Meta analysis of ovulation induction effect and pregnancy outcome of acupuncture & moxibustion combined with clomiphene in patients with polycystic ovary syndrome.

Objective: Using Mesh Meta Analysis to evaluate the efficacy of Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene for treating Polycystic Ovary Syndrome (PCOS), in order to provide evidence-based medical evidence for whether to recommend Acupuncture & Moxibustion or Combine western medicine to treat PCOS. Methods: Eight databases including The Cochrane Library, Pubmed, Embase, Web of Science, CNKI, Wanfang Date, VIP and CBM were searched by computer. The included research period is from the establishment of the database to May 2023, which concerned with randomized controlled trials involving Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene on ovulation induction and pregnancy outcome in patients with PCOS. The duration of the research paper is from 2016 to 2023.The inclusion criteria refer to the Rotterdam standards issued by the European Center for Human Reproduction and Embryology and the American Society of Reproductive Medicine in January 2003, or the Expert Consensus on the Diagnosis and Treatment of Polycystic Ovarian Syndrome by the Endocrinology Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association. Simultaneously exclude related diseases, repetitive literature, as well as literature with incomplete abstract information and no original data provided. Two researchers independently screened the literature, extracted data, and evaluated the risk of bias included in the study, using Stata17.0 software for a mesh meta-analysis. Results: Six randomized controlled trials were included, covering 1410 PCOS patients. Three interventions included Acupuncture & Moxibustion, Clomiphene, Acupuncture & Moxibustion combined with Clomiphene. Mesh Meta Analysis showed that in terms of improving ovulation rate, there was no statistical difference between Acupuncture & Moxibustion (A), Clomiphene (B), Clomiphene combined with Acupuncture & Moxibustion (C) (P>0.05).Acupuncture & Moxibustion (A) versus Clomiphene (B) [MD=0.15,95% CI (-0.51,0.80)], Acupuncture & Moxibustion (A) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.60,95% CI (0.97,2.23)], Clomiphene (B) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.45,95% CI (0.91,1.99)]. In terms of pregnancy outcome, the difference between the three intervention methods was statistically significant (P<0.05). Acupuncture & Moxibustion (A) versus Clomiphene (B) [MD=-0.80,95% CI (-1.84,0.23)], Acupuncture & Moxibustion (A) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=0.29,95% CI (-0.73,1.30)], and Clomiphene (B) versus Clomiphene combined with Acupuncture & Moxibustion (C) [MD=1.09,95% CI (0.39,1.79)], The order of pregnancy rate from high to low is Acupuncture & Moxibustion combined with Clomiphene (C), Acupuncture & Moxibustion (A), Clomiphene (C).In terms of influencing endometrial thickness, the difference between the three intervention methods was statistically significant (P<0.05). Acupuncture & Moxibustion (A) versus Clomiphene (B) [MD=-0.84,95% CI (-1.87,0.19)], Acupuncture & Moxibustion (A) versus Acupuncture & Moxibustion combined with Clomiphene (C) [MD=0.26,95% CI (-1.01,1.53)], Clomiphene (B) versus Acupuncture & Moxibustion combined with Clomiphene (C) [MD=1.10,95% CI (0.36,1.84)], Acupuncture & Moxibustion combined with Clomiphene (C) has the best effect on improving endometrial thickness. In subgroup analysis, the effect of Acupuncture & Moxibustion treatment frequency on ovulation rate and pregnancy rate was not statistically significant. The combination of Acupuncture & Moxibustion, Electroacupuncture and warm Acupuncture & Moxibustion has no effect on the pregnancy rate, but the combination of Electroacupuncture and Clomiphene has the best effect on improving the ovulation rate. In the observation of adverse reactions, compared with clomiphene alone, Acupuncture & Moxibustion combined with Clomiphene can reduce the occurrence of Luteinized Unruptured Follicle Syndrome (LUFS) and Ovarian Hyperstimulation Syndrome (OHSS), and reduce the occurrence of physical adverse reactions such as nausea, vomiting, headache and dermatitis. Conclusion: Acupuncture & Moxibustion is effective in improving the ovulation promoting effect and pregnancy outcome of PCOS patients. The ovulation promoting effect of Acupuncture & Moxibustion or combined with Clomiphene is similar to that of Clomiphene alone, but Acupuncture & Moxibustion combined with Clomiphene has more advantages in improving the pregnancy rate of PCOS, and it also can reduce the adverse reactions of Clomiphene alone. Acupuncture & Moxibustion can be used as a recommended treatment for PCOS. More cases should also be included in the subgroup analysis to study the impact of Acupuncture & Moxibustion programs on clinical efficacy and further optimize the Acupuncture & Moxibustion treatment program. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#myprospero, identifier (CRD42023433057).

Advances in CD73 inhibitors for immunotherapy: Antibodies, synthetic small molecule compounds, and natural compounds.

Tumors, a disease with a high mortality rate worldwide, have become a serious threat to human health. Exonucleotide-5'-nucleotidase (CD73) is an emerging target for tumor therapy. Its inhibition can significantly reduce adenosine levels in the tumor microenvironment. It has a better therapeutic effect on adenosine-induced immunosuppression. In the immune response, extracellular ATP exerts immune efficacy by activating T cells. However, dead tumor cells release excess ATP, overexpress CD39 and CD73 on the cell membrane and catabolize this ATP to adenosine. This leads to further immunosuppression. There are a number of inhibitors of CD73 currently under investigation. These include antibodies, synthetic small molecule inhibitors and a number of natural compounds with prominent roles in the anti-tumor field. However, only a small proportion of the CD73 inhibitors studied to date have successfully reached the clinical stage. Therefore, effective and safe inhibition of CD73 in oncology therapy still holds great therapeutic potential. This review summarizes the currently reported CD73 inhibitors, describes their inhibitory effects and pharmacological mechanisms, and provides a brief review of them. It aims to provide more information for further research and development of CD73 inhibitors.

Improving the Thermal Stability of the Fine-Grained Structure in the Cu-15Ni-8Sn Alloy during Solution Treatment by the Additions of Si and Ti.

Grain refinement has been found to be an effective method for simultaneously enhancing strength and toughness. To avoid the sharp coarsening of grains in Cu-Ni-Sn alloys during solution treatment and thereby overcoming the tradeoff between strength and ductility, this work attempted to modify the composition and improve the thermal stability of the fine-grained structure in Cu-Ni-Sn alloys. The grain growth behavior during a solution treatment of the Cu-15Ni-8Sn alloys with/without Si and Ti additions was systematically investigated. The result reveals that compared to the grain size of 146 µm in the based alloy (without trace additions) after solution processing at 1073 K for 2 h, the fine-grained structure with a size below 20 µm is maintained owing to the benefit from Si and Ti addition. It was observed that the addition of Si and Ti offer the inhibition effect on the dissolution of the γ phase and Ni16Si7Ti6 particles after solution treatment. The grain boundary movement is severely hindered by these two aspects: the pinning effect from these particles, and the drag effect induced by additional solute atoms. Based on the analysis of grain growth kinetics, the activation energy of grain growth is increased from 156 kJ/mol to 353 kJ/mol with the addition of Si and Ti.

Transplantation of neural stem progenitor cells from different sources for severe spinal cord injury repair in rat.

Neural stem progenitor cell (NSPC) transplantation has been regarded as a promising therapeutic method for spinal cord injury (SCI) repair. However, different NSPCs may have different therapeutic effects, and it is therefore important to identify the optimal NSPC type. In our study, we compared the transcriptomes of human fetal brain-derived NSPCs (BNSPCs), spinal cord-derived NSPCs (SCNSPCs) and H9 embryonic stem-cell derived NSPCs (H9-NSPCs) in vitro and subsequently we transplanted each NSPC type on a collagen scaffold into a T8-9 complete SCI rat model in vivo. In vitro data showed that SCNSPCs had more highly expressed genes involved in nerve-related functions than the other two cell types. In vivo, compared with BNSPCs and H9-NSPCs, SCNSPCs exhibited the best therapeutic effects; in fact, SCNSPCs facilitated electrophysiological and hindlimb functional recovery. This study demonstrates that SCNSPCs may be an appropriate candidate cell type for SCI repair, which is of great clinical significance.

Harnessing the immune system by targeting immune checkpoints: Providing new hope for Oncotherapy.

With the goal of harnessing the host's immune system to provide long-lasting remission and cures for various cancers, the advent of immunotherapy revolutionized the cancer therapy field. Among the current immunotherapeutic strategies, immune checkpoint blockades have greatly improved the overall survival rates in certain patient populations. Of note, CTLA4 and PD-1/PD-L1 are two major non-redundant immune checkpoints implicated in promoting cancer immune evasion, and ultimately lead to relapse. Antibodies or inhibitors targeting these two c+heckpoints have achieved some encouraging clinical outcomes. Further, beyond the canonical immune checkpoints, more inhibitory checkpoints have been identified. Herein, we will summarize recent progress in immune checkpoint blockade therapies, with a specific focus on key pre-clinical and clinical results of new immune checkpoint therapies for cancer. Given the crucial roles of immune checkpoint blockade in oncotherapy, drugs targeting checkpoint molecules expressed by both cancer and immune cells are in clinical trials, which will be comprehensively summarized in this review. Taken together, investigating combinatorial therapies targeting immune checkpoints expressed by cancer cells and immune cells will greatly improve immunotherapies that enhance host elimination of tumors.

Strength enhancement and modulus modulation in auxetic meta-biomaterials produced by selective laser melting.

Meta-biomaterials are applied to orthopedic implants to avoid stress shielding effects; however, there is no reason for the yield strength to be comparable to that of human bone. In this study, a composite unit cell was designed by combining the positive Poisson's ratio (PPR) and negative Poisson's ratio (NPR) unit cells, inspired by the second-phase strengthening theory. The purpose was to increase the strength while maintaining the elastic modulus. All structures were successfully fabricated from Ti-6Al-4V via selective laser melting. The relative density is between 0.08 and 0.24, which falls within the optimal range for bone growth. Mechanical tests indicated that the center of the inclined rod fractured in a stepwise fracture mode, which was consistent with the predictions of the Johnson-Cook model. The elastic modulus ranged from 0.652 ± 0.016 to 5.172 ± 0.021 GPa, and the yield strength varied from 10.62 ± 0.112 to 87.158 ± 2.215 MPa. An improved Gibson-Ashby law was proposed to facilitate the design of gradient structures. When the re-entrant angle was 40°, a hybrid body-centered cubic NPR structure was formed, resulting in a significant improvement in the mechanical properties. Importantly, the yield strength of the proposed composite structures increased by 43.23%, and the compression strength increased by 44.70% under the same elastic modulus. The strengthening mechanism has been proven to apply to other bending-dominated structures. Overall, this imparts unprecedented mechanical performance to auxetic meta-biomaterials and provides insights into improving the reported porous structures. STATEMENT OF SIGNIFICANCE: Auxetic meta-biomaterials exhibit auxetic properties that can improve the contact between the bone-implant interface and reduce the risk of aseptic failure. To avoid the stress shielding effect, the elastic modulus has traditionally been decreased by increasing the porosity. However, the strength is simultaneously reduced. Therefore, a composite unit cell was proposed to increase strength rather than modulus by combining the positive and negative Poisson's ratio unit cells, inspired by the second-phase strengthening theory. We observed a 43.23% increase in the yield strength of the composite structure without increasing the elastic modulus. This strengthening mechanism has been proven to apply to other bending-dominated structures. Our approach provides insights into improving other bending-dominated structures and broadening their applications for bone implantation.

Recent progress on FAK inhibitors with dual targeting capabilities for cancer treatment.

Focal adhesion kinase (FAK, also known as PTK2) is a tyrosine kinase that regulates integrin and growth factor signaling pathways and is involved in the migration, proliferation and survival of cancer cells. FAK is a promising target for cancer treatment. Many small molecule FAK inhibitors have been identified and proven in both preclinical and clinical studies to be effective inhibitors of tumor growth and metastasis. There are many signaling pathways, such as those involving FAK, Src, AKT, MAPK, PI3K, and EGFR/HER-2, that provide survival signals in cancer cells. Dual inhibitors that simultaneously block FAK and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, the antitumor mechanisms and research status of dual inhibitors of FAK and other targets, such as Pyk2, IGF-IR, ALK, VEGFR-3, JAK2, EGFR, S6K1, and HDAC2, are summarized, providing new ideas for the development of effective FAK dual-target preparations.

Single-cell RNA sequencing reveals Nestin+ active neural stem cells outside the central canal after spinal cord injury.

Neural stem cells (NSCs) in the spinal cord hold great potential for repair after spinal cord injury (SCI). The ependyma in the central canal (CC) region has been considered as the NSCs source in the spinal cord. However, the ependyma function as NSCs after SCI is still under debate. We used Nestin as a marker to isolate potential NSCs and their immediate progeny, and characterized the cells before and after SCI by single-cell RNA-sequencing (scRNA-seq). We identified two subgroups of NSCs: the subgroup located within the CC cannot prime to active NSCs after SCI, while the subgroup located outside the CC were activated and exhibited the active NSCs properties after SCI. We demonstrated the comprehensive dynamic transcriptome of NSCs from quiescent to active NSCs after SCI. This study reveals that Nestin+ cells outside CC were NSCs that activated upon SCI and may thus serve as endogenous NSCs for regenerative treatment of SCI in the future.

Single-cell analysis reveals dynamic changes of neural cells in developing human spinal cord.

During central nervous system development, neurogenesis and gliogenesis occur in an orderly manner to create precise neural circuitry. However, no systematic dataset of neural lineage development that covers both neurogenesis and gliogenesis for the human spinal cord is available. We here perform single-cell RNA sequencing of human spinal cord cells during embryonic and fetal stages that cover neuron generation as well as astrocytes and oligodendrocyte differentiation. We also map the timeline of sensory neurogenesis and gliogenesis in the spinal cord. We further identify a group of EGFR-expressing transitional glial cells with radial morphology at the onset of gliogenesis, which progressively acquires differentiated glial cell characteristics. These EGFR-expressing transitional glial cells exhibited a unique position-specific feature during spinal cord development. Cell crosstalk analysis using CellPhoneDB indicated that EGFR glial cells can persistently interact with other neural cells during development through Delta-Notch and EGFR signaling. Together, our results reveal stage-specific profiles and dynamics of neural cells during human spinal cord development.

Multi-Pharmaceutical Activities of Chinese Herbal Polysaccharides in the Treatment of Pulmonary Fibrosis: Concept and Future Prospects.

Pulmonary fibrosis is a fatal chronic progressive respiratory disease, characterized by continuous scarring of the lung parenchyma, leading to respiratory failure and death. The incidence of PF has increased over time. There are drugs, yet, there are some limitations. Hence, it is of importance to find new therapies and new drugs to replace the treatment of pulmonary fibrosis. In recent years, there have been a great number of research reports on the treatment of traditional Chinese medicine polysaccharides in various system fields. Among them, the treatment of PF has also gained extensive attention. This review summarized the source of polysaccharides, the drug activity of traditional Chinese medicine, and the protective effects on targets of Pulmonary fibrosis. We hope it can inspire researchers to design and develop polysaccharides, serving as a reference for potential clinical therapeutic drugs.

Novel compound heterozygous DNAAF2 mutations cause primary ciliary dyskinesia in a Han Chinese family.

PURPOSE: Primary ciliary dyskinesia (PCD), which commonly causes male infertility, is an inherited autosomal recessive disorder. This study aimed to investigate the clinical manifestations and screen mutations associated with the dynein axonemal assembly factor 2 (DNAAF2) gene in a Han Chinese family with PCD. METHODS: A three-generation family with PCD was recruited in this study. Eight family members underwent comprehensive medical examinations. Genomic DNA was extracted from the participants' peripheral blood, and targeted next-generation sequencing technology was used to perform the mutation screening. The DNAAF2 expression was analyzed by immunostaining and Western blot. RESULTS: The proband exhibited the typical clinical features of PCD. Spermatozoa from the proband showed complete immotility but relatively high viability. Two novel compound heterozygous mutations in the DNAAF2 gene, c.C156A [p.Y52X] and c.C26A [p.S9X], were identified. Both nonsense mutations were detected in the proband, whereas the other unaffected family members carried either none or only one of the two mutations. The two nonsense heterozygous mutations were not detected in the 600 ethnically matched normal controls or in the Genome Aggregation Database. The defect of the DNAAF2 and the outer dynein arms and inner dynein arms were notably observed in the spermatozoa from the proband by immunostaining. CONCLUSION: This study identified two novel compound heterozygous mutations of DNAAF2 leading to male infertility as a result of PCD in a Han Chinese family. The findings may enhance the understanding of the pathogenesis of PCD and improve reproductive genetic counseling in China.

Estrogen regulation of germline stem cell differentiation as a mechanism contributing to female reproductive aging.

Progressive loss of ovarian estrogen (E2) production is a hallmark feature of, if not a driving force behind, reproductive aging and the menopause. Recent genetic studies in mice have shown that female germline or oogonial stem cells (OSCs) contribute to maintenance of adult ovarian function and fertility under physiological conditions through support of de-novo oogenesis. Here we show that mouse OSCs express E2 receptor-α (ERα). In the presence of E2, ERα interacts with the stimulated by retinoic acid gene 8 (Stra8) promoter to drive Stra8 expression followed by oogenesis. Treatment of mice with E2 in vivo increases Stra8 expression and oogenesis, and these effects are nullified by ERα (Esr1), but not ERß (Esr2), gene disruption. Although mice lacking ERα are born with a normal quota of oocytes, ERα-deficient females develop premature ovarian insufficiency in adulthood due to impaired oogenesis. Lastly, mice treated with reversible ER antagonists show a loss of Stra8 expression and oocyte numbers; however, both endpoints rebound to control levels after ceasing drug treatment. These findings establish a key physiological role for E2-ERα signaling in promoting OSC differentiation as a potential mechanism to maintain adequate numbers of ovarian follicles during reproductive life.

Mangiferin induces islet regeneration in aged mice through regulating p16INK4a.

Previous studies by our group on mangiferin demonstrated that it exerts an anti­hyperglycemic effect through the regulation of cell cycle proteins in 3­month­old, partially pancreatectomized (PPx) mice. However, ß­cell proliferation is known to become severely restricted with advanced age. Therefore, it is unknown whether mangiferin is able to reverse the diabetic condition and retain ß­cell regeneration capability in aged mice. In the present study, 12­month­old C57BL/6J mice that had undergone PPx were subjected to mangiferin treatment (90 mg/kg) for 28 days. Mangiferin­treated aged mice exhibited decreased blood glucose levels and increased glucose tolerance, which was accompanied with higher serum insulin levels when compared with those in untreated PPx control mice. In addition, islet hyperplasia, elevated ß­cell proliferation and reduced ß­cell apoptosis were also identified in the mice that received mangiferin treatment. Further studies on the mRNA transcript and protein expression levels indicated comparatively increased levels of cyclins D1 and D2 and cyclin­dependent kinase 4 in mangiferin­treated mice, while the levels of p27Kip1 and p16INK4a were decreased relative to those in the untreated PPx controls. Of note, mangiferin treatment improved the proliferation rate of islet ß­cells in adult mice overexpressing p16INK4a, suggesting that mangiferin induced ß­cell proliferation via the regulation of p16INK4a. In addition, the mRNA transcription levels of critical genes associated with insulin secretion, including pancreatic and duodenal homeobox 1, glucose transporter 2 and glucokinase, were observed to be upregulated after mangiferin treatment. Taken together, it was indicated that mangiferin treatment significantly induced ß­cell proliferation and inhibited ß­cell apoptosis by regulating cell cycle checkpoint proteins. Furthermore, mangiferin was also demonstrated to regulate genes associated with insulin secretion. Collectively these, results suggest the therapeutic potential of mangiferin in the treatment of diabetes in aged individuals.

Nuclear GSK3ß induces DNA double-strand break repair by phosphorylating 53BP1 in glioblastoma.

Glioblastoma is the most malignant and lethal subtype brain tumors with high risk of recurrence and therapeutic resistance. Emerging evidence has indicated that glycogen synthesis kinase 3 (GSK3)ß plays oncogenic roles in multiple tumor types; however, the underlying mechanisms remain largely unknown. It has also been demonstrated that p53 binding protein 1 (53BP1) plays a central role in DNA double-strand break (DSB) repair. This study aimed to reveal the significance of GSK3ß translocation from the cytoplasm to the nucleus, and to determine whether GSK3ß induces DNA DSB repair in the nuclei of glioblastoma cells via phospho-53BP1. By performing in vitro experiments, we found that GSK3ß translocated from the cytoplasm to the nucleus, and it then bound to 53BP1 following exposure to IR (IR). In addition, 53BP1-mediated DNA DSB repair was observed to be abrogated by the inhibition of GSK3ß. Further experiments on the phosphorylation site of 53BP1 by GSK3ß revealed that the S/T-Q motif may play a critical role. Importantly, our in vivo and in vitro data clearly indicated that GSK3ß induced the phosphorylation of 53BP1 at the Ser166 site. Moreover, brain tumor xenograft models revealed that following exposure to IR plus SB216763, a specific GSK3ß inhibitor, tumor growth was markedly inhibited and the survival of mice markedly increased. Based on these results, we concluded that the phosphorylation of 53BP1 by GSK3ß was indispensable for DNA DSB repair. Our study also suggested that the inhibition of GSK3ß by SB216763 significantly inhibited the proliferation and induced the apoptosis of glioblastoma cells. Taken together, our data indicate that GSK3ß, a key phosphorylation protein for 53BP1, may be a potential target for enhancing the sensitivity of glioblastoma cells to radiation.

YAP and TAZ mediate steroid-induced alterations in the trabecular meshwork cytoskeleton in human trabecular meshwork cells.

Primary open angle glaucoma is an important type of glaucoma as it is one of the most common causes of blindness. Previous studies have demonstrated that in glaucomatous patients, the human trabecular meshwork (HTM) is markedly stiffened. The purpose of the present study was to determine the regulatory role of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in HTM cells. Primary HTM cells were cultured with different concentrations of dexamethasone (DEX), and the expression levels of YAP and TAZ were evaluated using reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that DEX increased the expression of YAP and TAZ in a dose-dependent manner. In addition, the western blot analysis of cytoskeleton-associated proteins revealed that the inhibition of YAP and/or TAZ using small interfering RNA resulted in the increased expression of collagen I, and decreased expression of fibronectin, laminin and collagen IV. The expression of ß-catenin, a key protein in the Wnt pathway, was also observed to be regulated by YAP and TAZ. A 5-ethynyl-2'-deoxyuridine staining assay indicated that YAP and TAZ induced the proliferation of HTM cells. The investigation of cross-linked actin network formation by the HTM cells demonstrated that the knockdown of YAP and TAZ genes rescued HTM cells from cytoskeletal reorganization. Furthermore, functional evaluation of a HTM cell monolayer using a permeability assay demonstrated that the inhibition of YAP and TAZ attenuated the DEX-induced impairment of permeability. These findings suggest that YAP and TAZ play pivotal roles in the DEX-induced cytoskeletal changes of HTM cells, and reveal novel potential mechanisms for the development and progression of glaucoma.

Amygdalin ameliorates the progression of atherosclerosis in LDL receptor­deficient mice.

Previous studies have demonstrated that regulatory T cells (Tregs) are pivotal in the regulation of T cell­mediated immune responses in atherosclerosis, a chronic autoimmune­like disease. In the authors' previous studies, it was demonstrated that amygdalin ameliorated atherosclerosis by the regulation of Tregs in apolipoprotein E­deficient (ApoE­/­) mice. Therefore, the aim of the present study was to investigate the therapeutic effect of amygdalin on low­density lipoprotein (LDL) receptor deficient (LDLR­/­) mice, and to examine its immune regulatory function by the stimulation of Tregs. To establish an atherosclerosis mouse model, the LDLR­/­ mice were fed a high fat and high cholesterol diet then the total plasma cholesterol, triglyceride, LDL and chemokines levels were measured by an ELISA. Following sacrificing the mice, the upper sections of the aorta were stained by hematoxylin and eosin, and Oil red O to assess the plaque area. Then western blotting and reverse transcription polymerase chain reactions were performed to analysis the expression levels of cluster of differentiation 68, monocyte chemoattractant protein­1, matrix metalloproteinase (MMP)­2, MMP­9 and forkhead box P3 (Foxp3). To further confirm the activation of FOXP3 by amygdalin, lentiviruses carrying Foxp3 shRNA were injected into the mice, and the serum cytokines levels were measured by ELISA. Following feeding of the mice with a high­fat/high­cholesterol diet, the LDLR­/­ mice demonstrated comparatively higher levels of triglyceride, total cholesterol and LDL, compared with levels in the amygdalin­treated mice. By comparing the vessel area, lumen area, plaque area, and percentage aortic plaque coverage, the effects of amygdalin on pre­existing lesions were assessed. In addition, the levels of CD68, monocyte chemoattractant protein­1, MMP­2 and MMP­9 were analyzed, and analysis of the expression of interleukin (IL)­1ß, IL­6 and tumor necrosis factor (TNF)­α indicated that the mice treated with amygdalin had decreased expression of pro­inflammatory cytokines. The mRNA and protein levels of Foxp3 were also quantified, and the mice treated with amygdalin demonstrated an increased number of Tregs. The knockdown of Foxp3mRNA resulted in the increased secretion of IL­1ß, IL­6 and TNF­α. Therefore, the data indicated that amygdalin regulated the formation of atherosclerosis and stabilized the plaque by suppressing inflammatory responses and promoting the immune­modulation function of Tregs. Taken together, the results demonstrated the therapeutic effect of amygdalin on atherosclerosis.

Mangiferin induces apoptosis in human ovarian adenocarcinoma OVCAR3 cells via the regulation of Notch3.

Ovarian cancer is the most lethal gynecological malignancy in the world. Our previous studies showed that mangiferin, purified from plant source, possessed anti-neoplasm effect on human lung adenocarcinoma A549 cells. This study aimed to determine the apoptosis-inducing effect of mangiferin on human ovarian carcinoma OVCAR3 cells. By in vitro studies, we found mangiferin significantly inhibited viability of OVCAR3 cells, and remarkably increased the sensitivity of OVCAR3 cells to cisplatin. In addition, the activation of caspase-dependent apoptosis was observed in mangiferin treated ovarian cancer cells. Importantly, we observed an obviously downregulated Notch expression after mangiferin treatment, indicating the crucial role of Notch in mangiferin mediated apoptosis. In contrast, overexpression of Notch3 abrogated the apoptosis-inducing efficacy of mangiferin, further demonstrating that mangiferin induced apoptosis via Notch pathway. Furthermore, OVCAR3 cell xenograft models revealed that mangiferin treatment inhibited tumor growth and expanded survival of tumor xenograft mice. Based on these results, we concluded that mangiferin could significantly inhibit the proliferation and induce apoptosis in OVCAR3 cells. Our study also suggested the anti-neoplasm effect of mangiferin might be via the regulation of Notch3. Taken together, by targeting cell apoptosis pathways and enhancing the response to cisplatin treatment, mangiferin may represent a potential new drug for the treatment of human ovarian cancer.

Supplementation of fermented Maillard-reactive whey protein enhances immunity by increasing NK cell activity.

OBJECTIVE: The objective of this study was to investigate the impact of supplementation with fermented Maillard-reactive whey protein (F-MRP) on natural killer (NK) cell activity, circulating cytokines, and serum protein levels. METHODS: A randomized, double-blind, placebo-controlled study was conducted on a sample of 80 participants without diabetes or obesity. Over an 8-week study period, the F-MRP group consumed 6 g of powder containing 4.2 g of F-MRP each day, whereas the placebo group consumed the same amount of maltodextrin. For each participant, NK cell activity was evaluated based on the ratio of effector cells (E; peripheral blood mononuclear cells, PBMCs) to target cells (T; K562 cells) at E : T ratios of 10 : 1, 5 : 1, 2.5 : 1, and 1.25 : 1. RESULTS: Body mass index (BMI) and NK cell activity under all assay conditions were significantly increased in the F-MRP group at the 8-week follow-up visit compared with the values at the baseline, whereas the placebo group showed significant reductions in NK cell activity (at an E : T ratio of 5 : 1), serum albumin, and pre-albumin at the 8-week follow-up visit compared with the values at the baseline. When comparing the changes between the placebo and F-MRP groups, the increases in NK cell activity under all assay conditions and serum interleukin (IL)-12 in the F-MRP group were greater than those in the placebo group after adjusting for baseline values. There were also significant differences in pre-albumin and insulin-like growth factor (IGF)-1 between the two groups; the change in (Δ) IL-12 was positively correlated with both Δpre-albumin (r = 0.435, P = 0.006) and ΔNK cell activity at an E : T ratio of 10 : 1 (r = 0.571, P < 0.001) in the F-MRP group. CONCLUSION: Daily consumption of F-MRP enhanced NK cell function, which was positively associated with ΔIL-12. Moreover, ΔIL-12 was positively correlated with Δpre-albumin.

Laparoscopic Radiofrequency Ablation Combined with Surgical Excision for Exophytic Renal Angiomyolipoma: A Novel Technique Based on Tumor Vasculature Features of Enhancing Renal Masses Toward Hilar Off-Clamping Nephron-Sparing Surgery.

OBJECTIVES: Symptomatic angiomyolipoma (AML) and asymptomatic AML larger than 4 cm in size are usually treated with nephron-sparing surgery or transarterial embolization. We used radiofrequency ablation to treat the vascular pedicle of exophytic AML with low R.E.N.A.L. nephrometry score and investigated its feasibility for hilar off-clamping nephron-sparing surgery. METHODS: Contrast-enhanced computed tomography (CT) showed enhanced, well-defined lipomatous tumors with a maximum diameter of 4-8 cm in the kidney of 15 patients. Results indicated that the exophytic tumors featured in the enlarged tumor vasculatures extended into the parenchyma of the involved kidney. The patients underwent radiofrequency ablation by using a Cool-tip™ probe placed into the root of the AML mass from different directions under laparoscopic ultrasonography guidance. After sealing the vascular pedicle of the tumor, the bloodless tumors were resected en bloc without renal hilar clamping or suturing the resection defect of the kidney. RESULTS: All patients underwent the procedure smoothly, and no perioperative complications occurred. The contrast-enhanced CT scan showed small defects in the contrast-enhanced renal parenchyma at third month after the procedure, and the decrease in function of the treated kidneys was <10% during the 12-month follow-up. CONCLUSIONS: Our initial experience suggests that sealing the tumor vessels by radiofrequency ablation based on the tumor vasculature features of a renal mass is an alternative to hilar clamping in laparoscopic nephron-sparing surgery. Laparoscopic radiofrequency ablation and tumor excision are a definitive and safe minimally invasive procedure that allows the successful removal of exophytic sporadic AML mass with low R.E.N.A.L. nephrometry score.

The association of serotonin transporter gene polymorphism and geriatric depression: a meta-analysis.

Serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is the genetic variant coding for the serotonin transporter and may play an important role in the etiology of depression. However, genetic studies examining the relationship between 5-HTTLPR polymorphism and geriatric depression have produced inconsistent results. We conducted a meta-analysis to compare the frequency of 5-HTTLPR variants in geriatric depression cases and non-depressed controls in the elderly. A total of 5 studies involving 579 geriatric cases and 1372 non-depressed controls met the inclusion criteria. With strong statistical power, pooled odds ratios (ORs) and 95% confidence intervals (CIs) for genotypic analyses (S carrier versus L/L, S/S versus L/L) were provided. The results of our analysis indicate statistically significant association between S allele and the risk of geriatric depression (OR ScarriervsS/S=1.29, 95% CI 1.01-1.66; OR S/SvsL/L=1.68, 95% CI 1.20-2.35). Our findings suggest that 5-HTTLPR polymorphism is of importance in the development of geriatric depression.