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Background: Traditional Chinese medicine (TCM) has been used to treat various diseases for thousands of years. However, the uncertainty of dosage as well as the lack of systemic evaluation of pharmacology and toxicology is one major reason why TCM remains mysterious and is not accepted worldwide. Hence, we aimed to propose an integrated dose–response metabolomics strategy based on both therapeutic effects and adverse reactions to guide the TCM dosage in treatment. Methods: The proposed methodology of integrated dose–response metabolomics includes four steps: dose design, multiple comparison of metabolic features, response calculation and dose–response curve fitting. By comparing the changes of all metabolites under different doses and calculating these changes through superposition, it is possible to characterize the global disturbance and thus describe the overall effect and toxicity of TCM induced by different doses. Rhubarb, commonly used for constipation treatment, was selected as a representative TCM. Results: This developed strategy was successfully applied to rhubarb. The dose–response curves clearly showed the efficacy and adverse reactions of rhubarb at different doses. The rhubarb dose of 0.69 g/kg (corresponding to 7.66 g in clinic) was selected as the optimal dose because it was 90% of the effective dose and three adverse reactions were acceptable in this case. Conclusion: An integrated dose–response metabolomics strategy reflecting both therapeutic effects and adverse reactions was established for the first time, which we believe is helpful to uncover the mysterious veil of TCM dosage. In addition, this strategy benefits the modernization and internationalization of TCM, and broadens the application of metabolomics. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial ovarian cancer (EOC) is the deadliest cancer in the female reproductive system. Currently, there are no effective early detection methods for this disease, and the treatments for advanced stages of EOC have a low success rate. Circular RNAs (circRNAs) are noncoding RNAs generated from the "back-splicing" of precursor messenger RNAs. Recent studies have shown that many circRNAs are aberrantly expressed in tumor tissues and/or plasma of EOC patients, and they regulate EOC cell activity and tumor growth. In this review, we provide an overview of EOC and circRNA biology. We then summarize circRNAs that are dysregulated and exert tumor-promoting or tumor-suppressive effects in EOC. We also discuss the possibility of using circRNAs as diagnostic/prognostic markers and therapeutic targets. Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, and more than 70% of patients are diagnosed at advanced stages. Despite the application of surgery and chemotherapy, the prognosis remains poor due to the high relapse rate. It is urgent to identify novel biomarkers and develop novel therapeutic strategies for EOC. Circular RNAs (circRNAs) are a class of noncoding RNAs generated from the "back-splicing" of precursor mRNA. CircRNAs exert their functions via several mechanisms, including acting as miRNA sponges, interacting with proteins, regulating transcription, and encoding functional proteins. Recent studies have identified many circRNAs that are dysregulated in EOC and may be used as diagnostic and prognostic markers. Increasing evidence has revealed that circRNAs play a critical role in ovarian cancer progression by regulating various cellular processes, including proliferation, apoptosis, metastasis, and chemosensitivity. The circRNA-based therapy may be a novel strategy that is worth exploring in the future. Here, we provide an overview of EOC and circRNA biogenesis and functions. We then discuss the dysregulations of circRNAs in EOC and the possibility of using them as diagnostic/prognostic markers. We also summarize the role of circRNAs in regulating ovarian cancer development and speculate their potential as therapeutic targets. [ABSTRACT FROM AUTHOR]

Screening drug combinations using tumor spheroids can play a vital role in the development of disease treatment and personalized medicine. However, current studies focus on drug gradients or combinations of two drugs in most cases, and it is difficult to find complex therapeutic combinations involving more drugs. The use of design-of-experiment (DOE) microfluidics is a potential strategy to study this area systematically. Here we develop a high-throughput, open-space multilayered PMMA microfluidic chip for combinational drug screening on tumor spheroids. This microchip is straightforward to fabricate, compatible with standard spheroid cultures, and friendly for end-users. The device consists of an inlet layer and multiple dispersing layers. In the inlet layer, different samples can be loaded into the chip simultaneously. The sample solutions flow into the dispersing layers to generate various combinations based on the specific DOE principle. We demonstrated that the chip performance is in quantitative agreement with the design, using water and doxycycline combinations as models. As a proof-of-concept study, we constructed a HeLa reporter cell line to quantify the autophagy of tumor spheroids and used the chip to identify critical factors relating to the growth of the spheroids. Specifically, we used L -glutamine, D -glucose, FBS, and cisplatin as the factors and studied the autophagy, growth curves, and spheroid sizes in response to different combinations of the four factors. We found that D -glucose can inhibit the effects of cisplatin on tumor spheroids, and cisplatin caused severe autophagy in 3D tumor spheroids compared to 2D monoculture cells. Our method has the potential to allow more drug combinations to be examined, and it can be extended to DOE approaches with seven or more inputs. [ABSTRACT FROM AUTHOR]

Objectives. The purpose of this study was to identify the molecular mechanism and prognosis-related genes of Jianpi Jiedu decoction in the treatment of hepatocellular carcinoma. Methods. The gene expression data of hepatocellular carcinoma samples and normal tissue samples were downloaded from TCGA database, and the potential targets of drug composition of Jianpi Jiedu decoction were obtained from TCMSP database. The genes were screened out in order to obtain the expression of these target genes in patients with hepatocellular carcinoma. The differential expression of target genes was analyzed by R software, and the genes related to prognosis were screened by univariate Cox regression analysis. Then, the LASSO model was constructed for risk assessment and survival analysis between different risk groups. At the same time, independent prognostic analysis, GSEA analysis, and prognostic analysis of single gene in patients with hepatocellular carcinoma were performed. Results. 174 compounds of traditional Chinese medicine were screened by TCMSP database, corresponding to 122 potential targets. 39 upregulated genes and 9 downregulated genes were screened out. A total of 20 candidate prognostic related genes were screened out by univariate Cox analysis, of which 12 prognostic genes were involved in the construction of the LASSO regression model. There was a significant difference in survival time between the high-risk group and low-risk group (p < 0.05). Among the genes related to prognosis, the expression levels of CCNB1, NQO1, NUF2, and CHEK1 were high in tumor tissues (p < 0.05). Survival analysis showed that the high expression levels of these four genes were significantly correlated with poor prognosis of HCC (p < 0.05). GSEA analysis showed that the main KEGG enrichment pathways were lysine degradation, folate carbon pool, citrate cycle, and transcription factors. Conclusions. In the study, we found that therapy target genes of Jianpi Jiedu decoction were mainly involved in metabolism and apoptosis in hepatocellular carcinoma, and there was a close relationship between the prognosis of hepatocellular carcinoma and the genes of CCNB1, NQO1, NUF2, and CHEK1. [ABSTRACT FROM AUTHOR]

Understanding the factors affecting activities of daily living (ADL) is important in Alzheimer's disease (AD), because decline in ADL contributes to many poor health outcomes. Existing studies often investigate the factors in isolation without a theoretical framework. The purpose of the present study was to provide preliminary results on how cognition, physical performance, and behavioral and psychological symptoms of dementia mediate the relationship of aerobic fitness and ADL in AD. A cross‐sectional analysis was used (n = 28: average age 78 [8] years, education 16 (3) years, Mini‐Mental State Examination scores 20 [4]). The results showed that aerobic fitness is not linked to ADL directly, and its association with ADL was mediated by physical performance and global cognition. Our findings provide preliminary support for aerobic fitness as a potential therapeutic target, as enhanced aerobic fitness could simultaneously modify other factors affecting ADL. Nurses are in a unique position for coordinating exercise safety assessment and prescription and educating older adults with AD about exercise participation. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) has received increasing attention from oncologists worldwide due to its poor prognosis and paucity of targeted therapies. MicroRNAs (miRs) are a group of small non‑coding RNAs that are responsible for the post‑transcriptional regulation of various target genes. The present study demonstrated that the expression of miR‑199b‑5p in breast cancer tissue was significantly reduced compared with that in normal breast tissues by reverse transcription‑quantitative polymerase chain reaction. In addition, western blot analysis and luciferase reporter assays revealed that miR‑199b‑5p in TNBC cells inhibited discoidin domain receptor tyrosine kinase 1 expression by directly targeting its 3'‑untranslated region. Furthermore, miR‑199b‑5p markedly suppressed the proliferation and invasion of TNBC cells, as demonstrated by using wound‑healing, migration, invasion and proliferation assays. Collectively, these results indicate that miR‑199b‑5p may be a novel alternative therapeutic target for TNBC. [ABSTRACT FROM AUTHOR]

Chronic cerebral hypofusion (CCH) after bilateral carotid artery occlusion (2VO) causes cognitive damage and neuronal degeneration in the cortex and hippocampal CA1 area, and influences the oxygen and glucose supply in the brain which often results in metabolic alterations and oxidative stress. AMP-activated protein kinase (AMPK) phosphorylation, a sensor of cellular energy status, directs metabolic adaptation to support cellular growth and survival after CCH. Autophagy is also likely to be involved in metabolic adaptation and plays an important role in neuronal deterioration and cognitive decline after CCH. Nimodipine, an L-type calcium channel antagonist, has been reported to exert neuroprotective effects. However, the potential role of nimodipine in autophagy and the energy sensing AMPK signal is not well understood. In addition, little is known about the relationship between autophagy and AMPK signal. Here, we designed a way to evaluate these issues. Adult male Wistar rats were subjected to 2VO and randomly divided into three groups: the Vehicle (2VO), Nimodipine (2VO + nimodipine 10 mg/kg) groups. A third group served as sham controls. Each group was investigated at 2 and 4 weeks post gavage and tested using the Morris water maze. The activities of LC3B and AMPK signal were examined using immunohistochemistry and western blotting. Nimodipine significantly alleviated spatial learning and memory impairments and the number of lesion neurons. At 2 weeks of durg administration, these drug effects, suppressing AMPK activation and excessive autophagy, were more pronounced at the cortex than at hippocampal CA1 area. The effects of nimodipine were significant in the hippocampal CA1 area after 4 weeks of administration. Furthermore, nimodipine inhibited expression of eIF2α/ATF4 signaling related to energy deficit stress in 2VO rats. These results suggest that excessive autophagy has promoted neuronal and tissue injury after 2VO in rats. Nimodipine protected the brain from CCH by inhibiting the autophagy activity. The p-AMPK and eIF2α/ATF4 pathway is likely part of an integrated pro-autophagy signaling network after CCH. [ABSTRACT FROM AUTHOR]

The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid-substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3 , 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC 50 values toward the V370A and ΔV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants. [ABSTRACT FROM AUTHOR]

Chronic cerebral hypofusion (CCH) promotes hyperphosphorylation of tau proteins, a key neuropathological trait that reflects neurodegenerative disorders. Nimodipine, an L-type calcium channel antagonist, has been reported to show neuroprotective effects. In this study, we investigated the potential mechanism of nimodipine in tauopathies induced by CCH. MiR-132 is downregulated in tauopathies such as AD and directly targets tau mRNA to regulate its expression. Here, we report that CCH induced miR-132 deficiency and increased tau phosphorylation at Ser396 while tau expression was not influenced. Nimodipine treatment attenuated CCH induced tau phosphorylation by up-regulating expression of miR-132. Furthermore, nimodipine inhibited activation of GSK-3β and neuronal apoptosis induced by CCH. Interestingly, GSK-3βmRNA level negatively correlated with the expression of miR-132. These findings support a role for nimodipine inhibiting tau phosphorylation at Ser396 via miR-132/GSK-3β. Therefore, nimodipine may be a candidate for the treatment of tauopathy present in CCH. [ABSTRACT FROM AUTHOR]

Current strategies for influenza virus vaccines primarily aim to elicit immune responses towards the globular head domain of the hemagglutinin (HA) protein so that binding of the virus to membrane receptors on the host cells is inhibited. In the present study, we show a novel strategy to generate immunity against the highly conserved region of the influenza virus. The globular head domain was replaced by different linkers to generate a headless HA (stalk domain) and then coexpressed with influenza M1 proteinin Tni insect cells. The expression was validated by western blot analysis, and stalk domain with peptides (GGGGS)4 linkers was identified to anchor in a stable way to the cell membrane. An immunoelectron microscope showed that stalk domain with (GGGGS)4 linkers were steadily incorporated to the surface of influenza virus-like particles (VLPs). Mice immunized with these VLPs exhibited enhanced systemic antibody responses with increased binding avidity and study found high titers of ADCC antibodies to the influenza virus, these VLPs also induced mucosal immune responses and produced antigen-specific IgG and IgA in nasal and lung washes. In addition, antigen-specific IgG antibody-secreting cells (ASCs) increased significantly in the spleen and lymph node. The results of this study suggest that the headless HA is a useful target in developing a universal vaccine against influenza virus. [ABSTRACT FROM AUTHOR]

Previous studies have demonstrated that 5ɑ-androst-3β,5,6β-triol (Triol), a synthesized steroid compound, showed notable neuroprotective effect in cultured cortical neurons. In the present study, we explored whether and how Triol have neuroprotective effect on retinal ganglion cells (RGCs) in a chronic ocular hypertension (COH) rat model. COH model was produced by injecting superparamagnetic iron oxide micro-beads into the anterior chamber, and Triol was administrated (4.8 μg/100 g, i.p., once daily for 4 weeks). Immunohistochemistry experiments showed that in whole flat-mounted COH retinas, the number of CTB-labeled survival RGCs was progressively reduced, while TUNEL-positive signals were significantly increased from 1 to 4 weeks after the micro-bead injection. Triol administration significantly attenuated the reduction in the number of CTB-labeled RGCs, and partially reduced the increased number of TUNEL-positive signals in COH retinas. Furthermore, Triol administration partially reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS), and significantly rescued the activities of mitochondrial respiratory chain complex (MRCC) I/II/III in COH retinas. Our results suggest that Triol prevents RGCs from apoptotic death in COH retinas by reducing the lipid peroxidation and enhancing the activities of MRCCs. [ABSTRACT FROM AUTHOR]

Objective: This study explored the protective effects of the microRNA-126 (miR-126)- mediated PI3K/Akt/eNOS signaling pathway on human cardiac microvascular endothelial cells (HCMECs) against hypoxia/reoxygenation (H/R)-induced injury and the inflammatory response. Methods: Untreated HCMECs were selected for the control group. After H/R treatment and cell transfection, the HCMECs were assigned to the H/R, miR-126 mimic, mimicnegative control (NC), miR-126 inhibitor, inhibitor-NC, wortmannin (an inhibitor of PI3K) and miR-126 mimic + wortmannin groups. Super oxide dismutase (SOD), nitric oxide (NO), vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS) were measured utilizing commercial kits. Quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to detect miR-126 expression and the mRNA and protein expression of inflammatory factors. Western blotting was used to determine the expression of key members in the PI3K/Akt/eNOS signaling pathway. ACCK- 8 assay and flow cytometry were employed to examine cell proliferation and apoptosis, respectively. The angiogenic ability in each group was detected by the lumen formation test. Results: Compared to the control group, p/t-PI3K, p/t-Akt and p/t-eNOS expression, NO, VEGF and SOD levels, cell proliferation and in vitro lumen formation ability were decreased, while the ROS content, interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-α expression and cell apoptosis were significantly increased in the H/R, mimic-NC, miR-126 inhibitor, inhibitor- NC, wortmannin and miR-126 mimic + wortmannin groups. Additionally, in comparison with the H/R group, the miR-126 mimic group had elevated p/t-PI3K, p/t-Akt and p/t-eNOS expression, increased NO, VEGF and SOD contents, and strengthened cell proliferation and lumen formation abilities but also exhibited decreased ROS content, reduced IL-6, IL-10 and TNF-α expressions, and weakened cell apoptosis, while the miR-126 inhibitor and wortmannin group exhibited the opposite results. Furthermore, decreased p/t-PI3K, p/t-Akt and p/t-eNOS expressions, decreased NO, VEGF and SOD contents, cell proliferation and lumen formation abilities, as well as increased ROS content, increased IL-6, IL-10 and TNF-α expression, and increased cell apoptosis were observed in the miR-126 mimic + wortmannin group compared to themiR-126 mimic group. Conclusions: These findings indicated that miR-126 protects HCMECs from H/R-induced injury and inflammatory response by activating the PI3K/Akt/ eNOS signaling pathway. [ABSTRACT FROM AUTHOR]

This study aims to investigate the therapeutic effects of papain elastic liposomes (PEL) on hypertrophic scar through topical application. PEL were prepared using the reverse-phase evaporation method and optimized by response surface methodology. The transdermal absorption of optimized PEL was tested by vertical Franz diffusion cells in vitro . The effects of PEL were investigated in rabbit model of hypertrophic scar in vivo , histological analysis and scar-related proteins were detected to reveal potential scar repair mechanism. The best formulation of PEL had EE (43.8 ± 1.4%), particle size (100.9 ± 2.2 nm), PDI (0.037 ± 0.003), zeta potential (−26.3 ± 1.3 mV), and DI (21.9 ± 3.1). PEL gave the cumulative amounts and steady state fluxes in the receiver solution of 381.9 ± 32.4 μg/cm 2 , 11.4 ± 1.5 μg/cm 2 /h, and showed drug deposition in skin of 19.1 ± 3.2% after 24 h. After topical application, the scar elevation index, microvascular density, and collagen fiber were significantly decreased with regular arrangement. The expressions of TGF-β 1 , P-Smad-3, P-NF-κB p65, and P-IKBa in hypertrophic scar were significantly down regulated in contrast with those in model group. PEL were proven as an excellent topical preparation for hypertrophic scar treatment. [ABSTRACT FROM AUTHOR]

Pain is one of the most challenging and stressful conditions to patients with sickle cell disease (SCD) and their clinicians. Patients with SCD start experiencing pain as early as 3 months old and continue having it throughout their lives. Although many aspects of the disease are well understood, little progress has been made in understanding and treating pain in SCD. This study aimed to investigate the functional involvement of Ca/calmodulin-dependent protein kinase II (CaMKIIα) in the persistent and refractory pain associated with SCD. We found that nonevoked ongoing pain as well as evoked hypersensitivity to mechanical and thermal stimuli were present in Berkeley sickle cell transgenic mice (BERK mice), but not nonsickle control littermates. Prominent activation of CaMKIIα was observed in the dorsal root ganglia and spinal cord dorsal horn region of BERK mice. Intrathecal administration of KN93, a selective inhibitor of CaMKII, significantly attenuated mechanical allodynia and heat hyperalgesia in BERK mice. Meanwhile, spinal inhibition of CaMKII elicited conditioned place preference in the BERK mice, indicating the contribution of CaMKII in the ongoing spontaneous pain of SCD. We further targeted CaMKIIα by siRNA knockdown. Both evoked pain and ongoing spontaneous pain were effectively attenuated in BERK mice. These findings elucidated, for the first time, an essential role of CaMKIIα as a cellular mechanism in the development and maintenance of spontaneous and evoked pain in SCD, which can potentially offer new targets for pharmacological intervention of pain in SCD. [ABSTRACT FROM AUTHOR]

Introduction: Tracheal papilloma presenting as asthma is a rare occurrence.Case Study: We report a case of a 32-year-old male patient who presented with features of asthma. Flexible bronchoscopy demonstrated a large growth arising from the lower end of the trachea. Successful treatment using snare loop and argon plasma coagulation (APC) of the polyploidal growth was performed via flexible bronchoscope.Results: The patient had immediate relief of airway obstruction and histopathological examination of the neoplasm demonstrated features of papilloma.Conclusion: Primary tracheal papilloma is mimicker of asthma, CT scan should be considered in patients with persistent chronic cough, or stridor. Endoscopic papillectomy is a safe and effective treatment and should be considered as first-line therapy for tracheal papilloma. [ABSTRACT FROM PUBLISHER]

The ubiquitin-proteasome system (UPS) is a complicated tightly controlled system in charge of degrading 80-90% of proteins, and is central to regulating cellular function and keeping protein homeostasis. Therefore, the components of UPS attract considerable attention as potential targets for hepatocellular carcinoma (HCC) therapy. The clinical success of bortezomib in multiple myeloma and mantle cell lymphoma patients has set the precedent for therapeutically targeting this pathway. This review will provide an overview of the UPS in HCC and the current status of therapeutic strategies. [ABSTRACT FROM AUTHOR]

A series of novel oxazolidinone compounds with a substituted ligustrazine C-ring unit and different substituted groups at the C-5 side chain were designed and synthesized using linezolid as a lead and based on a scaffold hopping strategy. Their antibacterial and anti-inflammatory activities were evaluated. The results of in vitro antibacterial assays showed that all fourteen target compounds displayed potent activity against Gram-positive pathogens, particularly 8b, 13b, 14a, 14b, 15a, and 15b. Moreover, 14a and 14b exhibited significant inhibitory activities on the production of inflammatory mediators, including nitric oxide, interleukin-6, and tumor necrosis factor-alpha. Thus, these derivatives could serve as valuable candidates to develop anti-infective agents for the treatment of chronic wounds. [ABSTRACT FROM AUTHOR]

Background: Total extraperitoneal (TEP) inguinal hernia repair gained popularity in the past two decades for its advantage, especially single incision laparoscopic surgery (SILS) for TEP inguinal hernia repair (SILS TEP), however, which is a technically demanding procedure.Methods: The study retrospectively analyzed 6 cases of the superior of inguinal ligament approach of S-SILS TEP repair from August 2015 to July 2016. A detailed review of medical records and the perioperative data including patient characteristics, operative details, and postoperative hospital stay was conducted.Results: S-SILS TEP repair for inguinal hernia was successfully completed for 6 patients, and the mean operation time was 59.2 minutes (range 55-70 minutes), and the mean blood loss was 7.5 mL (range 5-15 mL) and the postoperative recovery was uneventful about 3 days after operation with a single wound over inguinal ligament.Conclusions: S-SILS TEP repair provides a new operative view, which combines the advantage of laparoscopic and open surgery, especially in surgical technique and minimal invasiveness. Our experience suggests that the S-SILS TEP repair may be a safe and feasible alternative in inguinal hernias repair. [ABSTRACT FROM AUTHOR]

Background: The association between hyperinsulinemia and obesity is well known. However, it is uncertain especially in childhood obesity, if initial fasting hyperinsulinemia predicts obesity, or obesity leads to hyperinsulinemia through insulin resistance. Objective: To investigate the predictive effect of fasting plasma insulin on subsequent weight change after a 5-year interval in childhood. Methods: 424 Children from Da Qing city, China, were recruited at 5 years of age and followed up for 5 years. Blood pressure, anthropometric measurements, fasting plasma insulin, glucose and triglycerides were measured at baseline and 5 years later. Results: Fasting plasma insulin at 5 years of age was significantly correlated with change of weight from 5 to 10 years (ΔWeight). Children in the lowest insulin quartile had ΔWeight of 13.08±0.73 kg compare to 18.39±0.86 in the highest insulin quartile (P<0.0001) in boys, and similarly 12.03±0.71 vs 15.80±0.60 kg (P<0.0001) in girls. Multivariate analysis showed that the predictive effect of insulin at 5 years of age on subsequent weight gain over 5 years remained statistically significant even after the adjustment for age, sex, birth weight, TV-viewing time and weight (or body mass index) at baseline. By contrast, the initial weight at 5 years of age did not predict subsequent changes in insulin level 5 years later. Children who had both higher fasting insulin and weight at 5 years of age showed much higher levels of systolic blood pressures, fasting plasma glucose, the homeostasis model assessment for insulin resistance (HOMA-IR) and triglycerides at 10 years of age. Conclusions: Fasting plasma insulin at 5 years of age predicts weight gain and cardiovascular risk factors 5 year later in Chinese children of early childhood, but the absolute weight at 5 years of age did not predict subsequent change in fasting insulin. [ABSTRACT FROM AUTHOR]

Vaccination is the most effective means of preventing infectious diseases; however, few vaccines are effective against Streptococcus iniae ( S. iniae ) in grouper. This work presents an efficacious and safe vaccine against S. iniae infections in the grouper Epinephelus coioides . The vaccine candidate was the S. iniae GSI-310 strain. The vaccination was administered by intraperitoneal injection, and consisted of formalin-inactivated antigens combined with an AS-F or ISA763A adjuvant. Peripheral blood samples were collected for RT-qPCR and phagocytosis and agglutination assays. Our results indicated that immunoglobulin M ( igm ) was maximally expressed in the two vaccinated groups at 3 months post-secondary vaccination (PSV). A significant upregulation of mRNA expression for interleukin-1β ( il-1β) and tumor necrosis factor-α ( tnf-α) was also observed in fish treated with antigens combined with ISA763A, which peaked at 3 months PSV. In fish treated with antigens combined with AS-F, il-1β and tnf-α expression peaked at 14 days post-primary vaccination (PPV). Phagocytic activity and index increased significantly in the two vaccinated groups. Furthermore, fish in the two vaccinated groups exhibited significantly elevated agglutination titers compared to fish in the control group, in which almost no agglutination reaction was detected. In the efficacy test, the vaccinated and control groupers were treated with S. iniae at 1, 3, and 6 months PSV. The relative percentage survival (RPS) values of antigens with AS-F and antigens with ISA763A were both 100% at 1 and 3 months PSV; at 6 months PSV, the RPS values for these groups were 100% and 97.7%, respectively. Furthermore, the level of protection observed in the field trial closely resembled that achieved on a laboratory scale. Therefore, the proposed vaccine mixed with AS-F or ISA763A improved immune responses and provided safe and long-lasting protection in farmed groupers. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are characterized by intrinsic self-renewal and tumorigenic properties, and play important roles in tumor initiation, progression, and resistance to diverse forms of anticancer therapy. Accordingly, targeting signaling pathways that are critical for CSC maintenance and biofunctions, including the Wnt, Notch, Hippo, and Hedgehog signaling cascades, remains a promising therapeutic strategy in multiple cancer types. Furthermore, advances in various cancer omics approaches have largely increased our knowledge of the molecular basis of CSCs, and provided numerous novel targets for anticancer therapy. However, the majority of recently identified targets remain 'undruggable' through small-molecule agents, whereas the implications of exogenous RNA interference (RNAi, including siRNA and miRNA) may make it possible to translate our knowledge into therapeutics in a timely manner. With the recent advances of nanomedicine, in vivo delivery of RNAi using elaborate nanoparticles can potently overcome the intrinsic limitations of RNAi alone, as it is rapidly degraded and has unpredictable off-target side effects. Herein, we present an update on the development of RNAi-delivering nanoplatforms in CSC-targeted anticancer therapy and discuss their potential implications in clinical trials. [ABSTRACT FROM AUTHOR]

Standard therapy for asthma, a highly heterogeneous disease, is primarily based on bronchodilators and immunosuppressive drugs, which confer short-term symptomatic relief but not a cure. It is difficult to discover novel bronchodilators, although potential new targets are emerging. Traditional Chinese Medicine (TCM) formulas have been used to treat asthma for more than 2000 years, forming the basis for representative asthma treatments. Based on the efficacy of TCM formulas, anti-asthmatic herbal compounds bind proteins are potential targets for asthma therapy. This analysis will provide new drug targets and discovery strategies for asthma therapy. A list of candidate herbs for asthma was selected from the classical formulas (CFs) of TCM for the treatment of wheezing or dyspnea recorded in Treatise on Cold Damage and Miscellaneous Diseases (TCDMD) and from modern herbal formulas identified in the SAPHRON TCM Database using the keywords "wheezing" or "dyspnea". Compounds in the selected herbs and compounds that directly bind target proteins were acquired by searching the Herbal Ingredients' Targets Database (HITD), TCM Data Bank (TCMDB) and TCM Integrated Database (TCMID). Therapeutic targets of conventional medicine (CM) for asthma were collected by searching Therapeutic Target Database (TTD), DrugBank and PubMed as supplements. Finally, the enriched gene ontology (GO) terms of the targets were obtained using the Database for Annotation Visualization and Integrated Discovery (DAVID) and protein-protein interactions (PPI) networks were constructed using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING). The effects of two selected TCM compounds, kaempferol and ginkgolide A, on cellular resistance in human airway smooth muscle cells (ASMCs) and pulmonary resistance in a mouse model were investigated. The list of 32 candidate herbs for asthma was selected from 10 CFs for the treatment of wheezing or dyspnea recorded in TCDMD and 1037 modern herbal formulas obtained from the SAPHRON TCM Database. A total of 130 compounds from the 32 selected herbs and 68 herbal compounds directly bind target proteins were acquired from HITD and TCMDB. Eighty-eight therapeutic targets of CM for asthma were collected by searching TTD and PubMed as supplements. DAVID and STRING analyses showed targets of TCM formulas are primarily related to cytochrome P450 (CYP) family, transient receptor potential (TRP) channels, matrix metalloproteinases (MMPs) and ribosomal protein. Both TCM formulas and CM act on the same types of targets or signaling pathways, such as G protein-coupled receptors (GPCRs), steroid hormone receptors (SHRs), and JAK-STAT signaling pathway. The proteins directly targeted by herbal compounds, TRPM8, TRPA1, TRPV3, CYP1B1, CYP2B6, CYP1A2, CYP3A4, CYP1A1, PPARA, PPARD, NR1I2, MMP1, MMP2, ESR1, ESR2, RPLP0, RPLP1 and RPLP2, are potential targets for asthma therapy. In vitro results showed kaempferol (1 × 10−2 mM) and ginkgolide A (1 × 10−5 mM) significantly increased the cell index (P < 0.05 vs. histamine, n = 3) and therefore relaxed human ASMCs. In vivo results showed kaempferol (145 μg/kg) and ginkgolide A (205 μg/kg) significantly reduced pulmonary resistance (P < 0.05 vs. methacholine, n = 6). Potential target discovery for asthma treatment based on the clinical effectiveness of TCM is a feasible strategy. Image 1 • 10 classical formulas for asthma and sovereign medicinal herbs of the classical formulas are discussed. • 130 herb compounds of 32 herbs and 68 targets for asthma are discussed. • 88 modern medicine targets for asthma from TTD and PubMed are discussed. • 18 proteins directly targeted by herbal compounds are potential targets for asthma therapy. [ABSTRACT FROM AUTHOR]

Epilepsy is associated with increased morbidity and mortality together and places a large financial burden on individuals and society. To evaluate the anticonvulsant action of protodioscin (PDSN) in experiments with animals with pilocarpine-induced convulsions. We assessed the activity of PDSN in pilocarpine induced seizures in combination with different agents which are acting via diverse receptors, such as atropine, memantine, nimodipine, diazepam, and flumazenil, to determine the exact receptors responsible for the action of PDSN. Furthermore, the level of antioxidant markers was investigated in the cerebellum and cerebral cortex in mice to define the antioxidant action of PDSN. The effects of PDSN on proapoptotic markers (i.e., Bcl-2, Bax, and caspase-3) was investigated via western blot analysis. PDSN significantly enhanced latency to the first convulsion and survival compared to the group treated with pilocarpine alone. Moreover, PDSN improved animal survival, and subjects experiencing no convulsions. Striatal glutamate and aspartate levels were not modified, and gamma amino butyric acid (GABA) levels increased, as a result of treatment with PDSN. The results suggest that the anticonvulsive action of PDSN is dependent on inhibitory amino acids. PDSN treatment also significantly decreased nitrite levels in the blood and brain cortex compared to the normal control. In the western blot analysis, PDSN exerted its neuroprotective effect via the upregulation of Bcl-2 and downregulation of Bax and caspase-3. The results of this study suggest that PDSN exerts neuroprotective effects via multiple mechanisms. [ABSTRACT FROM AUTHOR]

Advances in methodologies and tools often lead to new insights into cardiovascular diseases. Intravascular ultrasound (IVUS) is a well-established diagnostic method that provides high-resolution images of the vessel wall and atherosclerotic plaques. High-frequency (>50 MHz) ultrasound enables the spatial resolution of IVUS to approach that of optical imaging methods. However, the penetration depth decreases when using higher imaging frequencies due to the greater acoustic attenuation. An imaging method that improves the penetration depth of high-resolution IVUS would, therefore, be of major clinical importance. Modulated excitation imaging is known to allow ultrasound waves to penetrate further. This paper presents an ultrasound system specifically for modulated-excitation-based IVUS imaging. The system incorporates a high-voltage waveform generator and an image processing board that are optimized for IVUS applications. In addition, a miniaturized ultrasound transducer has been constructed using a Pb(Mg1/3Nb2/3)O3–PbTiO3 single crystal to improve the ultrasound characteristics. The results show that the proposed system was able to provide increases of 86.7% in penetration depth and 9.6 dB in the signal-to-noise ratio for 60 MHz IVUS. In vitro tissue samples were also investigated to demonstrate the performance of the system. [ABSTRACT FROM PUBLISHER]

Postoperative cognitive dysfunction (POCD) is a common complication of elderly patients after surgery. The mechanisms of POCD have not been clarified. Iron accumulation is a feature of neurodegeneration. Recent reports showed that iron content was increased with impaired cognition induced by surgery. We sought to investigate whether iron chelation would attenuate POCD. In this study, male aged (18 months) Sprague-Dawley rats received 100 mg/kg deferoxamine or saline solution (0.9%) for 6 days before exploratory laparotomy. Cognition was evaluated by Morris water maze before and after surgery. Additional rats received deferoxamine or saline were used to determine hippocampal iron content, iron transport-related proteins (transferrin receptor, divalent metal transporter 1, ferroportin 1 and hepcidin), oxidative stress, microglial activation and brain cell apoptosis. It was found that deferoxamine improved postoperative spatial memory in aged rats. Deferoxamine significantly reduced hippocampal iron concentration and ferritin. Surgery increased divalent metal transporter 1 and hepcidin, decreased transferrin receptor and ferroportin 1, and enhanced ferroportin 1 mRNA. However, deferoxamine reversed the changes of these proteins. Furthermore, deferoxamine sharply reduced the hippocampal reactive oxygen species, malondialdehyde concentration and OX-42 that is a marker of microglia, which might reduce postoperative brain cell apoptosis. This study showed that deferoxamine may improve postoperative cognition of aged rats by ameliorating oxidative stress induced by hippocampal iron accumulation, microglial activation and brain cell apoptosis. This study suggests a potential therapeutic method for reducing POCD. [ABSTRACT FROM AUTHOR]

The butyryl galactose ester-modified coix component microemulsions (But-Gal-CMEs) was developed for enhanced liver tumor-specific targeting. The study was aimed to evaluate the hepatoma-targeting potential of But-Gal-CMEsin vitroandin vivo. But-Gal-CMEs with a uniform spherical shape exhibited a small particle size (56.68 ± 0.07 nm), a narrow polydispersity (PDI, 0.144 ± 0.005) and slightly negative surface charge (−0.102 ± 0.008 mV). In the cell uptake studies, But-Gal-CMEs showed a significant enhancement on the intracellular fluorescent intensity on HepG2 cells model, which was 1.93-fold higher relative to coix component microemulsions (CMEs). The IC50of But-Gal-CMEs against HepG2 cells was 64.250 μg/mL, which was notably stronger than that of CMEs. In the cell apoptosis studies, compared with CMEs, But-Gal-CMEs (50 μg/mL) treatment resulted in a 1.34-fold rise in total apoptosis cells of HepG2. In the biodistribution studiesin vivo, the intratumorous fluorescence of Cy5-loaded But-Gal-CMEs was 1.43-fold higher relative to that of Cy5-loaded CMEs, suggesting an obviously enhanced accumulation in the tumor sites. Taken as together, But-Gal could be incorporated into the coix component microemulsions as a novel ligand for realizing hepatoma-targeting drugs delivery. [ABSTRACT FROM AUTHOR]

Luteolin (LUT) is an active agent in cancer prevention and a potential candidate for clinical chemotherapy. However, poor water solubility and extensive excretion have limited the clinical use of luteolin. Herein, we attempted to develop vitamin E d-α-tocopherol acid polyethylene glycol 1000 succinate (TPGS) coated liposomes to improve the accumulation of luteolin in lung cancer. Luteolin or coumarin-6 loaded liposomes were prepared using film-dispersion methods and characterized according to their particle size, polydispersity, zeta potential, and drug encapsulation efficiency. Cellular uptake properties and cytotoxicities of luteolin or coumarin-6 loaded liposomes were determined in A549 cells. Optical in vivo imaging was employed as a method of assessing tumor targeting. The antitumor effect was evaluated in mice xenotransplanted with A549 cancer cells. The results showed that TPGS coated liposomes are spherical, and are ∼176.2 nm in size. TPGS coated liposomes enhanced cellular uptake and apoptosis by upregulating the Bax/Bcl-2 ratio, resulting in improved cytotoxicity in A549 cells. TPGS coated liposomes significantly accumulated in tumor tissue and enhanced tumor inhibition without altering the structures of other organs. Thereby, TPGS coated liposomes provide an effective strategy in cancer chemotherapy for model drugs with poor water solubility such as luteolin. [ABSTRACT FROM AUTHOR]

The development of tumor therapeutic resistance is one of the important reasons for the failure of antitumor therapy. Starting with multiple targets and multiple signaling pathways is helpful in understanding the mechanism of tumor resistance. The overexpression of prolyl isomerase Pin1 is highly correlated with the malignancy of cancer, since Pin1 controls many oncogenes and tumor suppressors, as well as a variety of cancer-driving signaling pathways. Strikingly, numerous studies have shown that Pin1 is directly involved in therapeutic resistance. In this review, we mainly summarize the functions and mechanisms of Pin1 in therapeutic resistance of multifarious cancers, such as breast, liver, and pancreatic carcinomas. Furtherly, from the perspective of Pin1-driven cancer signaling pathways including Raf/MEK/ERK, PI3K/Akt, Wnt/β-catenin, NF-κB, as well as Pin1 inhibitors containing juglone, epigallocatechin-3-gallate (EGCG), all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), it is better to demonstrate the important potential role and mechanism of Pin1 in resistance and sensitization to cancer therapies. It will provide new therapeutic approaches for clinical reversal and prevention of tumor resistance by employing synergistic administration of Pin1 inhibitors and chemotherapeutics, implementing combination therapy of Pin1-related cancer signaling pathway inhibitors and Pin1 inhibitors, and exploiting novel Pin1-specific inhibitors. [Display omitted] [ABSTRACT FROM AUTHOR]

Background. Cerebral infarction (CI) is a common brain disease in clinical practice, which is mainly due to the pathological environment of ischemia and hypoxia caused by difficult cerebral circulation perfusion function, resulting in ischemic necrosis of local brain tissue and neurological impairment. In traditional Chinese medicine (TCM) theory, CI is mainly due to blood stasis in the brain. Therefore, blood-activating and stasis-dissipating drugs are often used to treat CI in clinical practice. Salvia miltiorrhiza Bunge (SMB) is a kind of traditional Chinese medicine with good efficacy in promoting blood circulation and removing blood stasis, and treatment of CI with it is a feasible strategy. Based on the above analysis, we chose network pharmacology to investigate the feasibility of SMB in the treatment of CI and to study the possible molecular mechanisms by providing some reference for the treatment of CI with TCM. Methods. The active ingredients and related targets of SMB were obtained through the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database, and CI-related targets were obtained from the GeneCards and DisGeNET databases. The target of SMB for the treatment of CI was obtained using Cytoscape software and visualized. GO and KEGG enrichment analysis was performed based on "clusterProfiler" within R, and the prediction results were validated by molecular docking technique. Results. By constructing a compound-target (C-T) network, it was found that the active components in SMB mainly treated CI by regulating key proteins such as AKT1, IL-6, and EGFR. These key proteins mainly involve in pathways such as immune regulation, cancer and lipid metabolism, such as lipid and atherosclerosis, chemical carcinogenesis-receptor activation pathways, and IL-17 signaling pathway. In the GO term, it mainly regulates the response to steroid hormones, membrane rafts, and G protein-amine receptor coupled activity. Eventually, we verified that the luteolin and tanshinone IIA components in SMB have a good possibility of action with AKT1 and IL-6 by in silico techniques, indicating that SMB has some scientificity in the treatment of CI. Conclusion. SMB mainly treats CI by regulating 94 proteins involved in lipid and atherosclerosis, chemical carcinogenesis-receptor activation, and IL-17 signaling pathway. Our research strategy provided a template for the drug development of TCM for the treatment of CI. [ABSTRACT FROM AUTHOR]

Moluodan concentrated pill (MLD) is a traditional herbal formula used in China for the treatment of chronic atrophic gastritis (CAG). However, its pharmacological mechanism of action remains unclear. The aim of this study was to investigate the therapeutic effect and mechanism of action of MLD in the treatment of CAG using network pharmacology and in vivo experiments. The active compounds of MLD were determined using network pharmacology, utilizing various Chinese medicine databases such as the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, Traditional Chinese Medicine Integrated Database, Integrative Pharmacology-based Research Platform of Traditional Chinese Medicine, and a comprehensive database of Traditional Chinese Medicine on Immuno-Oncology. The compounds found in the root of Anemone altaica Fisch. were extracted from the China National Knowledge Infrastructure literature database. Additionally, the Swiss Target Prediction database and Similarity Ensemble Approach were employed to identify the potential targets of these components. CAG-related targets were gathered from the GeneCards and DisGeNET databases. Protein-protein interactions (PPIs) of the genes associated with the drug-disease crossover were examined, and a core PPI network was constructed using the STRING database (version 11.5) and Cytoscape (version 3.7.2). A gene-pathway network was established to identify significant target genes and pathways through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Finally, based on these findings and existing data, the tumor necrosis factor (TNF) signaling pathway was selected for further validation through in vivo experiments. A total of 724 active molecules in MLD yielded 961 identified target genes, of which 179 were found to be potentially associated with CAG. From the common targets, a PPI network revealed ten core targets. Enrichment analysis suggested that MLD may primarily target TNF and AKT in the treatment of CAG. Essential signaling pathways, such as the PI3K-AKT and TNF pathways, were found to be crucial for the therapeutic effects of MLD on CAG. Furthermore, potential interactions and crosstalk between these pathways were identified. Moreover, we confirmed that MLD effectively improved gastric mucosa atrophy and cellular ultrastructural damage, while increasing pepsinogen secretion and decreasing gastrin, somatostatin, and motilin levels. Subsequent molecular biology studies in rat models of CAG demonstrated that MLD treatment significantly reduced the expression levels of TNF-α, phosphatidylinositol 3′-kinase (PI3K), and phosphorylated Akt (P < 0.05). Notably, the expression of nuclear factor kappa-B (NF-κB) exhibited a contrasting trend (P < 0.05), potentially associated with the crucial tumor suppressor role of NF-κB p105. This study provides evidence that MLD effectively alleviates stomach mucosal atrophy through modulation of the TNF/PI3K/AKT signaling pathway. These findings establish a solid theoretical foundation for the practical management of CAG. [Display omitted] • A rat model of chronic atrophic gastritis was established by the MNNG multifactorial modeling method. • The efficacy and mechanism of Moluodan for chronic atrophic gastritis were revealed in vivo experiments for the first time. • Moluodan exerts gastric mucosal protective effects via the TNF/PI3K/AKT signaling pathway. [ABSTRACT FROM AUTHOR]

The present study aims to investigate the roles of herb pairs containing Angelicae Sinensis Radix (Danggui) in Xin-Sheng-Hua Granule (XSHG) on hemolytic and aplastic anemia (HAA) mice. HAA model mice were induced by acetyl phenylhydrazine and cyclophosphamide; then the samples of XSHG and its decomposed recipes (DY, DC, DT, DH, DJ, and DZ) were orally administrated to these mice. Indicators of peripheral blood routine, organ index, and ATPase activities were tested. Moreover, the main effective components in these samples were also analyzed by UHPLC-TQ-MS/MS. Clear separation between the control and model groups from score plot of principal component analysis (PCA) was easily seen, indicating that HAA model was successfully conducted. Afterwards, relative distance calculation method between dose groups and control group from PCA score plot was adopted to evaluate the integrated effects of hematinic function of different samples. And the orders of hematinic effects were as follows: XHSG > DJ > DT > DZ > DH > DC > DY. Further analysis of these samples by UHPLC-TQ-MS/MS revealed that XSHG underwent complicated changes when herb pairs containing Danggui were excluded from XSHG, respectively. Compared with XSHG, the vast majority of active compounds in sample DY (formula minus herb pair Danggui-Yimucao) decreased significantly, which could partly explain why herb pair Danggui-Yimucao made great contribution to XSHG. These findings showed that withdrawal analysis method is a valuable tool to analyze the impacts of herb pairs containing Danggui on XSHG, which could lay foundation to reveal the compatibility rules of this formula. [ABSTRACT FROM AUTHOR]

Objective. To systematically evaluate the efficacy of Chinese herbal medicine Qiju Dihuang Decoction (QDD) for hypertension. Methods. A comprehensive literature search of randomized controlled trials using QDD to treat hypertension was conducted in 7 electronic databases, including Chinese databases. Subjects and abstracts of the trials were read in NoteExpress for preliminary screening, and the full text was read for further screening. The data extraction table was made for the selected 19 trials, and risk of bias was assessed by using the Cochrane collaboration tool, followed by data analysis using Rev Man 5.3. Results. The antihypertensive efficacy of QDD is 1.45 times that of antihypertensive drugs and 1.56 times that of conventional therapies, which can also reduce the endothelin level. QPAD exhibits an antihypertensive effect, and its clinical efficacy is 1.34 times and 1.61 times that of antihypertensive drugs, which can not only significantly lower the diastolic blood pressure but also reduce the 24 h mean ambulate blood pressure. At the same time, it can decrease the TCM syndrome score, inhibit the inflammation, protect the renal function, reduce the insulin resistance, and improve the life quality of patients. Conclusion. QDD can effectively reduce blood pressure and improve the life quality of patients with hypertension, which plays a certain role in preventing hypertension complications. However, due to the methodological deficiencies, more rigorous randomized controlled trials will be needed in the future to provide stronger evidence. [ABSTRACT FROM AUTHOR]

Background. Qixuehe capsule (QXH), a Chinese patent medicine, has been demonstrated to be effective in the treatment of menstrual disorders. In traditional Chinese medicine (TCM) theory, qi stagnation and blood stasis syndrome (QS-BSS) is the main syndrome type of menstrual disorders. However, the pharmacodynamic effect of QXH in treating QS-BSS is not clear, and the main active compounds and underlying mechanisms remain unknown. Methods. A rat model of QS-BSS was established to evaluate the pharmacodynamic effect of QXH. Thereafter, a network pharmacology approach was performed to decipher the active compounds and underlying mechanisms of QXH. Results. QXH could significantly reduce the rising whole blood viscosity (WBV) and plasma viscosity (PV) but also normalize prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB) content in QS-BSS rats. Based on partial least-squares-discriminant analysis (PLS-DA), the low-dose QXH-intervened (QXH-L) and the high-dose QXH-intervened (QXH-H) groups seemed the most effective by calculating the relative distance to normality. Through network pharmacology, QXH may improve hemorheological abnormality mainly via 185 compounds-51 targets-28 pathways, whereas 184 compounds-68 targets-28 pathways were associated with QXH in improving coagulopathy. Subsequently, 25 active compounds of QXH were verified by UPLC-Q/TOF-MS. Furthermore, 174 active compounds of QXH were shared in improving hemorheological abnormality and coagulopathy in QS-BSS, each of which can act on multiple targets to be mainly involved in complement and coagulation cascades, leukocyte transendothelial migration, PPAR signaling pathway, VEGF signaling pathway, and arachidonic acid metabolism. The attribution of active compounds indicated that Angelicae Sinensis Radix (DG), Paeoniae Radix Rubra (CS), Carthami Flos (HH), Persicae Semen (TR), and Corydalis Rhizoma (YHS) were the vital herbs of QXH in treating QS-BSS. Conclusion. QXH can improve the hemorheology abnormality and coagulopathy of QS-BSS, which may result from the synergy of multiple compounds, targets, and pathways. [ABSTRACT FROM AUTHOR]

Currently, the use of magnetic resonance imaging (MRI) in patients with esophageal carcinoma is limited. However, the quality of MRI for esophageal carcinoma continues to improve and the importance of MRI in patients with esophageal carcinoma has been gradually recognized. Compared with endoscopic ultrasound and computed tomography applied in T and N staging, MRI has now achieved excellent results after the imaging technique has been optimized. We review the literature on MRI and discuss the future of MRI in esophageal carcinoma. While the role of MRI in staging, tumor volume target delineation and evaluation for preoperative chemoradiotherapy, prognosis and recurrence is still evolving. The application of MRI in esophageal carcinoma has a bright future and potential to improve precision of T and N staging as well as treatment delivery. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the effects of transitional health management on adherence and prognosis in elderly patients with acute myocardial infarction undergoing percutaneous coronary intervention. Methods: We conducted the trial from June 2016 to December 2016. A total of one hundred and fifty patients with acute myocardial infarction after PCI who met the inclusion criteria were randomly divided into an experimental (n = 75) group and a control (n = 75) group. The participants in the experimental group received transitional health management for three months. The two groups of patients were evaluated for treatment adherence, quality of life, clinical indicators, adverse cardiovascular events and statistics regarding readmission rates at baseline and 6 months after discharge. Results: Compared with the controls, patients in the intervention group demonstrated better medication adherence, reexamination adherence, healthy lifestyle and clinical indicators (all P<0.05) and lower rates of adverse cardiovascular events and readmission (all P<0.05). Conclusion: Transitional health management effectively improved adherence in elderly patients with acute myocardial infarction after PCI, ameliorated clinical indicators, and effectively reduced the incidence of adverse cardiovascular events and readmission rates. Transitional health management was an effective intervention for PCI patients after discharge. [ABSTRACT FROM AUTHOR]

The receptor‐tyrosine‐kinase (RTK)‐like orphan receptor 1 (ROR1) is a transmembrane glycoprotein regarded as a tumor‐associated antigen. ROR1 plays an important role in cancer development, but the detailed function of ROR1 in diffuse large B‐cell lymphoma (DLBCL) remains unclear. In this study, we first detected ROR1 expression and evaluated the relationship between ROR1 expression and the clinicopathological characteristics of DLBCL patients. Next we employed shRNA‐mediated knockdown of ROR1 in DLBCL cell line to explore the characteristics of ROR1 in DLBCL development both in vitro and in vivo. The results showed a significantly higher level of ROR1 in DLBCL tissues than in lymphatic hyperplasia tissues. High ROR1 expression was correlated with unfavorable prognosis in DLBCL patients. Furthermore, ROR1 knockdown inhibited the growth and induced the apoptosis in DLBCL cells and xenografts. In addition, shROR1 inhibited activation of the PI3K/Akt/mTOR signaling pathway, both in vitro and in vivo. Taken together, our results suggest that ROR1 is a novel prognostic marker for DLBCL survival and ROR1 significantly promotes DLBCL tumorigenesis by regulating the PI3K/Akt/mTOR signaling pathway. Targeting ROR1 may provide a promising strategy for DLBCL treatment. © 2019 BioFactors, 45(3):416–426, 2019 [ABSTRACT FROM AUTHOR]

Microbes in the human body are closely linked to many complex human diseases and are emerging as new drug targets. These microbes play a crucial role in drug development and disease treatment. Traditional methods of biological experiments are not only time-consuming but also costly. Using computational methods to predict microbe-drug associations can effectively complement biological experiments. In this experiment, we constructed heterogeneity networks for drugs, microbes, and diseases using multiple biomedical data sources. Then, we developed a model with matrix factorization and a three-layer heterogeneous network (MFTLHNMDA) to predict potential drug-microbe associations. The probability of microbe-drug association was obtained by a global network-based update algorithm. Finally, the performance of MFTLHNMDA was evaluated in the framework of leave-one-out cross-validation (LOOCV) and 5-fold cross-validation (5-fold CV). The results showed that our model performed better than six state-of-the-art methods that had AUC of 0.9396 and 0.9385 + /− 0.0000, respectively. This case study further confirms the effectiveness of MFTLHNMDA in identifying potential drug-microbe associations and new drug-microbe associations. [Display omitted] • Microbes in the human body are closely associated with many complex human diseases and are emerging as new drug targets. • Sparse learning methods are used to decompose the matrix to extract data information. • Multiple sources of data are introduced and a generic global network update algorithm is built to optimize the model. • Model evaluation results show the predictive advantage of MFTLHNMDA and its good generalization performance. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) continues to be a leading cause of cancer related death in the world. Conventional chemotherapeutic agents such as cisplatin (CDDP) have an unsatisfactory efficacy on HCC due to the poor response, severe toxicity and drug resistance. Curcumin (CUR) could improve the chemosensitivity of HCC to chemotherapy drugs by regulating a variety of signaling pathways. Herein, we describe a combination strategy using co-loaded liposomes to effectively deliver and release CDDP and curcumin (CUR) to HCC for overcoming the unsatisfactory clinical outcome of CDDP monotherapy. In the study, CDDP and CUR co-loaded liposomes (CDDP/CUR-Lip) were prepared by a reverse microemulsion and film dispersion method and their average particle size 294.6 ± 14.8 nm with uniform size distribution. In vitro study showed that the nano sized CDDP/CUR-Lip could synchronously release both CDDP and CUR to achieve the synergistic effect against HCC cells based on the optimal ratio (1:8) of both drugs. Compared with free drug or encapsulated mono-drug therapy, CDDP/CUR-Lip demonstrated the higher anti-tumor activity in vitro against HepG2 cells with the IC 50 of 0.62 μM. In addition, CDDP/CUR-Lip also increased intracellular ROS level during the HCC cells treatment. Furthermore, compared with single drug formulation, CDDP/CUR-Lip showed the elongated retention time (t 1/2  = 2.38 h) and improved antitumor effect in both mouse hepatoma H22 and human HCC HepG2 xenograft models with reduced side effects. In conclusion, CDDP/CUR-Lip provide an attractive and potential strategy to attain synergistic effect of CDDP and CUR for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide (CGRP) has a potent protective action on the cardiovascular system; however, little is known about the role of CGRP in angiotensin II- (Ang II-) induced inflammation of vascular smooth muscle cells (VSMCs). This study is aimed at determining the anti-inflammatory effect of CGRP in Ang II-treated VSMCs and whether a disintegrin and metalloproteinase 17 (ADAM17) modulates this protective action. Small interference RNA (siRNA) and inhibitors of CGRP, epidermal growth factor receptor (EGFR), and extracellular signal-regulated kinase 1/2 (ERK1/2) were adopted to investigate their effect on Ang II-induced inflammation in VSMCs. Here, we found that CGRP could inhibit inflammation and decrease ADAM17 expression and activation of EGFR and ERK1/2 in VSMCs stimulated with Ang II. Results of siRNA demonstrated that ADAM17 siRNA attenuated Ang II-induced inflammation and up-regulation of activities of EGFR and ERK1/2 in VSMCs. Furthermore, the EGFR-ERK1/2 pathway promoted Ang II-induced VSMC inflammation. In summary, these findings identify the anti-inflammatory effect of CGRP in VSMCs stimulated by Ang II and suggest that ADAM17 is involved in the protective effect of CGRP against Ang II-induced inflammation via the EGFR-ERK1/2 pathway in VSMCs. [ABSTRACT FROM AUTHOR]

Background: Accumulating literature proved that miRNAs can regulate the sensitivity of platinum and act as a promising candidate to predict the response of patients with lung adenocarcinoma to chemotherapy. However, most studies on miRNAs were restricted to in vitro experiments. This study aimed to evaluate whether miRNAs alone or in combination (miRNA signature) can act as predictive biomarkers of platinum-based chemotherapy in patients with lung adenocarcinoma.Methods: Eight miRNAs that most probably predict the efficacy of platinum were screened in 111 tumor tissues of lung adenocarcinoma. Univariate and multivariate Cox analyses, Kaplan–Meier survival curve analysis, Chi-square test, and univariate and multivariate logistic regression analyses were employed to determine whether miRNA expression is associated with the response of patients to platinum-based chemotherapy. The maximum significant odds ratio value was acquired by multiple cycles of multivariate logistic regression analysis. The cut-off points of miRNAs were obtained. A miRNA chemo-sensibility index (CI) formula was established, and its prediction performance was confirmed in another independent set (n = 31).Results: Underexpression of three miRNAs (miRNA-21, miRNA-125b, and miRNA-224) was independently associated with the chemotherapy sensitivity of patients with lung adenocarcinoma. The miRNA CI formula containing these three miRNAs was calculated as (1.364 × miR-21) + (1.323 × miR-125b) + (1.131 × miR-224). A high CI was related to platinum-based chemotherapy resistance, and its prediction performance was confirmed in the testing set. The MAPK, PI3K-Akt, Ras, and cGMP-PKG signaling pathways were considered to be most probably correlated with platinum resistance.Conclusion: Our miRNA CI formula can act as an independent predictor to predict the response of patients with lung adenocarcinoma to platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: Local immune regulation therapy has been one of the therapeutic methods used for the treatment of autoimmune thyroid disease in patients with pretibial myxedema (PTM). However, the poor response rate and high recurrence rate are still major problems. Whether a premixed corticosteroid, compound betamethasone, could enhance remission rate and decrease recurrence rate in patients with PTM was investigated in the present study.Subjects and Methods: We have performed a clinical utility observation of compound betamethasone with intralesional injections based on basic thyroid disease treatment in 32 PTM patients between January 2008 and August 2016. The patients were followed up for 2 years, and the clinical outcomes and side effects were calculated and analyzed.Results: All patients had a complete remission after different times of injection. A total of 21.7% patients had complete remission with one time of injection, 34.8% with two times of injection, 17.4% with three times of injection, 4.3% with four times of injection, and 4.3% with five times of injection. In all, 56.3% patients with a disease duration of <6 months had complete remission after a 1-month treatment, 37.5% patients with a disease duration between 6 months and 12 months had complete remission after a 2-month treatment, 3.1% patients with a disease duration of 2 years had complete remission after a 5-month treatment, and 3.1% with a disease duration of 5 years had complete remission after a 7-month treatment.Conclusion: Compound betamethasone with multipoint intralesional injection is a feasible, effective, and secure novel strategy in the treatment of PTM. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal infection has become a public health challenge globally. However, information about cryptococcal infection in patients with hematological diseases remains relatively rare.Methods: HIV-uninfected cryptococcosis cases with hematological diseases admitted to Huashan Hospital from January 2001 to December 2014 were reviewed.Results: In total, 33 cryptococcosis patients were enrolled, including 12 malignant and 21 non-malignant hematological cases. Twenty-six patients had central nervous system (CNS) involvement, which was observed more often in patients with non-malignancies than with malignancies (20/21 vs. 6/12, P = 0.001) Most patients (25/26) with CNS infection were confirmed by cerebrospinal fluid (CSF) culture or smear, and 100% (20/20) of them tested positive for the CSF cryptococcal antigen test. Eighteen out of 26 cryptococcal meningitis patients were treated with amphotericin B (AmB)-based therapy, 16 of them with AmB deoxycholate (d-AmB) and 2 patients with liposomal AmB. The clinical success rate was 55.6%. D-AmB was well-tolerated at 0.35-0.59 mg/kg/d (median 0.43 mg/kg/d) and only 12 patients had mild adverse events.Conclusions: CNS cryptococcal infection was more frequent in patients with hematological non-malignancies, and cryptococcal antigen test as well as the CSF fungal culture or smear are suggested for early diagnosis. D-AmB could be used as an alternative therapy for CNS-infected patients with hematological diseases. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cells (hiPSCs) may provide potential resource for regenerative medicine research, including generation of insulin-producing cells for diabetes research and insulin production. Testosterone (T) is an androgen hormone which promotes protein synthesis and improves the management of type 2 diabetes in clinical studies. Concurrently, co-existed hyperandrogenism and hyperinsulinism is frequently observed in polycystic ovary syndrome, congenital adrenal hyperplasia and some of Wermer's syndrome. However, the relationship among androgens, insulin and the differentiation of pancreatic β cells is still not fully clear. Here we find that T improves the differentiation efficiency of insulin-producing cells from hiPSCs. The addition of T into routine differentiation formula for pancreatic β cells increases the differentiation efficiency from 12% to 35%. The administration of T promotes the expression of key genes associated with β cells differentiation including NGN3, NEUROD1 and INS. This finding benefits the ongoing process to optimize the differentiation protocol of pancreatic β cells from hiPSCs, and provides some degree of understanding the clinical management of T for type 2 diabetes. [ABSTRACT FROM AUTHOR]

This work introduced an eco-friendly approach for the synthesis of sliver nanoparticles (AgNPs) with a water-soluble fraction of polysaccharides extracted from the roots of Astragalus membranaceus (AMWP). AMWP mediated AgNPs (AMWP-AgNPs) were successfully synthesized using 1.0 mM AgNO 3 and 1.25 mg/mL AMWP, reacting in aqueous environment at 25 °C for 6 h. The synthesized AMWP-AgNPs exhibited a broad surface plasmon resonance peak (SPR) at 445 nm in Ultraviolet-visible (UV–vis) spectrum, which was characteristic of a poly-dispersed AMWP-AgNPs. Transmission electron microscopy (TEM) and Dynamic light scattering (DLS) analysis revealed that the AMWP-AgNPs were almost spherical shaped with an average diameter of 65.08 nm. The antibacterial activities of AMWP-AgNPs were assessed on four strains of clinical isolated multidrug resistant (MDR) bacteria and four relative reference strains using modified agar disk diffusion and tetrazolium methods. All strains, especially the resistant strains, were significantly inhibited by AMWP-AgNPs at comparatively low concentration (minimum inhibition concentrations (MICs) ranging from 0.032 to 0.063 mg/mL). Therefore, we propose that the AMWP-AgNPs will have a great potential in anti-MDR bacterial applications. [ABSTRACT FROM AUTHOR]

Chlorogenic acid (CGA), a polyphenolic compound, exists widely in medicinal herbs, which has been shown a strong antioxidant and anti-inflammatory effect. This study investigated the protective effects and mechanism of CGA on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Treatment of CGA successfully ameliorates LPS-induced renal function and pathological damage. Moreover, CGA dose-dependently suppressed LPS-induced blood urea nitrogen (BUN), creatinine levels, and inflammatory cytokines TNF-α, IL-6, and IL-1β in serum and tissue. The relative proteins' expression of TLR4/NF-κB signal pathway was assessed by western blot analysis. Our results showed that CGA dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. CGA also suppressed LPS-induced TNF-α, IL-6, and IL-1β production both in serum and kidney tissues. Furthermore, our results showed that CGA significantly inhibited the LPS-induced expression of phosphorylated NF-κB p65 and IκB as well as the expression of TLR4 signal. In conclusion, our results provide a mechanistic explanation for the anti-inflammatory effects of CGA in LPS-induced AKI mice through inhibiting TLR4/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) remains incurable and new treatments are needed, especially in the relapsed/refractory setting. We therefore investigated the effects of carfilzomib, a novel, long-acting, second-generation proteasome inhibitor, in MCL cells. Eight established MCL cell lines and freshly isolated primary MCL cells were treated with carfilzomib. Cell proliferation was assessed by a 3H-thymidine incorporation assay. Cell apoptosis was evaluated by flow cytometry with annexin V and propidium iodide. Electrophoresis mobility shift (EMSA), Western blot, and luciferase assays were used to analyze NF-κB activation and related signaling proteins. Carfilzomib inhibited growth and induced apoptosis in both established MCL cell lines and freshly isolated primary MCL cells in a dose-dependent manner. In contrast, carfilzomib was less toxic to normal peripheral blood mononuclear cells from healthy individuals. The carfilzomib-induced apoptosis of MCL cells occurred in a caspase-dependent manner through both intrinsic and extrinsic caspase pathways. In addition, carfilzomib inhibited constitutive activation of the NF-κB signaling cascade, both in MCL cell lines and primary MCL cells, by completely blocking the phosphorylation of IκBα. Our results demonstrate that carfilzomib can induce growth arrest and apoptosis in MCL cells and that the mechanism may involve the NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Chemotherapy is critical for the treatment of liver cancer. Despite the pro-apoptotic effects of corosolic acid (CA) have been revealed, the methods to enhance its efficacy are unclear. The aim of this study is to investigate the target that might reduce CA efficacy and figure out the way to conquer it. We found reduction of Yes-associated protein (YAP) might be a critical event that suppresses efficacy of CA. Treatment of CA accelerated degradation of YAP via enhancing its phosphorylation by LATS1. Moreover, we found CA boosts βTrCP-dependent Ubiquitination of YAP. Interestingly, the protein stability of βTrCP per se could be enhanced by CA. Notably, ActionomycinD (AD) strengthened CA-induced apoptosis of liver cancer cells via elevating YAP while down-regulating βTrCP. Importantly, combined treatment of CA and AD had much more obvious influences against transformative phenotypes of liver cancer cells than those under treatment of CA alone. Combined usage of AD successfully reduced IC50 value of CA. In summary, we have first uncovered that suppression of YAP might reduce efficacy of CA to treat liver cancer, combined treatment of AD and CA might solve this problem. [ABSTRACT FROM AUTHOR]

Background: ALK rearrangement-advanced NSCLC patients respond to crizotinib. ALK rearrangement is currently determined with RT-PCR. VENTANA IHC is a standard method to identify ALK protein overexpression in NSCLC; however, VENTANA IHC has rarely been used to determine the response to crizotinib in Chinese patients with NSCLC and ALK overexpression. To better clarify the clinical implication of VENTANA IHC to detect ALK rearrangements, we conducted this study to analyze VENTANA IHC and RT-PCR in a large cohort of Chinese patients with NSCLC undergoing screening for ALK rearrangements.Methods: A total of 1720 patients with NSCLC who had ALK rearrangements detected by VENTANA IHC and/or RT-PCR were included in this analysis. We compared the efficacy and survival of ALK-positive patients detected by VENTANA IHC and RT-PCR. We used NGS to identify patients in whom the two methods were inconsistent.Results: Among 1720 patients, 187 (10.87%) were shown to be ALK-positive by VENTANA IHC and/or RT-PCR, and 66 received crizotinib treatment. We identified 10.27% (172/1674) of patients as ALK-positive by the VENTANA IHC method, and 12.73% (41/322) of patients had ALK rearrangements by the RT-PCR method. Twenty-nine of 276 (10.51%) ALK-positive patients were simultaneously analyzed using VENTANA IHC and RT-PCR. The overall response rates were 65.90% (29/44) by VENTANA IHC and 55.88% (19/34) by RT-PCR. The disease control rates were 86.36% (38/44) by VENTANA IHC and 76.47% (26/34) by RT-PCR. In contrast, the median progression-free survival for VENTANA IHC and RT-PCR was 8.5 and 9.2 months, respectively. The VENTANA IHC and RT-PCR results obtained for 6 of 17 ALK-positive patients were inconsistent based on NGS; specifically, 4 patients had EML4-ALK fusions, 2 patients had non EML4-ALK fusions, 1 patient had a KCL1-ALK fusion, and one patient had a FBXO36-ALK fusion.Conclusions: VENTANA IHC is a reliable and rapid screening tool used in routine pathologic laboratories for the identification of suitable candidates for ALK-targeted therapy. VENTANA IHC has moderate sensitivity and a slightly higher association with response to therapy with ALK inhibitors, and some VENTANA IHC-positive, but RT-PCR-negative cases may benefit from crizotinib. [ABSTRACT FROM AUTHOR]

The epithelial-mesenchymal transition (EMT) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) development and progression. TWIST activated by intra-tumoral hypoxia functions to promote the EMT. We hypothesized that TWIST and the downstream gene pathway could mediate PDAC progression under hypoxia. Therefore, 90 PDAC tissue specimens were immunostained for TWIST and other proteins. Pancreatic cancer cell lines were used for in vitro experiments and nude mice were used to confirm the in vivo data. Expression of TWIST and HIF-1α proteins was significantly upregulated, whereas expression of E-cadherin and p16 was down-regulated in PDAC tissues compared to that of non-tumor tissues and in tumor tissues obtained from patients with tumor involving splenic artery than those without splenic artery involvement. Up-regulated TWIST in tumor tissues were associated with worse prognosis in PDAC patients. The in vitro data showed that HIF-1α-induced TWIST overexpression promoted tumor cell growth and EMT under a hypoxic condition via TWIST interaction with Ring1B and EZH2. In vivo data showed that TWIST overexpression or a hypoxic condition induce xenograft growth, abdominal metastasis and low mouse survival, whereas knockdown of either Ring1B or EZH2 expression suppressed tumor xenograft growth and metastasis and prolonged survival of nude mice. TWIST was the key player in promotion of pancreatic cancer development and metastasis under a hypoxic condition through interaction with Ring1B and EZH2 to regulate expression of E-cadherin and p16 proteins in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of the combination of topical 20% autologous serum eye drops (ASEs) and silicone-hydrogel soft contact lenses (SCLs) for the treatment of corneal persistent epithelial defects (PEDs), and to compare the recurrence of epithelial breakdown with or without continuous use of ASEs after silicone-hydrogel SCLs removal.Methods: We conducted a prospective interventional study of 21 eyes of 21 patients with PEDs treated with combined ASEs and silicone-hydrogel SCLs from September 2014 to August 2015. SCLs were removed after total re-epithelialization and patients were subsequently randomized divided into two groups: (1) with and (2) without continuous use of ASEs for an additional 2 weeks. PEDs healing rate and epithelial defect recurrence were evaluated.Results: PEDs healed in all eyes within 3 weeks. Recurrence was noted in five eyes (50%) in patients without continued use of ASEs for 2weeks after total re-epithelialization and SCLs removal during a 3-month follow-up (odds ratio: 23.0; P<0.05). Recurrent epithelial defects were successfully treated with secondary SCLs application combined with autologous serum use. No adverse events were noted during the entire treatment period.Conclusions: The combined use of ASEs and silicone-hydrogel SCLs can successfully treat recalcitrant PEDs. Prolonged use of ASEs after total re-epithelialization can decrease recurrence rates. [ABSTRACT FROM AUTHOR]