ischemic stroke

Tian-Jiao Xu,1,2,* Qi Wang,1,* Xiao-Wen Ma,1 Zhen Zhang,3 Wei Zhang,1 Xiao-Chang Xue,1 Cun Zhang,1 Qiang Hao,1 Wei-Na Li,1 Ying-Qi Zhang,1 Meng Li11State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi’an, People’s Republic of China; 2The Institute of Medicine, Qiqihar Medical University, Qiqihar, People’s Republic of China; 3Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, USA*These authors contributed equally to this workObjective: Thymosin beta 4 (Tβ4) is a peptide with 43 amino acids that is critical for repair and remodeling tissues on the skin, eye, heart, and neural system following injury. To fully realize its utility as a treatment for disease caused by injury, the authors constructed a cost-effective novel Tβ4 dimer and demonstrated that it was better able to accelerate tissue repair than native Tβ4.Methods: A prokaryotic vector harboring two complete Tβ4 genes with a short linker was constructed and expressed in Escherichia coli. A pilot-scale fermentation (10 L) was performed to produce engineered bacteria and the Tβ4 dimer was purified by one-step hydrophobic interaction chromatography. The activities of the Tβ4 dimer to promote endothelial cell proliferation, migration, and sprouting were assessed by tetramethylbenzidine (methylthiazol tetrazolium), trans-well, scratch, and tube formation assays. The ability to accelerate dermal healing was assessed on rats.Results: After fermentation, the Tβ4 dimer accounted for about 30% of all the bacteria proteins. The purity of the Tβ4 dimer reached 98% after hydrophobic interaction chromatography purification. An average of 562.4 mg/L Tβ4 dimer was acquired using a 10 L fermenter. In each assay, the dimeric Tβ4 exhibited enhanced activities compared with native Tβ4. Notably, the ability of the dimeric Tβ4 to promote cell migration was almost two times higher than that of Tβ4. The rate of dermal healing in the dimeric Tβ4-treated rats was approximately 1 day faster than with native Tβ4-treated rats.Conclusion: The dimeric Tβ4 exhibited enhanced activity on wound healing than native Tβ4, and the purification process was simple and cost-effective. This data could be of significant benefit for the high pain and morbidity associated with chronic wounds disease. A better strategy to develop Tβ4 as a treatment for other diseases caused by injuries such as heart attack, neurotrophic keratitis, and multiple sclerosis was also described.Keywords: thymosin beta 4, dimer, wound healing, tissue repair, peptide, genetic engineering

Abstract: Necrozoospermia is a poorly documented condition with a low incidence, and its definition and clinical significance are unclear. Herein, we provide a reference range for necrozoospermia and discuss its possible etiology and impact on male fertility and assisted reproductive outcomes. We extracted relevant information from 650 Chinese male partners of infertile couples and statistically analyzed sperm vitality. Necrozoospermia was present in 3.4% (22/650) of our study population, and the lower cut-off value for sperm vitality was 75.3%. We compared two methods for assessing sperm vitality (eosin-nigrosin head staining and hypo-osmotic swelling test [HOST]), for which the percentage in the eosin-nigrosin group (mean ± standard deviation [s.d.]: 77.5% ± 10.5%) was significantly higher than that in the HOST group (mean ± s.d.: 58.1% ± 6.7% [5-10 min after incubation] and 55.6% ± 8.2% [25-30 min after incubation]; both P < 0.001). The incidence of necrozoospermia increased with age (odds ratio [OR] = 1.116, 95% confidence interval [CI]: 1.048-1.189, P = 0.001), while the percentage of normal sperm morphology and DNA fragmentation index (DFI) were significantly associated with necrozoospermia, with ORs of 0.691 (95% CI: 0.511-0.935, P = 0.017) and 1.281 (95% CI: 1.180-1.390, P < 0.001), respectively. In the following 6 months, we recruited 166 patients in the nonnecrozoospermia group and 87 patients in the necrozoospermia group to compare intracytoplasmic sperm injection (ICSI) and pregnancy outcomes between the two groups. The necrozoospermia group had a significantly lower normal fertilization rate (74.7% vs 78.2%, P = 0.041; OR = 0.822; 95% CI: 0.682-0.992) than that in the nonnecrozoospermia group. This study presents substantial information on necrozoospermia to establish comprehensive and applicable reference values for sperm vitality for spontaneous conception and artificially assisted reproductive management., (Copyright © 2024 Copyright: ©The Author(s)(2024).)

Recent therapeutic strategies for the treatment of triple-negative breast cancer (TNBC) have shifted the focus from vascular growth factors to endothelial cell metabolism. This study highlights the underexplored therapeutic potential of peri-tumoral electroacupuncture, a globally accepted non-pharmacological intervention for TNBC, and molecular mechanisms. Our study showed that peri-tumoral electroacupuncture effectively reduced the density of microvasculature and enhanced vascular functionality in 4T1 breast cancer xenografts, with optimal effects on day 3 post-acupuncture. The timely integration of peri-tumoral electroacupuncture amplified the anti-tumor efficacy of paclitaxel. Multi-omics analysis revealed Glyoxalase 1 (Glo1) and the associated methylglyoxal-glycolytic pathway as key mediators of electroacupuncture-induced vascular normalization. Peri-tumoral electroacupuncture notably reduced Glo1 expression in the endothelial cells of 4T1 xenografts. Using an in vivo matrigel plug angiogenesis assay, we demonstrated that either Glo1 knockdown or electroacupuncture inhibited angiogenesis. In contrast, Glo1 overexpression increased blood vessel formation. In vitro pharmacological inhibition and genetic knockdown of Glo1 in human umbilical vein endothelial cells inhibited proliferation and promoted apoptosis via downregulating the methylglyoxal-glycolytic pathway. The study using the Glo1-silenced zebrafish model further supported the role of Glo1 in vascular development. This study underscores the pivotal role of Glo1 in peri-tumoral electroacupuncture, spotlighting a promising avenue for enhancing vascular normalization and improving TNBC treatment outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Ionic liquids have been widely used to improve the efficiency and stability of perovskite solar cells (PSCs), and are generally believed to passivate defects on the grain boundaries of perovskites. However, few studies have focused on the relevant effects of ionic liquids on intragrain defects in perovskites which have been shown to be critical for the performance of PSCs. In this work, the effect of ionic liquid 1-hexyl-3-methylimidazolium iodide (HMII) on intragrain defects of formamidinium lead iodide (FAPbI 3 ) perovskite is investigated. Abundant {111} c intragrain planar defects in pure FAPbI 3 grains are found to be significantly reduced by the addition of the ionic liquid HMII, shown by using ultra-low-dose selected area electron diffraction. As a result, longer charge carrier lifetimes, higher photoluminescence quantum yield, better charge carrier transport properties, lower Urbach energy, and current-voltage hysteresis are achieved, and the champion power conversion efficiency of 24.09% is demonstrated. These observations suggest that ionic liquids significantly improve device performance resulting from the elimination of {111} c intragrain planar defects., (© 2024 Wiley‐VCH GmbH.)

Advances in modern medicine have extended human life expectancy, leading to a world with a gradually aging society. Aging refers to a natural decline in the physiological functions of a species over time, such as reduced pain sensitivity and reaction speed. Healthy-level physiological pain serves as a warning signal to the body, helping to avoid noxious stimuli. Physiological pain sensitivity gradually decreases in the elderly, increasing the risk of injury. Therefore, geriatric health care receives growing attention, potentially improving the health status and life quality of the elderly, further reducing medical burden. Health food is a geriatric healthcare choice for the elderly with Ganoderma tsuage (GT), a Reishi type, as the main product in the market. GT contains polysaccharides, triterpenoids, adenosine, immunoregulatory proteins, and other components, including anticancer, blood sugar regulating, antioxidation, antibacterial, antivirus, and liver and stomach damage protective agents. However, its pain perception-related effects remain elusive. This study thus aimed at addressing whether GT could prevent pain sensitivity reduction in the elderly. We used a galactose-induced animal model for aging to evaluate whether GT could maintain pain sensitivity in aging mice undergoing formalin pain test, hot water test, and tail flexes. Our results demonstrated that GT significantly improved the sensitivity and reaction speed to pain in the hot water, hot plate, and formalin tests compared with the control. Therefore, our animal study positions GT as a promising compound for pain sensitivity maintenance during aging., (© 2024. The Author(s).)

Abnormal iron metabolism has long been regarded as a key metabolic hallmark of cancer. As a critical cofactor, iron contributes to tumor progression by participating in various processes such as mitochondrial electron transport, gene regulation, and DNA synthesis or repair. Although the role of iron in tumor cells has been widely studied, recent studies have uncovered the interplay of iron metabolism between tumor cells and immune cells, which may affect both innate and adaptive immune responses. In this review, we discuss the current understanding of the regulatory networks of iron metabolism between cancer cells and immune cells and how they contribute to antitumor immunity, and we analyze potential therapeutics targeting iron metabolism. Also, we highlight several key challenges and describe potential therapeutic approaches for future investigations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The clinical applications of acrosin activity are limited. We analyzed 61 578 male partners in infertile couples who visited the outpatient department of the Reproductive and Genetic Hospital of CITIC-Xiangya (Changsha, China) between August 2014 and December 2019 to determine the reference ranges and thresholds for acrosin activity in infertile Chinese men; to determine whether correlations exist between acrosin activity and age, sperm concentration, sperm morphology, or sperm motility; and to evaluate whether acrosin activity could serve as an effective prognostic indicator for choosing between in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) in the clinic. The cut-off value for the normal reference range of acrosin activity for male partners in infertile couples was 24.78 µIU per 10 6 sperm. There was no significant association between acrosin activity and age, sperm concentration, semen volume, total sperm count, progressive motility, or total motile spermatozoa. A weak positive correlation was found between acrosin activity and normal sperm morphology. There was a statistically significant difference in abnormal acrosome morphology between the group with high acrosin activity (>24.78 µIU per 10 6 sperm) and the group with low acrosin activity (<24.78 µIU per 10 6 sperm). The group with a low IVF fertilization rate had a high index of abnormal acrosomal morphology at 21.2%, while the group with a high IVF fertilization rate had a low index of 0.2%. At an acrosin activity of <24.78 µIU per 10 6 sperm, in one cycle of the same patient, the fertilization rate, normal fertilization rate, and good-quality embryo rate for ICSI were significantly higher than those for IVF. Therefore, the most promising application of acrosin activity could be in the selection of ICSI over IVF for infertile male patients with complete fertilization failure or a low fertilization rate., (Copyright © 2023 Copyright: © The Author(s)(2023).)

Ligustrum robustum has been not only used as a heat-clearing and detoxicating functional tea (Ku-Ding-Cha) but also consumed as a hypotensive, anti-diabetic, and weight-reducing folk medicine. From the leaves of L. robustum , ten new monoterpenoid glycosides named ligurobustosides T 10 ( 1a ), T 11 ( 1b ), T 12 ( 2a ), T 13 ( 2b ), T 14 ( 3a ), T 15 ( 3b ), F 1 ( 4b ), T 16 ( 5a ), T 17 ( 5b ), and E 1 ( 6b ), together with five known ones ( 4a , 6a , 7 , 8a , 8b ), were separated and identified using the spectroscopic method and chemical method in this research. The results of biological tests exhibited that the fatty acid synthase (FAS) inhibitory action of compound 5 (IC 50 : 4.38 ± 0.11 μM) was as strong as orlistat (IC 50 : 4.46 ± 0.13 μM), a positive control; the α-glucosidase inhibitory actions of compounds 1 - 4 and 7 - 8 , and the α-amylase inhibitory actions of compounds 1 - 8 were medium; the ABTS radical scavenging capacities of compounds 1 - 3 and 5 - 8 (IC 50 : 6.27 ± 0.23 ~ 8.59 ± 0.09 μM) were stronger than l-(+)-ascorbic acid (IC 50 : 10.06 ± 0.19 μM) served as a positive control. This research offered a theoretical foundation for the leaves of L. robustum to prevent diabetes and its complications.

Arrhythmia is one of the commonly heart diseases with observed abnormal heart-beat rhythm that caused by the obstacles of cardiac activity and conduction. The arrhythmic pathogenesis is complex and capricious and related with other cardiovascular diseases that may lead to heart failure and sudden death. In particular, calcium overload is recognized as the main reason causing arrhythmia through inducing apoptosis in cardiomyocytes. Moreover, calcium channel blockers have been widely used as the routine drugs for the treatment of arrhythmia, but the different arrhythmic complications and adverse effects limit their further applications and demand new drug discovery. Natural products have always been the rich minerals for the development of new drugs that could be employed as the versatile player for the discovery of safe and effective anti-arrhythmia drugs with new mechanisms. In this review, we summarized natural products with the activity against calcium signaling and the relevant mechanism of actions. We are expected to provide an inspiration for the pharmaceutical chemists to develop more potent calcium channel blockers for the treatment of arrhythmia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Glucocorticoid modulatory element-binding protein 1 (GMEB1), which has been identified as a transcription factor, is a protein widely expressed in various tissues. Reportedly, the dysregulation of GMEB1 is linked to the genesis and development of multiple cancers., Aim: To explore GMEB1's biological functions in hepatocellular carcinoma (HCC) and figuring out the molecular mechanism., Methods: GMEB1 expression in HCC tissues was analyzed employing the StarBase database. Immunohistochemical staining, Western blotting and quantitative real-time PCR were conducted to examine GMEB1 and Yes-associate protein 1 (YAP1) expression in HCC cells and tissues. Cell counting kit-8 assay, Transwell assay and flow cytometry were utilized to examine HCC cell proliferation, migration, invasion and apoptosis, respectively. The JASPAR database was employed for predicting the binding site of GMEB1 with YAP1 promoter. Dual-luciferase reporter gene assay and chromatin immunoprecipitation-qPCR were conducted to verify the binding relationship of GMEB1 with YAP1 promoter region., Results: GMEB1 was up-regulated in HCC cells and tissues, and GMEB1 expression was correlated to the tumor size and TNM stage of HCC patients. GMEB1 overexpression facilitated HCC cell multiplication, migration, and invasion, and suppressed the apoptosis, whereas GMEB1 knockdown had the opposite effects. GMEB1 bound to YAP1 promoter region and positively regulated YAP1 expression in HCC cells., Conclusion: GMEB1 facilitates HCC malignant proliferation and metastasis by promoting the transcription of the YAP1 promoter region., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Study Question: Does YAP1 inhibition alleviate progesterone resistance in endometriosis?, Summary Answer: YAP1 inhibition reduces progesterone resistance in vitro and in vivo., What Is Known Already: Progesterone resistance not only causes treatment failure for endometriosis but also inhibits eutopic endometrial cell proliferation, dysregulates decidualization, and reduces the success rates of pregnancy. Hippo/yes-associated protein 1 (YAP1) signaling pathway plays an important role in the pathogenesis of endometriosis., Study Design, Size, Duration: Paraffin-embedded tissues containing paired endometriotic and endometrial specimens (n = 42) and serum samples isolated from normal controls (n = 15) or endometriotic patients with (n = 25) or without (n = 21) prior dienogest treatment were analyzed. A mouse model of endometriosis was also used to evaluate the effects of YAP1 inhibition on progesterone resistance., Participants/materials, Setting, Methods: Primary endometriotic and endometrial stromal cells treated with YAP1 inhibitor or miR-21 mimic/inhibitor were used for the in vitro studies including decidualization induction, chromatin immunoprecipitation (ChIP), and RNA immunoprecipitation. Tissue specimens and serum from human and mouse were used for immunohistochemistry staining, exosome isolation, and microRNA (miRNA) quantification, respectively., Main Results and the Role of Chance: Herein, we report, by using ChIP-PCR and RNA-IP, that YAP1 inhibits progesterone receptor (PGR) expression through upregulation of miR-21-5p. Upregulation of miR-21-5p not only reduces PGR expression but also inhibits endometrial stromal cell decidualization. Indeed, levels of YAP1 and miR-21-5p are inversely correlated with the level of PGR in human endometrial samples. In contrast, knockdown of YAP1 or treatment with verteporfin (VP), a YAP1 inhibitor, reduces miR-21-5p expression, thus leading to an increase in PGR expression in ectopic endometriotic stromal cells. In the mouse model of endometriosis, treatment with VP increases PGR expression and enhances decidualization. More importantly, VP synergistically increases the treatment effect of progestin in causing the regression of endometriotic lesions and improves the decidualization capability of the endometrium. Interestingly, treatment with dienogest, a synthetic progestin, reduces YAP1 and miR-21-5p expression in human cells and in the mouse model of endometriosis. Patients who received dienogest treatment for 6 months show a significant decrease in serum extracellular vesicle-associated miR-21-5p level., Large Scale Data: A public dataset (GSE51981) containing a large cohort of endometriotic tissues is available from the Gene Expression Omnibus (GEO)., Limitations, Reasons for Caution: A large cohort of clinical samples is needed to verify the current diagnostic value of miR-21-5p in future studies., Wider Implications of the Findings: The reciprocal regulation of YAP1 and PGR suggests that combined YAP1 inhibitor and progestin may be a better therapeutic approach for treating endometriosis., Study Funding/competing Interest(s): This study was supported by the Ministry of Science and Technology, Taiwan (MOST-111-2636-B-006-012, MOST-111-2314-B-006-075-MY3, and MOST-106-2320-B-006-072-MY3). The authors have no conflict of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the effects of combined blockade of interleukin-33 (IL-33) and inducible co-stimulatory molecule (ICOS) on carbon tetrachloride-induced chronic liver fibrosis and imbalance of T helper lymphocyte subsets in mice. Methods: There were 40 BALB/c mice in each model and control group. Flow cytometry was used to determine the proportion of Th1/Th2/Th17 cells in the splenic lymphocyte suspension of mice, the expression levels of interferon γ, IL-4, and IL-17 in the splenic lymphocyte suspension of liver fibrosis mice after combined blockade of IL-33 and ICOS, and the pathological changes of liver histopathology in mice with liver fibrosis. Two independent sample t -test was used to compare data between groups. Results: Compared with the non-blocking group, the proportion of Th2 and Th17 cells in the IL-33/ICOS blocking group was significantly down-regulated (Th2: 65.96% ± 6.04% vs. 49.09% ± 7.03%; Th17: 19.17% ± 4.03% vs. 9.56% ± 2.03%), while the proportion of Th1 cells and Th1/Th2 ratio were up-regulated (Th1: 17.14% ± 3.02% vs. 31.93% ± 5.02%; Th1/Th2: 0.28 ± 0.06 vs. 0.62 ± 0.23), and the difference was statistically significant ( t = 5.15, 6.03, 7.14, 4.28, respectively, with P < 0.05). After entering the chronic inflammation stage of liver fibrosis in mice (10 weeks), compared with the non-blocking group, the expression levels of IL-4 and IL-17 in the blockade group were significantly down-regulated [IL-4: (84.75 ± 14.35) pg/ ml vs. (77.88 ± 19.61) pg/ml; IL-17: (72.38 ± 15.13) pg/ml vs. (36.38 ± 8.65) pg/ml], while the expression of interferon γ was up-regulated [(37.25 ± 11.51) pg/ml vs. (77.88 ± 19.61) pg/ml], and the difference was statistically significant ( t : IL-4: 4.71; IL-17: 5.84; interferon γ: 5.05, respectively, with P < 0.05). Liver histopathological results showed that hepatic necrosis, hepatic lobular structural disorder, and fibrous tissue hyperplasia were significantly lower in the blockade group than those in the non-blocking group at 13 weeks of liver fibrosis. Conclusion: Combined blockade of the ICOS signaling pathway and IL-33 can regulate Th2 and Th17 polarization, down-regulate the inflammatory response, and inhibit or prevent the occurrence and progression of fibrosis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD comprises a continuum of liver abnormalities from nonalcoholic fatty liver to nonalcoholic steatohepatitis, and can even lead to cirrhosis and liver cancer. However, a well-established treatment for NAFLD has yet to be identified. Exosomes have become an ideal drug delivery tool because of their high transmissibility, low immunogenicity, easy accessibility and targeting. Exosomes with specific modifications, known as engineered exosomes, have the potential to treat a variety of diseases. Here, we review the treatment of NAFLD with engineered exosomes and the potential use of exosomes as biomarkers and therapeutic targets for NAFLD., Competing Interests: Conflict-of-interest statement: All the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Purpose: To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer., Patients and Methods: Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors., Results: In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo., Conclusion: The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer.The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The mechanism of internet game addiction is unclear. Whether anxiety mediates between resourcefulness and internet game addiction and whether gender affect its mediation role have not been studied previously., Methods: A total of 4,889 college students from a college in southwest China were included in this study to complete the investigation, in which three questionnaires were used for evaluation., Results: Pearson's correlation analysis indicated a remarkable negative correlation between resourcefulness with internet game addiction and anxiety, as well as a significant positive correlation between anxiety and this addiction. The structural equation model confirmed the mediation role of anxiety. The multi-group analysis confirmed the moderating role of gender in the mediation model., Discussion: These findings have advanced the results of existing studies, indicating the buffering effect of resourcefulness on internet game addiction and revealing the potential mechanism of this relationship., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Zhong, Luo, He, Lin, Zauszniewski, Zhou, Chen, Wu, Wang, Li, Tang, Li, Wu and Luo.)

The leaves of Ligustrum robustum have been consumed as Ku-Ding-Cha for clearing heat and removing toxins, and they have been used as a folk medicine for curing hypertension, diabetes, and obesity in China. The phytochemical research on the leaves of L. robustum led to the isolation and identification of two new hexenol glycosides, two new butenol glycosides, and five new sugar esters, named ligurobustosides X ( 1a ), X 1 ( 1b ), Y ( 2a ), and Y 1 ( 2b ) and ligurobustates A ( 3a ), B ( 3b ), C ( 4b ), D ( 5a ), and E ( 5b ), along with seven known compounds ( 4a and 6 - 10 ). Compounds 1 - 10 were tested for their inhibitory effects on fatty acid synthase (FAS), α-glucosidase, and α-amylase, as well as their antioxidant activities. Compound 2 showed strong FAS inhibitory activity (IC 50 4.10 ± 0.12 μM) close to that of the positive control orlistat (IC 50 4.46 ± 0.13 μM); compounds 7 and 9 revealed moderate α-glucosidase inhibitory activities; compounds 1 - 10 showed moderate α-amylase inhibitory activities; and compounds 1 and 10 displayed stronger 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) ammonium salt (ABTS) radical scavenging effects (IC 50 3.41 ± 0.08~5.65 ± 0.19 μM) than the positive control l-(+)-ascorbic acid (IC 50 10.06 ± 0.19 μM). This study provides a theoretical foundation for the leaves of L. robustum as a functional tea to prevent diabetes and its complications.

Myometrial contraction is stringently controlled throughout pregnancy and parturition. Progesterone signaling, effecting through the progesterone receptor (PR), is pivotal in modulating uterine activity. Evidence has shown that two major PR isoforms, PR-A and PR-B, have distinct activities on gene regulation, and the ratio between these isoforms determines the contractility of the myometrium at different gestational stages. Herein, we focus on the regulation of PR activity in the myometrium, especially the differential actions of the two PR isoforms, which maintain uterine quiescence during pregnancy and regulate the switch to a contractile state at the onset of labor. To demonstrate the PR regulatory network and its mechanisms of actions on myometrial activity, we summarized the findings into three parts: Regulation of PR Expression and Isoform Levels, Progesterone Receptor Interacting Factors, and Biological Processes Regulated by Myometrial Progesterone Receptor Isoforms. Recent genomic and epigenomic data, from human specimens and mouse models, are recruited to support the existing knowledge and offer new insights and future directions in myometrial biology., (Published by Elsevier Ltd.)

Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation.

Rationale: Macrophages play multi-dimensional roles in hepatic fibrosis. Studies have implicated Notch signaling mediated by the transcription factor RBP-J in macrophage activation and plasticity. Additionally, we have previously shown that myeloid-specific disruption of RBP-J can ameliorate hepatic fibrosis in mice. Accordingly, we next asked whether blocking Notch signaling in macrophages could serve as a therapeutic strategy to treat hepatic fibrosis. In this study, we used a combination of transcription factor decoy oligodeoxynucleotides (ODNs) and exosomes to test this possibility. Methods: Hairpin-type decoy oligodeoxynucleotides (ODNs) were designed for the transcription factor RBP-J. The effects of RBP-J decoy ODNs on Notch signaling were evaluated by western blot, quantitative RT-PCR, luciferase reporter assays, and electrophoretic mobility shift assays. ODNs were loaded into HEK293T-derived exosomes by electroporation. A hepatic fibrosis mouse model was established by the intraperitoneal injection of carbon tetrachloride or bile duct ligation. Mice with hepatic fibrosis were administered exosomes loaded with RBP-J decoy ODNs via tail vein injection. The in vivo distribution of exosomes was analyzed by fluorescence labeling and imaging. Liver histology was examined using hematoxylin and eosin, Sirius red, and Masson staining, as well as immunohistochemical staining for Col1α1 and αSMA. Results: We found that RBP-J decoy ODNs could be efficiently loaded into exosomes and inhibit the activation of Notch signaling. Furthermore, exosomes administered via the tail vein were found to be primarily taken up by hepatic macrophages in mice with liver fibrosis. Importantly, RBP-J decoy ODNs delivered by exosomes could efficiently inhibit Notch signaling in macrophages and ameliorate hepatic fibrosis in mice. Conclusions: Combined, our data showed that the infusion of exosomes loaded with RBP-J decoy ODNs represents a promising therapeutic strategy for the treatment of hepatic fibrosis., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background/Aim: Essential oils of sunflower receptacles (SEOs) have antibacterial and antioxidant potential. However, the differences of biological activities from the different varieties of sunflowers have not been studied till now. The purpose of this study was to compare the differences of chemical compounds, antioxidant activities, and inhibitory activities against xanthine oxidase (XO) of SEOs from the three varieties of sunflowers including LD5009, SH363, and S606. Methods: SEOs were extracted by using the optimal extraction conditions selected by response surface methodology (RSM). Chemical compounds of SEOs were identified from the three varieties of sunflowers by gas chromatography-mass spectrometry (GC-MS). Antioxidant activities of SEOs were detected by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and iron ion reduction ability. Inhibitory activities of SEOs against XO were measured by using UV spectrophotometer. XO inhibitors were selected from the main chemical compounds of SEOs by the high-throughput selections and molecular simulation docking. Results: The extraction yields of SEOs from LD5009, SH363, and S606 were 0.176, 0.319, and 0.580%, respectively. A total of 101 chemical compounds of SEOs were identified from the three varieties of sunflowers. In addition, the results of inhibitory activities against XO showed that SEOs can reduce uric acid significantly. Eupatoriochromene may be the most important chemical compounds of SEOs for reducing uric acid. The results of antioxidant activities and inhibitory activities against XO showed that SEOs of LD5009 had the strongest antioxidant and XO inhibitory activities. The Pearson correlation coefficient ( r > 0.95) showed that γ-terpinene, (E)-citral, and L-Bornyl acetate were highly correlated with the antioxidant activities and XO inhibitory ability. Conclusion: SEOs had antioxidant activities and XO inhibitory ability. It would provide more scientific information for utilization and selection of varieties of sunflowers, which would increase the food quality of sunflowers and incomes of farmers., Competing Interests: The authors declare that this study received funding from Jilin Teyi Food Technology Corporation Ltd. The funder had the following involvement in the study: design, sample collection and the decision to submit it for publication., (Copyright © 2021 Liu, Gao, Dong, Qiao, Yan, Han, Li and Han.)

Background: Retinitis pigmentosa (RP) is a rare, progressive, and hereditary disorder that leads to the progressive loss of vision and visual field, and in some cases blindness. The specific relationship between RP and glaucoma has been debated for decades., Methods: In this study, we examined a Han RP family with concomitant angle-closure glaucoma (ACG), performed an inductive analysis of their clinical features and assistant results, and applied whole-exome sequencing (WES) technology for a molecular diagnosis., Results: A novel transversion mutation (c.626 T > A) was identified in the peripherin-2 (PRPH2) gene in the proband, resulting in the substitution of Valine to aspartic acid in codon 209. A full ophthalmic examination showed that the proband with the c.626 T > A mutation had a typical RP manifestation, with close angles; however, the proband's elder brother, who lacked the novel mutation, had a normal fundus and open angles., Conclusion: Our results extend the genetic mutation spectrum of PRPH2 in RP, and provide evidence to support a genetic correlation between RP and ACG., (© 2021. The Author(s).)

Objective: To explore the efficacy of voriconazole combined with glucocorticoid on the nephrotic syndrome in children., Patients and Methods: A total of 62 children with nephrotic syndrome were enrolled in this study. They were treated in our hospital from February 2016 to August 2019, including 35 children treated with voriconazole in a control group, and 27 children treated with glucocorticoid combined with voriconazole in a research group. The efficacy was evaluated, and a logistic regression analysis was carried out to find out the risk factors affecting the efficacy. The enzyme-linked immunosorbent assay (ELISA) was used to determine the serum creatinine and urine protein expression before and after treatment. In addition, receiver operating characteristic (ROC) curves were drawn to analyze the predictive value of serum creatinine and urine protein expression., Results: The marked efficacy and total effective rate in the research group were significantly higher than those in the control group, while the non-efficacy in the research group was significantly lower than that in the control group (p<0.05). After treatment, the expression of serum creatinine and urine protein in the research group was significantly lower than that in the control group (p<0.05). The area under the curve (AUC) of urine protein was 0.798. The AUC of serum creatinine was 0.724. Multivariate logistic regression analysis revealed that serum albumin, high edema, infection, serum creatinine, and urine protein were independent risk factors., Conclusions: Glucocorticoid can improve clinical efficacy. Serum creatinine and urine protein can be adopted as predictive factors for efficacy on children with nephrotic syndrome. Serum albumin, high edema, infection, serum creatinine, and urine protein were independent risk factors for the efficacy on children with nephrotic syndrome.

Background: Norcantharidin (NCTD) is suitable for the treatment of primary liver cancer, especially early and middle primary liver cancer. This compound can reduce tumors and improve immune function. However, the side effects of NCTD have limited its application. There is a marked need to reduce the side effects and increase the efficacy of NCTD., Aim: To develop a nanomaterial carrier, NCTD-loaded metal-organic framework IRMOF-3 coated with a temperature-sensitive gel (NCTD-IRMOF-3-Gel), aiming to improve the anticancer activity of NCTD and reduce the drug dose., Methods: NCTD-IRMOF-3-Gel was obtained by a coordination reaction. The apparent characteristics and in vitro release of NCTD-IRMOF-3-Gel were investigated. Cell cytotoxicity assays, flow cytometry, and apoptosis experiments in mouse hepatoma (Hepa1-6) cells were used to determine the anti-liver cancer activity of NCTD-IRMOF-3-Gel in in vitro models., Results: The particle size of NCTD-IRMOF-3-Gel was 50-100 nm, and the particle size distribution was uniform. The release curve showed that NCTD-IRMOF-3-Gel had an obvious sustained-release effect. The cytotoxicity assays showed that the free drug NCTD and NCTD-IRMOF-3-Gel treatments markedly inhibited Hepa1-6 cell proliferation, and the inhibition rate increased with increasing drug concentration. By flow cytometry, NCTD-IRMOF-3-Gel was observed to block the Hepa1-6 cell cycle in the S and G2/M phases, and the thermosensitive gel nanoparticles may inhibit cell proliferation by inducing cell cycle arrest. Apoptosis experiments showed that NCTD-IRMOF-3-Gel induced the apoptosis of Hepa1-6 cells., Conclusion: Our results indicated that the NCTD-IRMOF-3-Gel may be beneficial for liver cancer disease treatment., Competing Interests: Conflict-of-interest statement: The authors report no conflicts of interest in this work., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: Endometriosis is a bothersome disease affected women worldwide, the mechanism of disease development is still under investigation. Several inflammatory responses after clinical hyaluronic acid (HA) use were reported. Cyclooxygenase (COX)-2 mediated inflammation pathway is involved in the pathogenesis of endometriosis. Thus, we tried to investigate the inflammatory role of hyaluronic acid in endometriosis., Materials and Methods: Peritoneal fluid was collected in endometriosis and disease-free patients for the measurement of HA. Endometriotic stromal cells were treated with IL-1β and HA and expression of COX-2 was evaluated. Mice model of endometriosis was established and treated with fluid or gel form of HA. Endometriotic lesion size and weight were recorded and level of COX-2 was evaluated by immunohistochemistry staining., Results: The level of HA in the peritoneal fluid had no statistically significant difference between normal, early and advanced stage endometriosis patients. The overexpression of COX-2 protein was detected when treating endometriotic stromal cell with HA in the presence of IL-1β (P < 0.001). The endometriotic lesion size was reduced in mice model when treated with higher concentration gel form HA. It further showed less proportion of strong COX-2 expression compare of gel form HA to fluid form treatment in COX-2 expression score of endometriosis lesion., Conclusion: Both proinflammatory evidence, elevated COX-2 expression, and anti-inflammatory result, reduced endometriosis lesion size and COX-2 expression score, were noted in our study after treating HA in in vivo and in vitro models. We hypothesized it is possible that HA may induce an acute proinflammatory response followed by chronic anti-inflammatory reaction in the formation of endometriosis., Competing Interests: Declaration of competing interest There is no conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Background: Coronavirus disease 2019 (COVID-19) is a serious and even lethal respiratory illness. The mortality of critically ill patients with COVID-19, especially short term mortality, is considerable. It is crucial and urgent to develop risk models that can predict the mortality risks of patients with COVID-19 at an early stage, which is helpful to guide clinicians in making appropriate decisions and optimizing the allocation of hospital resoureces., Methods: In this retrospective observational study, we enrolled 949 adult patients with laboratory-confirmed COVID-19 admitted to Tongji Hospital in Wuhan between January 28 and February 12, 2020. Demographic, clinical and laboratory data were collected and analyzed. A multivariable Cox proportional hazard regression analysis was performed to calculate hazard ratios and 95% confidence interval for assessing the risk factors for 30-day mortality., Results: The 30-day mortality was 11.8% (112 of 949 patients). Forty-nine point nine percent (474) patients had one or more comorbidities, with hypertension being the most common (359 [37.8%] patients), followed by diabetes (169 [17.8%] patients) and coronary heart disease (89 [9.4%] patients). Age above 50 years, respiratory rate above 30 beats per minute, white blood cell count of more than10 × 10 9 /L, neutrophil count of more than 7 × 10 9 /L, lymphocyte count of less than 0.8 × 10 9 /L, platelet count of less than 100 × 10 9 /L, lactate dehydrogenase of more than 400 U/L and high-sensitivity C-reactive protein of more than 50 mg/L were independent risk factors associated with 30-day mortality in patients with COVID-19. A predictive CAPRL score was proposed integrating independent risk factors. The 30-day mortality were 0% (0 of 156), 1.8% (8 of 434), 12.9% (26 of 201), 43.0% (55 of 128), and 76.7% (23 of 30) for patients with 0, 1, 2, 3, ≥4 points, respectively., Conclusions: We designed an easy-to-use clinically predictive tool for assessing 30-day mortality risk of COVID-19. It can accurately stratify hospitalized patients with COVID-19 into relevant risk categories and could provide guidance to make further clinical decisions., Competing Interests: None., (Copyright © 2021 The Chinese Medical Association, published by Wolters Kluwer Health, Inc.)

Objective: To explore the difficulties and surgical decision of laparoscopic technique in patients with complicated hepatolithiasis. Methods: The clinical data of 13 patients with complicated hepatolithiasis who underwent laparoscopic hepatectomy at Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College from December 2019 to December 2020 were collected. There were 3 males and 10 females with average age of 50.8 years (range: 14 to 67 years). All patients had upper abdominal pain and a history of cholecystectomy, 4 of them had fever.Seven cases underwent laparoscopic left hemihepatectomy+bile duct exploration, 2 cases underwent laparoscopic right hemihepatectomy+bile duct exploration, 2 cases underwent laparoscopic quadrate hepatectomy (liver 4B+Part 5)+hilar cholangioplasty+bile duct exploration, 2 cases underwent laparoscopic quadrate lobe resection (liver 4B+Part 5)+cholangioplasty+cholangiojejunostomy. All patients were re-examined with abdominal ultrasound and choledochoscope 3 months after operation. Results: The median operation time was 5.2 hours (range: 3.6-6.5 hours), blood loss was 278 ml (range: 120-580 ml). During the operation, 1 case had duodenal bulb injury, and the defect area was about 1.0 cm × 1.2 cm. After timely detection, the defect area was carefully evaluated and trimmed. Absorbable suture was used to suture duodenal bulb, and gastrojejunostomy was performed after repair. One case had small intestinal serosa injury, which was intermittently sutured and embedded with absorbable suture. All the patients recovered smoothly without death. Three months after the operation, 12 patients completed abdominal ultrasound and T-tube sinus choledochoscopy. Residual stones were found in 3 patients, stones were removed in 2 patients by T-tube sinus choledochoscopy 3 months after the operation, 1 patient was still in the recovery period (within 3 months after surgery). No residual stones were found in the remaining 10 patients. Conclusion: The three key laparoscopic techniques in operation of complex hepatolithiasis: adhesiolysis and porta hepatis exposure, laparoscopic hepatectomy, and laparoscopic choledochojejunostomy are very important.

Quercetin and crocin are the main active constituents of Eucommia and Gardenia species, respectively. This study was conducted to explore the effects of quercetin and crocin on fat reduction and renal fibrosis and the relationship of these compounds with autophagy. First, a model of high-fat diet- and streptozotocin-induced type 2 diabetes was established and then subjected model animals to 8 weeks of metformin, quercetin and crocin gavage. Then, a high glucose-induced rat mesangial cells (RMCs) model was established, and these cells were cocultured with quercetin and crocin. The results showed that quercetin and crocin can decrease fasting blood glucose levels, reduce fat accumulation in the liver, alleviate renal fibrosis, and reduce blood lipid levels. Quercetin and crocin increased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the liver and decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the kidneys. Moreover, quercetin and crocin inhibited the excessive proliferation of RMCs induced by high-glucose (HG) conditions, decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels, and decreased TGF-β1 expression. Importantly, cotreatment with quercetin and crocin had a more significant effect than treatment with either compound alone. These results suggest that combined administration of quercetin and crocin can more significantly reduce blood glucose/lipid levels and improve renal fibrosis than administration of either compound alone and that AMPK-dependent autophagy might be involved in this process. Eucommia ulmoides Oliv. and Gardenia could be developed as drugs for Type 2 diabetes treatment.

Objective: To investigate the diagnosis method of Gilbert syndrome (GS) and the relationship between UGT1A1 gene polymorphism distribution with serum bilirubin. Methods: Clinical data of 115 GS cases diagnosed in our hospital from January 2013 to November 2018 were retrospectively analyzed. Chi-square test, Fisher's exact probability method, t-test, and non-parametric test were used for data analysis. Results: 115 cases with GS had an average age of (36.89 ± 12.77) years and an average serum total bilirubin level of (44.01 ± 18.78) μmol/L.UGT1A1*28/*28 (21, 18.3%), UGT1A1*1/*28 (17, 14.8%), and UGT1A1*1/*6 (17, 14.8%) were the most common single-site mutations. UGT1A1*1/*28 + *1/*6 (26, 22.6%), UGT1A1*28/*28 + *1/*27 (5, 4.3%) and UGT1A1*1/*28 + *1/*6 + *1/* 27 (5, 4.3%) were the most common multiple-site mutations. Among 110 cases with Gilbert syndrome combined with non-hemolytic diseases, pairwise comparisons showed that the total bilirubin levels of patients with UGT1A1*28/*28 mutations were significantly higher than UGT1A1*6/*6 and UGT1A1*1/*28 + *1/*6 mutation ( P < 0.05). Additionally, with the increase of UGT1A1*28 distribution, the serum total bilirubin level had gradually increased ( P = 0.028), but UGT1A1*6 was opposite ( P = 0.021). There were no significant differences in gene distribution and bilirubin level between GS group (67 cases) and GS combined with viral hepatitis group (32 cases) ( P > 0.05). Conclusion: UGT1A1 gene sequencing detection is a simple, safe, specific and sensitive effective method to assist GS diagnosis. It can reduce the misdiagnosis and mistreatment of clinical jaundice, thus reducing the patients' psychological burden and saving the limited medical resources. It is worthy of clinical application.

Percutaneous coronary intervention (PCI) is the most widely used therapy for treating ischemic heart disease. However, intimal hyperplasia and restenosis usually occur within months after angioplasty. Modern pharmacological researchers have proven that osthole, the major active coumarin of Cnidium monnieri (L.) Cusson, exerts potent antiproliferative effects in lung cancer cells, the human laryngeal cancer cell line RK33 and TE671 medulloblastoma cells, and its mechanism of action is related to cell cycle arrest. The goal of the present study was to observe the effect of osthole on vascular smooth muscle cell (VSMC) proliferation using platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs isolated from rats and vascular balloon injury as models to further elucidate the molecular mechanisms underlying this activity. We detected the relative number of VSMCs by the MTT assay and EdU staining and examined cell cycle progression by flow cytometry. To more deeply probe the mechanisms, the protein expression levels of PCNA, the cyclin D1/CDK4 complex and the cyclin E1/CDK2 complex in balloon-treated rat carotid arteries and the mRNA and protein expression levels of the cyclin D1/CDK4 and cyclin E1/CDK2 complexes in VSMCs were detected by real-time RT-PCR and western blotting. The data showed that osthole significantly inhibited the proliferation of VSMCs induced by PDGF-BB. Furthermore, osthole caused apparent VSMC cycle arrest early in G0/G1 phase and decreased the expression of cyclin D1/CDK4 and cyclin E1/CDK2. Our results demonstrate that osthole can significantly inhibit PDGF-BB-induced VSMC proliferation and that its regulatory effects on cell cycle progression and proliferation may be related to the downregulation of cyclin D1/CDK4 and cyclin E1/CDK2 expression as well as the prevention of cell cycle progression from G0/G1 phase to S phase. The abovementioned mechanism may be responsible for the alleviation of neointimal hyperplasia in balloon-induced arterial wall injury by osthole., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Li, Li, Lv, Gao, Li, Gong and Yang.)

Endometriosis is a benign gynecological disease that affects about 10% of women of reproductive age. Patients with endometriosis suffer from long-term coexistence with dysmenorrhea, dyspareunia, and even infertility, which severely reduces quality of life. So far, surgical removal and hormonal medication are the major treatment options; however, high recurrence and severe adverse effects hamper the therapeutic efficacy. Hypoxia is an inevitable cellular stress in many diseases that regulates the expression of a significant subset of genes involved in pathophysiological processes. A growing body of evidence demonstrates that hypoxia plays critical role in controlling the disease phenotypes of endometriosis, such as increasing adhesion ability, causing dysregulation of estrogen biosynthesis, aberrant production of proinflammatory cytokines, increasing angiogenic ability, and suppression of immune functions. In this review, we summarize the findings of the most recent studies in exploring the underlying mechanisms of hypoxia involved in endometriosis. Potential therapeutic options for targeting HIF and downstream effectors will also be discussed.

Histidine-containing dipeptides (HCDs) are a family of non-protein, nitrogen-containing compounds with multiple physiological roles and are mainly present in excitable tissues of vertebrates. The distribution of HCDs in various animal species has been the subject of study for nearly 100 years. The aim of this research was to determine the content of the HCDs in the aquatic species collected from the Zhoushan fishing ground of the East China Sea. Using LC-MS/MS technology, the occurrence of carnosine, anserine, and homocarnosine in skeletal muscle of 38 aquatic species (26 teleosts, 6 molluscs, and 6 crustaceans) and chicken breast was investigated. Of the 38 aquatic species examined, 24 species (23 teleosts and 1 mollusc) contained considerable amounts (>5 ng/g wet tissue) of HCDs, and anserine was the major component of HCDs in their skeletal muscles. Only 5 teleosts contained homocarnosine. Most invertebrates, with the exception of the sepia Uroteuthis chinensis , did not contain HCDs. The present findings greatly expand the HCD distribution data and provide insight into understanding the roles of HCDs in different animals and a nutritional assessment for marine aquatic species., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Sunflower ( Helianthus annuus L.) contains active ingredients, such as flavonoids, alkaloids and tannins. Nevertheless, few studies have focused on essential oil from the receptacle of sunflower (SEO). In this work, we investigated the chemical composition and antimicrobial and antioxidant activities of SEO. The yield of SEO was about 0.42% ( v / w ) by hydrodistillation. A total of 68 volatile components of SEO were putatively identified by gas chromatography-mass spectrometry (GC-MS). The main constituents of SEO were α-pinene (26.00%), verbenone (7.40%), terpinolene (1.69%) and α-terpineol (1.27%). The minimum inhibitory concentration (MIC) of SEO against P. aeruginosa and S. aureus was 0.2 mg/mL. The MIC of SEO against S. cerevisiae was 3.2 mg/mL. The MIC of SEO against E. coli and Candida albicans was 6.4 mg/mL. The results showed that SEO had high antibacterial and antifungal activities. Three different analytical assays (DPPH, ABTS and iron ion reducing ability) were used to determine the antioxidant activities. The results showed that SEO had antioxidant activities. To summarize, the results in this study demonstrate the possibility for the development and application of SEO in potential natural preservatives and medicines due to its excellent antimicrobial and antioxidant activities.

Endometriosis is a highly prevalent gynecological disease with severe negative impacts on life quality and financial burden. Unfortunately, there is no cure for this disease, which highlights the need for further investigation about the pathophysiology of this disease to provide clues for developing novel therapeutic regimens. Herein, we identified that vascular endothelial growth factor (VEGF)-C, a potent lymphangiogenic factor, is up-regulated in endometriotic cells and contributes to increased lymphangiogenesis. Bioinformatic analysis and molecular biological characterization revealed that VEGF-C is negatively regulated by an orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII). Further studies demonstrated that proinflammatory cytokines, via suppression of COUP-TFII level, induce VEGF-C overexpression. More importantly, we show that functional VEGF-C is transported by extracellular vesicles (EVs) to enhance the lymphangiogenic ability of lymphatic endothelial cells. Autotransplanted mouse model of endometriosis showed lenvatinib treatment abrogated the increased lymphatic vessels development in the endometriotic lesion, enlarged retroperitoneal lymph nodes, and immune cells infiltration, indicating that blocking VEGF-C signaling can reduce local chronic inflammation and concomitantly endometriosis development. Evaluation of EV-transmitted VEGF-C from patients' sera demonstrates it is a reliable noninvasive way for clinical diagnosis. Taken together, we identify the vicious cycle of inflammation, COUP-TFII, VEGF-C, and lymphangiogenesis in the endometriotic microenvironment, which opens up new horizons in understanding the pathophysiology of endometriosis. VEGF-C not only can serve as a diagnostic biomarker but also a molecular target for developing therapeutic regimens., Competing Interests: The authors declare no competing interest.

This study aimed to explore the protective effects of the traditional Chinese Medicine formula Shenkang VII recipe (SK-7) on renal fibrosis and the mechanisms. Renal fibrosis was induced by unilateral ureteral obstruction (UUO) in rats. The rats were then divided into 5 groups: control group (Sham operation), UUO model group, UUO model plus low to high doses of SK-7 (0.5, 1.0, or 2.0 g/kg/day, for 14 days) groups. The animals were sacrificed on the 7th or 14th day. Kidney tissues were collected for histopathological examinations (hematoxylin and eosin and Masson's trichrome staining). Immunohistochemistry was used to detect the expression of collagen type III (Col III), fibronectin (FN), α-smooth muscle actin (α-SMA), TIMP metallopeptidase inhibitor 2 (TIMP2), matrix metallopeptidase 2 (MMP2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and monocyte chemotactic protein-1 (MCP-1). The TGF-β1/Smad, NF-kB and Sonic hedgehog signaling proteins were detected by Western blotting. Our results showed that SK-7 prevented UUO-induced renal injury and accumulation of collagen fibrils. Renal fibrosis biomarkers Col III, FN, α-SMA and TIMP2 were increased in the rats after UUO and decreased by SK-7, while MMP2 was upregulated after treatment. SK-7 also suppressed the levels of TNF-α, IL-1β and MCP-1 in UUO rats. In addition, SK-7 inhibited activation of the TGF-β/Smad, NF-κB and sonic hedgehog signaling (SHH) pathways. Taken together, these findings suggest that SK-7 may regulate the synthesis and degradation of extracellular matrix, reduce inflammation and suppress the proliferation of fibroblasts, by blocking the TGF-β1/Smad, NF-κB and SHH signaling pathways to exert its anti-renal fibrosis effect in UUO rats.

Background: The prevalence of human immunodeficiency virus (HIV) varies markedly among different risk groups in China, spreading fromhigh-risk populations to the general population. Indeed, China is in a critical period of HIV/acquired immunodeficiency syndrome (AIDS) prevention and control; however, data regarding HIV testing, infection and coinfection among infertile couples are lacking. This study aimed to estimate the HIV/AIDS prevalence to identify risk factors among infertile couples in Hunan, China., Methods: A cross-sectional hospital-based study was conducted to evaluate the prevalence of HIV/other infections (hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, and Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium (MG) infections) among 338,432 infertile individuals in Hunan, China, from 2012 to 2018. We calculated linear trends in prevalence using bivariate linear regression., Results: The overall prevalence rates of HIV, chlamydia, gonorrhea, MG, syphilis, and HBV and HCV antibody positivity in this study were 0.04%, 1.73%, 0.05%, 2.60%, 2.15%, 12.01% and 0.56%, respectively. The predominant infection was HBV, followed by MG, syphilis, and chlamydia. Only 1.13% of the participants (382/338432) reported sexually transmitted disease (STD) signs and symptoms suggesting genital tract infection. However, from 2012-2018, the variation in HIV prevalence was not significant (β = 0.000, PTREND = 0.907). The characteristics of the HIV-infected infertile population have not shifted dramatically, with women accounting for 32.56% of HIV cases in China. Overall, 87.60% of HIV-infected individuals have a relatively low education. In total, 37.98% of HIV-positive patients engage in high-risk behaviors., Conclusions: This study expands upon existing knowledge of HIV prevalence in the infertile Chinese population. However, much work is needed to achieve popularization of prevention knowledge and change concept. Routine HIV screening is urgently needed for all adults with high-risk behaviors., Competing Interests: The funder (Hunan Guangxiu Hi-tech Life Technology Co., Ltd) provided support in the form of a salary for the author (Wei-Na Li). The commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.

Icariin (ICA), a flavonol glycoside isolated from Epimedium, has been considered as a potential alternative therapy for ischemic stroke. However, the protective mechanisms of ICA on cerebral ischemia-reperfusion (I/R) are not fully illuminated yet. The effects of ICA on ER stress and inflammatory response which were involved in the pathological process of cerebral I/R were investigated in vitro. Microglia and neurons were subjected to OGD/R. ICA was administrated to microglia 1 h before OGD and maintained 2 h throughout OGD. At 24 h after reoxygenation, the protein expression of IL-1 β, IL-6, TNF-α in the supernatant of microglia was measured using ELISA assay; neuronal apoptosis was assessed by TUNEL staining; and cell viability was detected using CKK-8 assay; the expression of IRE1α, XBP1u, XBP1s, and cleaved caspase-3 in neurons was examined by western blotting and qRT-PCR; the expression of p-IRE1α in neurons was detected by western blotting. We found that OGD/R induced the expression of IL-1 β, IL-6, TNF-α in the supernatant of microglia; OGD/R and these proinflammatory cytokines promoted the mRNA as well as protein expression of XBP1u, XBP1s and cleaved caspase-3, increased the ratio of p-IRE1α/IRE1α, as well as apoptosis, and decreased cell viability in primary cortical neurons, while ICA reversed the levels of the above factors. IRE1 overexpression enhanced ER stress as well as apoptosis, and impaired the protective effects of ICA. These results suggested that ICA can inhibit apoptosis in neurons after OGD/R through IRE1/XBP1 signaling pathway beside its anti-inflammatory effect., Competing Interests: Declaration of competing interest The authors declared that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Long noncoding RNAs (lncRNAs) play critical roles in many pathological and biological processes, such as post-transcription, cell differentiation and gene regulation. Increasingly more studies have shown that lncRNAs function through mainly interactions with specific RNA binding proteins (RBPs). However, experimental identification of potential lncRNA-protein interactions is costly and time-consuming. In this work, we propose a novel convolutional neural network-based method with the copy-padding trick (named LPI-CNNCP) to predict lncRNA-protein interactions. The copy-padding trick of the LPI-CNNCP convert the protein/RNA sequences with variable-length into the fixed-length sequences, thus enabling the construction of the CNN model. A high-order one-hot encoding is also applied to transform the protein/RNA sequences into image-like inputs for capturing the dependencies among amino acids (or nucleotides). In the end, these encoded protein/RNA sequences are feed into a CNN to predict the lncRNA-protein interactions. Compared with other state-of-the-art methods in 10-fold cross-validation (10CV) test, LPI-CNNCP shows the best performance. Results in the independent test demonstrate that our LPI-CNNCP can effectively predict the potential lncRNA-protein interactions. We also compared the copy-padding trick with two other existing tricks (i.e., zero-padding and cropping), and the results show that our copy-padding rick outperforms the zero-padding and cropping tricks on predicting lncRNA-protein interactions. The source code of LPI-CNNCP and the datasets used in this work are available at https://github.com/NWPU-903PR/LPI-CNNCP for academic users., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Panax ginseng is a traditional Chinese medicine with significant pharmaceutical effects and broad application. Rare ginsenosides with high antitumor activities can be generated via oriented modification of their glycosyl moiety. For this purpose, suitable microorganisms and their enzymatic systems can be used. In this review, we address several issues associated with these systems. Under aerobic conditions, fungus biotransformation provides an efficient and inexpensive biotransformation process that can be easily scaled up. Considering the profound use of probiotics, wild strains generally recognized as safe have shown a potential through classical fermentation in food manufacturers of deglycosylated ginsenosides. Commonly applied recombinant enzymes from E. coli, especially recombinant hyperthermophilic enzymes, showed efficient conversion in biomedical or pharmaceutical industries. In this review, key genes dedicated to the production of ginsenosides (especially in Saccharomyces cerevisiae) are highlighted in relation to the large-scale production of ginsenosides. We also evaluate biocatalytic strategies that are aimed to improve product specificity and biocatalytic efficiency with industrial applications. Perspectives of protein engineering and solvent engineering in the development and large-scale preparation of ginsenosides in anticancer drugs, food and health care products are explored. KEY POINTS : • Modification of ginsenosides with food/engineered microorganisms is summarized. • Optimization of cell factories by protein engineering remains challenging. • Solvent engineering offers an attractive potential alternative.

Early dissemination is a unique characteristic and a detrimental process of pancreatic ductal adenocarcinoma (PDAC); however, the underlying mechanism remains largely unknown. Here, we investigate the role of dual-specificity phosphatase-2 (DUSP2)-vascular endothelial growth factor-C (VEGF-C) axis in mediating PDAC lymphangiogenesis and lymphovascular invasion. Expression of DUSP2 is greatly suppressed in PDAC, which results in increased aberrant expression of extracellular vesicle (EV)-associated VEGF-C secretion. EV-VEGF-C exerts paracrine effects on lymphatic endothelial cells and autocrine effects on cancer cells, resulting in the lymphovascular invasion of cancer cells. Tissue-specific knockout of Dusp2 in mouse pancreas recapitulates PDAC phenotype and lymphovascular invasion. Mechanistically, loss-of-DUSP2 enhances proprotein convertase activity and vesicle trafficking to promote the release of the mature form of EV-VEGF-C. Collectively, these findings represent a conceptual advance in understanding pancreatic cancer lymphovascular invasion and suggest that loss-of-DUSP2-mediated VEGF-C processing may play important roles in early dissemination of pancreatic cancer. Abbreviations: DUSP2: dual-specificity phosphatase-2; VEGF-C: vascular endothelial growth factor-C; EV: extracellular vesicles; PDAC: pancreatic ductal adenocarcinoma; KD: knockdown., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.)

Background: The most common type of male infertility is asthenospermia. We cloned DnaJ heat shock protein family member B13 (Dnajb13/DNAJB13), a type II HSP40 family member that is highly expressed in the testis. DNAJB13 plays a crucial role in sperm flagellar function., Objectives: The aim of this study was to investigate whether a correlation exists between DNAJB13 and low sperm motility in infertile men., Materials and Methods: In the present study, we performed a mutation screening of the DNAJB13 gene in 92 idiopathic asthenozoospermia patients and 200 men with normal fertility. Additionally, we used immunoelectron microscopy, co-immunoprecipitation, mass spectrometric detection, indirect immunofluorescence assay, transmission electron microscopy studies, isobaric tags for relative and absolute quantitation, and multiple reaction monitoring studies to analyze changes in DNAJB13 protein., Results: A novel c.106T>C mutation of DNAJB13 was present in nearly 10% (9/92) of idiopathic asthenozoospermia patients and was absent in 200 fertile men. A computer-assisted sperm analyzer and transmission electron microscopy analysis using samples from 9 patients with DNAJB13 mutations demonstrated that most spermatozoa were immotile due to sperm tail defects. Multiple reaction monitoring results indicated that DNAJB13 protein levels were reduced after gene mutation. We achieved a pregnancy rate of 100% in 8 patients with DNAJB13 mutations using ICSI., Discussion and Conclusion: The DNAJB13 heterozygous variant may affect fertility. ICSI can help these patients with low fertility to father children., (© 2019 American Society of Andrology and European Academy of Andrology.)

Background: Mycoplasma genitalium infection is significantly associated with an increased risk of male infertility. To date, few large M. genitalium studies have been conducted in China., Objective: This study aimed to estimate the M. genitalium incidence and treatment failure and to provide information regarding the resistance of M. genitalium to macrolide and tetracycline antibiotics among men of infertile couples in China., Materials and Methods: This study was performed as a retrospective survey of seminal and meatus urinarius secreta specimens of 30,094 men of infertile couples collected and used for microbiological tests for the evaluation of genital tract infections (Mycoplasma genitalium, Chlamydia trachomatis, and Neisseria gonorrhoeae) between October 2016 and December 2017. Mycoplasma genitalium RNA was detected using novel simultaneous amplification testing. Macrolide and tetracycline resistance screening was introduced using polymerase chain reaction (PCR) and Sanger sequencing., Results: The incidence of M. genitalium was 2.49% (749 of 30,094; 95% confidence interval (CI), 2.31-2.66%). After antibiotic treatment, the mean values of semen parameters increased from those measured before treatment. The overall incidence of treatment failure was 17.56% (82/467; 95% CI, 14.10%-21.02%) (112-26-4 = 82), irrespective of the drug used. Resistance to macrolide and tetracycline antibiotics was detected in 58 samples (58/60, 96.67%; 95% CI, 91.99-101.34%) and 27 samples (27/60, 45.00%; 95% CI, 32.04-57.96%), respectively., Conclusions: Although the M. genitalium incidence was relatively low, the detection of macrolide antibiotic resistance in >96.67% of the treatment failure samples most likely explained the high azithromycin treatment failure rate (73/195, 37.44%) in our study. These findings indicate the need to provide resistance testing and to reappraise the recommended antimicrobial options in China., (© 2019 American Society of Andrology and European Academy of Andrology.)

Background: The aim of this study was to provide information on the semen quality pattern of infertile men and age thresholds for semen parameters in China., Methods: This was a retrospective cross-sectional study investigating 71,623 infertile men from the Reproductive and Genetic Hospital of CITIC Xiangya in Hunan, China, from 2011 to 2017. The Kruskal-Wallis test, Mann-Kendall test, linear regression model and joinpoint regression were used., Results: Although erratic changes were observed in the median semen parameters (sperm concentration 40.1-52.1 × 10 6 /ml, total sperm count 117.8-153.1 × 10 6 , sperm progressive motility 33.4-38.1%) during the 7 years of observation, no significant decrease in semen quality was found, and 47.88% of infertile men showed normal semen parameters according to the World Health Organization (WHO) criteria. According to the joinpoint regression analysis, sperm progressive motility appeared to decrease earlier than the sperm concentration and total sperm count (at 28, 58, and 42 years of age, respectively)., Conclusions: There is no evidence of a deterioration in semen quality among infertile men in Hunan, China. Semen parameters decreased with increasing age, with turning points noted at different ages. Semen parameters are not absolute evidence for the assessment of male fertility potential. Therefore, we believe that, among semen parameters, the sperm concentration is the best predictor of fertility for ART, followed by motility. Decreased sperm motility may affect natural pregnancy, but it is not necessary for successful IVF.

The aim of this study was to investigate the cardioprotective effect of mangiferin (MAF) in vitro and in vivo . Oxidative stress and inflammatory injury were detected in coronary artery ligation in rats and also in hypoxia-reoxygenation- (H/R-) induced H9c2 cells. MAF inhibited myocardial oxidative stress and proinflammatory cytokines in rats with coronary artery occlusion. The ST segment of MAF treatment groups also resumed. Triphenyltetrazolium chloride (TTC) staining and pathological analysis showed that MAF could significantly reduce myocardial injury. In vitro data showed that MAF could improve hypoxia/reoxygenation- (H/R-) induced H9c2 cell activity. In addition, MAF could significantly reduce oxidative stress and inflammatory pathway protein expression in H/R-induced H9c2 cells. This study has clarified the protective effects of MAF on myocardial injury and also confirmed that oxidative stress and inflammation were involved in the myocardial ischemia-reperfusion injury (I/R) model.