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Introduction: We designed 5 convolutional neural network (CNN) models and ensemble models to differentiate malignant and benign thyroid nodules on CT, and compared the diagnostic performance of CNN models with that of radiologists. Material and methods: We retrospectively included CT images of 880 patients with 986 thyroid nodules confirmed by surgical pathology between July 2017 and December 2019. Two radiologists retrospectively diagnosed benign and malignant thyroid nodules on CT images in a test set. Five CNNs (ResNet50, DenseNet121, DenseNet169, SE-ResNeXt50, and Xception) were trained-validated and tested using 788 and 198 thyroid nodule CT images, respectively. Then, we selected the 3 models with the best diagnostic performance on the test set for the model ensemble. We then compared the diagnostic performance of 2 radiologists with 5 CNN models and the integrated model. Results: Of the 986 thyroid nodules, 541 were malignant, and 445 were benign. The area under the curves (AUCs) for diagnosing thyroid malignancy was 0.587–0.754 for 2 radiologists. The AUCs for diagnosing thyroid malignancy for the 5 CNN models and ensemble model was 0.901–0.947. There were significant differences in AUC between the radiologists’ models and the CNN models (p < 0.05). The ensemble model had the highest AUC value. Conclusions: Five CNN models and an ensemble model performed better than radiologists in distinguishing malignant thyroid nodules from benign nodules on CT. The diagnostic performance of the ensemble model improved and showed good potential.

Rectus abdominis diastasis is a common pathology and an esthetic and symptomatic problem; its reconstruction, either through a surgical strategy, standard vertical plication, or endoscopic surgery with or without mesh or through non-surgical physical training, is under debate. This study further aimed to compare the results of surgery and non-surgery interventions in cases with rectus abdominis diastasis. A systematic literature search of PubMed, Embase, and the Cochrane Library databases from the earliest data available to November 2018 was performed. Studies assessing symptomatic relief, adverse events, or symptomatic recurrence after surgery or a physical training program were included. A modified Downs and Black checklist for randomized and non-randomized studies of healthcare interventions was used to evaluate the methodological quality of the studies. Of 3908 citations, there were 27 studies with a total of 2372 patients finally being included in this study. In the surgery group, there was no patient relapsed after a follow-up of 12 months, while a 40% recurrence rate was reported after a follow-up of 5 years in one study. The adverse events associated with surgery mainly included seroma (5.13%), a sensibility disorder of the abdominal skin (2.26%), and minor scarring (1.56%). There were no adverse events or reports of recurrence in patients with physical training; however, negative effects of improving rectus muscle function were reported in 4 studies (40%). In conclusion, this review found a limited strength of evidence that abdominoplasty and diastasis recti repair were effective at restoring the functions of the rectus muscles and at improving the stability of the abdominal wall and quality of life in the short-term. A moderate strength of evidence was found that strength training has a limited effect, especially for patients suffering from rectus abdominis diastasis combined with a hernia.

Graphical abstract, Highlights • Bruceine A displays potent anti-pancreatic cancer activity in vitro and in vivo. • Phosphoproteomic analyses identify bruceine A induces phosphorylation of p38α MAPK. • Octet system and microscale thermophoresis reveal p38α MAPK has high affinity for bruceine A. • Molecular simulations illustrate determinants of bruceine A binding with p38α MAPK., Pancreatic cancer remains one of the cancers with the poorest prognosis bearing an overall 5-year survival rate of about 5%. Efficient new chemotherapic drugs are still highly desired. Here, bruceine A, a quassinoid identified from the dried fruits of Brucea javanica (L.) Merr., displayed the most potent anti-proliferation activity against pancreatic cancer in vitro and in vivo. Phosphoproteomic analysis revealed p38α MAPK phosphorylation was involved in bruceine A’s action in MIA PaCa-2 cells. Utilizing fortebio octet system and microscale thermophoresis, we found p38α MAPK had high affinity for bruceine A. Molecular docking and molecular dynamic simulations showed that bruceine A widely bound to residues (Leu171, Ala172, Met179, Thr180, Val183) in P-loop of p38α MAPK. Key determinants of bruceine A binding with P-loop of p38α MAPK were 19-C Created by potrace 1.16, written by Peter Selinger 2001-2019 O, 22-CH3, 32-CH3, and 34-CH3. Taken together, our findings demonstrate that bruceine A binds directly to p38α MAPK, which can be used to probe the role of p38α MAPK phosphorylation in pancreatic cancer progression, and as a novel lead compound for pancreatic cancer therapy.

Background Mucus production is a process involved in the pathogenesis of Community-acquired pneumonia (CAP). The study is to determine Mucin 5B (MUC5B) protein concentration and its proportion in the bronchoalveolar lavage fluid (BALF) of CAP patients and evaluate its value to help assess disease severity. Methods A total of 118 patients were enrolled in this cross-sectional study, including 45 with severe CAP (SCAP) and 73 with non-severe CAP (NSCAP). MUC5B concentration in BALF were determined by immunoblotting analysis. Total protein concentration of BALF was detected by Pierce BCA kit. Cytokines IL6, IL10, IFNγ, IL13, and IL17 in BALF were measured using commercial enzyme-linked immunosorbent assay (ELISA). Spearman’s correlation analysis was applied to evaluate the relationships between MUC5B concentration or MUC5B/total protein ratio and the CURB-65 score, as well as cytokines. Logistic regression analysis was used to identify the independent factors associated with severe CAP. Receiver operating characteristic (ROC) curve was used to evaluate the assessment value of MUC5B/total protein ratio and other indexes for CAP severity. Results MUC5B concentration in the BALF of NSCAP group was higher than that in SCAP group [NSCAP 13.56 µg/ml (IQR 5.92–25.79) vs. SCAP 8.20 µg/ml (IQR 4.97–14.03), p = 0.011]. The total protein concentration in the BALF of NSCAP group was lower than that in SCAP group [NSCAP 0.38 mg/ml (IQR 0.15–1.10) vs. SCAP 0.68 mg/ml (IQR 0.46–1.69), p = 0.002]. The MUC5B/total protein ratio was remarkably higher in NSCAP group than that in SCAP groups [NSCAP 3.66% (IQR 1.50–5.56%) vs. SCAP 1.38% (IQR 0.73–1.76%), p s = − 0.576, p s = − 0.312, p = 0.001), IL10 (rs = − 0.228, p = 0.013), IL13 (rs = − 0.183, p = 0.048), IL17 (rs = − 0.282, p = 0.002) and CURB-65 score (rs = − 0.239, p = 0.009). Logistic regression identified that MUC5B/total protein ratio, IL6 level and CURB-65 score as independent variables related to CAP severity. ROC curve demonstrated best assessment value of MUC5B/total protein ratio for SCAP (AUC 0.803, p Conclusions Respiratory MUC5B disproportion is related to CAP severity. MUC5B/total protein ratio may serve as an assessment marker and a potential therapeutic target for severe CAP.

Whether pre-intravenous thrombolysis (IVT) provides any extra benefits to mechanical thrombectomy (MT) remains controversial. We conducted a systematic review and meta-analysis to compare MT with pre-IVT (IVT + MT) and MT without pre-IVT (MT) for acute ischemic stroke of large vessel occlusion. We systematically searched PubMed, EMBASE and Cochrane Library to identify studies comparing outcomes between IVT + MT and MT from inception to Jan 24, 2019. Random effects mode was used to pool relative risk (RR) with confidence intervals (CI) to compare functional independence in terms of modified Rankin Scale (mRS) 0–2, favorable outcome (mRS 0–1) and mortality at three-months, symptomatic intracerebral hemorrhage, successful reperfusion, and complete reperfusion between the two treatments groups. We included 30 studies enrolling 8970 patients with acute ischemic stroke of large vessel occlusion. Compared with MT, IVT + MT significantly increased the rate of 3-month functional independence (RR 1.20, 95% CI 1.12–1.30; P

The incidence of gestational diabetes mellitus (GDM) has increased recently worldwide with a subsequent occurrence of the associated adverse pregnancy outcomes. The objective of this study was to estimate the association between women with GDM and adverse pregnancy outcomes based on a cohort study and an integrated meta-analysis. A retrospective cohort of 15,097 pregnant women (1718 GDM with 13,379 non-GDM controls) who delivered at two affiliated medical centers of Nantong University from Jan. 1, 2014 to Sep. 30, 2015, was conducted. Then, a meta-analysis was performed to explore and compare adverse pregnancy outcomes between GDM and non-GDM women. In our cohort study, women with GDM were at significantly greater risk for cesarean section [crude relative risk (RR): 2.20, 95% confidence interval (CI): 1.97–2.44], macrosomia (crude RR: 2.36, 95% CI: 2.04–2.74) and large for gestational age (LGA) (crude RR: 2.03, 95% CI: 1.81–2.27), and a lower risk of low birth weight (LBW) (crude RR: 0.64, 95% CI: 0.47–0.86) and small for gestational age (SGA) (crude RR: 0.60, 95% CI: 0.45–0.80) than GDM-free women. However, the preterm birth incidence was not associated with GDM [crude RR: 1.08, 95% CI: 0.91–1.29]. Similarly, the meta-analysis including our cohort study also showed a significant association between GDM and preterm birth (pooled RR: 1.36, 95% CI: 1.26–1.48). Women with GDM still have an increased incidence of adverse pregnancy outcomes, which indicated that early prevention and clinical treatment of disease should be enhanced.

The efficacy and safety of mechanical thrombectomy (MT) for M2 segment occlusion of middle cerebral artery in patients with acute ischemic stroke (AIS) was investigated. We searched PubMed and EMBASE from inception to 16 April 2019 for relevant studies, calculated the pool relative risks (RRs) of 3-month functional independence (modified Rankin scale score 0–2), death and symptomatic intracerebral hemorrhage (sICH) in MT for M2 segment occlusion in patients with AIS versus those of M1 segment or best medical care. Nine studies enrolling 2152 patients compared MT for patients with AIS of M2 segment occlusion and those of M1 segment occlusion. MT for M2 occlusion had a higher rate of 3-month functional independence compared to the patients with M1 occlusion. (RR 1.27, 95% CI 1.11–1.44, P

Chronic or non-communicable diseases are the leading cause of death worldwide; they usually result in long-term illnesses and demand long-term care. Despite advances in molecular therapeutics, specific biomarkers and targets for the treatment of these diseases are required. The dysregulation of de novo lipogenesis has been found to play an essential role in cell metabolism and is associated with the development and progression of many chronic diseases; this confirms the link between obesity and various chronic diseases. The main enzyme in this pathway-ATP-citrate lyase (ACLY), a lipogenic enzyme-catalyzes the critical reaction linking cellular glucose catabolism and lipogenesis. Increasing lines of evidence suggest that the modulation of ACLY expression correlates with the development and progressions of various chronic diseases such as neurodegenerative diseases, cardiovascular diseases, diabetes, obesity, inflammation, and cancer. Recent studies suggest that the inhibition of ACLY activity modulates the glycolysis and lipogenesis processes and stimulates normal physiological functions. This comprehensive review aimed to critically evaluate the role of ACLY in the development and progression of different diseases and the effects of its downregulation in the prevention and treatment of these diseases.

In spite of billions of dollars expended on cancer research every year, the incidence rate and the mortality rate due to this widespread disease has increased drastically over the last few decades. Recent reports from the World Health Organization advocate that overall global cancer burden and deaths due to cancer are expected to double by the next decade. Synthetic drugs developed as chemotherapeutics have repeatedly shown adverse side effects and development of chemoresistance. Cancer is basically a multifactorial disease that necessitates the modulation of multiple targets and oncogenic signaling pathways. Honokiol (C18H18O2) is a biphenolic natural compound isolated from the leaves and barks of Magnolia plant species and has been extensively studied for its beneficial effects against several chronic diseases. Honokiol is capable of efficiently preventing the growth of wide variety of tumors such as those of brain, breast, cervical, colon, liver, lung, prostate, skin, and hematological malignancies. Recent work has shown that this phytochemical can modulate various molecular targets such as activation of pro-apoptotic factors, suppression of anti-apoptotic proteins and different transcription factors, downregulation of various enzymes, chemokines, cell surface adhesion molecules, and cell cycle proteins, and inhibition of activity of protein tyrosine kinases and serine/threonine kinases. Because of its pharmacological safety, honokiol can either be used alone or in combination with other chemotherapeutic drugs for the prevention and treatment of cancer. The current review describes in detail the various reports supporting these anti-cancer studies documented with this promising agent.

Several active compounds from ‘Mother Nature’ have been found to be tailor-made therapeutics for the better management of numerous chronic ailments, with fewer adverse side effects. Zerumbone is one such molecule isolated from the rhizomes of Zingiber zerumbet (L.) Smith, a Zingiberaceae plant with significant medicinal values that has been used traditionally for treating stomach ache, ulcers, diabetes, leprosy, asthma, and skin diseases. Zerumbone has been found to be the most important active compound of Z. zerumbet, contributing to its anti-inflammatory, anti-microbial, anti-hypersensitivity, chemopreventive and chemotherapeutic activities. It has been established as a multi-targeted agent with potential to treat chronic diseases such as osteoarthritis, obesity, diabetes, diabetic nephropathy, diabetic retinopathy, chronic gastritis, neuropathic pain, atherosclerosis, inflammation and cancer through modulation of various cellular signaling cascades and antigen presentation pathways. Therefore, the present study focuses on zerumbone, its sources and biological activities against various chronic diseases by summarizing the literature available.

Sorcin (Soluble resistance related calcium binding protein) is a small soluble penta EF family (PEF) of calcium (Ca2+) binding protein (22,000 Da). It has been reported to play crucial roles in the regulation of calcium homeostasis, apoptosis, vesicle trafficking, cancer development, and multidrug resistance (MDR). Overexpression of sorcin has been reported to be associated with different cancers such as breast cancer, colorectal cancer, gastric cancer, leukemia, lung cancer, nasopharyngeal cancer, ovarian cancer, etc. Essentially, expression of sorcin has been found to be elevated in cancer cells as compared to normal cells, indicating that it has prominent role in cancer. Moreover, sorcin was found to be the regulator of various proteins that has an association with carcinogenesis including NF-κB, STAT3, Akt, ERK1/2, VEGF, MMPs, caspases, etc. Sorcin was also found to regulate apoptosis, as silencing of the same resulted in increased levels of proapoptotic genes and induced mitochondrial apoptotic pathway in cancer. Interestingly, mutations in the sorcin gene have been closely linked with poor overall survival in bladder cancer, brain lower-grade glioma, glioblastoma, glioblastoma multiforme, kidney renal clear cell carcinoma, and stomach adenocarcinoma. Additionally, overexpression of sorcin was also found to induce MDR against different chemotherapeutic drugs. All these findings mark the importance of sorcin in cancer development and MDR. Therefore, there is urgent need to explore the functional mechanism of sorcin and to analyze whether silencing of sorcin would able to chemosensitize MDR cells. The current review summarizes the structure, expression, and functions of sorcin and its importance in the regulation of various malignancies and MDR.

Diabetic cardiomyopathy (DCM) is one of the most severe cardiovascular complications in diabetes. Caffeic acid para-nitro phenethyl ester (CAPE-pNO2) could ameliorate diabetic nephropathy in the diabetic mice in our previous study. This paper was aimed to investigate the effect of CAPE-pNO2 on DCM and its potential mechanism. The DCM mice were established by intraperitoneal injection with streptozotocin (STZ, 50 mg/kg) for 5 days. When the fasting blood glucose level remains above 11.1 mmol/L, treated the mice with CAPE and CAPE-pNO2 for 8 weeks, then the mice were executed, and the samples of blood and heart tissue were collected for the subsequent experiments. The results showed that CAPE-pNO2 can alleviate CK, LDH, TC and TG levels, as well as depress the activity of ROS by down-regulating the expression of NOX4 and improving SOD activity in the serum of STZ-induced DCM mice. Meanwhile, it can also reduce the content of MDA and inhibit lipid accumulation. Besides, CAPE-pNO2 could repress the expression of TNF-α, IL-1β and IL-6 IL - 6 via the NOX4/NF-κB pathway to improve the development of inflammation. Furthermore, it can suppress the expression of collagen and fibronectin to inhibit myocardial fibrosis through the TGF-β1/Smad pathway, and inhibit ECM deposition by regulating TGF-β1 directly, as shown in cardiac tissue section. Importantly, the above results showed that CAPE-pNO2 had better effects of reversing pathological changes than CAPE in a significant difference of p

Pain, especially chronic pain, can lead to cognitive deficits. Mismatch negativity (MMN) is a change-specific component of the auditory event-related brain potential (ERP) that is thought to provide a unique window into sensory memory processes. The present study was designed to determine how chronic and acute pain affects auditory sensory memory. In experiment 1, MMNs elicited by standard and deviant auditory stimuli at short and long inter-stimulus intervals (ISIs) were compared between trigeminal neuralgia (TN) patients and demographically matched healthy controls (HCs). The TN patients were found to have stronger attenuation of the MMN at longer ISIs than HCs. Correlation analysis revealed a significant positive correlation between the sensory subscale of McGill Pain Questionnaire and MMN amplitude reduction across ISI conditions. In experiment 2, MMNs recorded before, during, and after the cold pressor test were compared in healthy subjects. MMN amplitude was significantly reduced during pain exposure and recovered immediately thereafter. These results suggest that both chronic pain and acute pain can interfere with automatic change detection processes in the brain. This study provides the first evidence that chronic pain patients have a faster auditory memory trace decay than HCs.

Immunosuppressive tumor microenvironment in hepatocellular carcinoma (HCC) is critical in tumor development. C-type (Ca2+ -dependent) lectin (CLEC) receptors, essential in innate pattern recognition, have potential regulatory effects on immune cell trafficking and modulatory effects on cancer cell activity. However, information on the expression and prognostic value of CLECs in HCC is scanty. Herein, we explored the potential role of CLECs in HCC based on TCGA, ONCOMINE, GEPIA, UALCAN, cBioPortal, Metascape, TRRUST, and TIMER databases. Results demonstrated a significantly higher mRNA level of CLEC4A and CLEC4L in HCC tissues than normal liver tissues. Contrarily, we found significantly low CLEC4G/H1/H2/M expression in HCC tissues. The IHC analysis revealed the following: Absence of CLEC4A/J/K/M in normal and liver cancer tissues; high CLEC4C expression in HCC tissues; low expression and zero detection of CLEC4D/E/H1/H2/L in HCC tissues and normal tissues, respectively. And the HepG2 and LX-2 were used to verify the expression level of CLEC4s via qRT-PCR in vitro. Furthermore, the expression of CLEC4H1 (ASGR1) and CLEC4H2 (ASGR2) exhibited a significant relation to clinical stages. However, the expression of CLEC4A, CLEC4D, CLEC4E, CLEC4J (FCER2), CLEC4K (CD207), CLEC4G, CLEC4H1, CLEC4M, and CLEC4H2 decreased with tumor progression. Patients expressing higher CLEC4H1/H2 levels had longer overall survival than patients exhibiting lower expression. Moreover, CLEC4A/D/E/J/K/G/H1/M/H2 had significant down-regulated levels of promoter methylation. The expression level of CLEC4s was correlated with the infiltration of B cells, CD8 + T cells, CD4 + T cells, macrophage cells, neutrophil cells, and dendritic cells. Functional analysis revealed the potential role of CLECL4s in virus infection, including COVID-19. Also, hsa-miR-4278 and hsa-miR-324-5p, two potential miRNA targets of CLEC4s, were uncovered. This article demonstrates that CLEC4 is crucial for the development of HCC and is associated with infiltration of various immune cells, providing evidence for new immunotherapy targets in HCC.

Background High rates of co-morbidity have been reported in patients with diabetes mellitus with depression (DD). Danggui Buxue Decoction (DBD), a Traditional Chinese Medicine formula composed of Angelica and Astragalus, has been historically used for the treatment of diabetes. Purpose This study aimed to investigated whether DBD and its main active component, ferulic acid (FA) from Angelica, could ameliorate depression-like behavior in DD and the underlying mechanisms. Methods Goto-Kakizaki (GK) rats were administered DBD (4 or 8 g/kg) by oral gavage during a 4-week period of chronic unpredictable mild stress. After 4 weeks, blood glucose, glycated serum protein, serum insulin, oral glucose tolerance and depression-like behavior were examined, along with brain-derived neurotrophic factor (BDNF)-related signaling pathway proteins and the ultrastructure of hippocampal tissues. UPLC-QTOF-MS was adopted to detect the absorption of FA in the serum and hippocampus. Rat primary hippocampal cells were cultured in a DD model. Protein and mRNA levels of genes involved in BDNF-related signaling and neuroplasticity were analyzed. Results DBD effectively improved glucose tolerance in DD rats and relieved depression-like behavior. Upregulation of cAMP response element binding protein (CREB), BDNF, and tropomyosin receptor kinase B (TrkB) and improvement of the hippocampal neuron ultrastructure supported the antidepressant-Like effects of DBD on the hippocampal neurons. In addition, DBD enhanced the protein and mRNA levels of components of the CREB/BDNF/TrkB pathway in rat primary hippocampal cells induced by elevated glycemia and cortisol. Interestingly, FA, the main component of DBD absorbed in the blood and hippocampus, showed similar effects as DBD on primary hippocampal cells. Conclusion :This study suggests that the TCM formula DBD effectively serves as a potential therapeutic agent for prevention of DD through regulatory effects on the CREB/BDNF/TrkB pathway to protect and remodel hippocampal neurons. Moreover, FA contributes significantly to the treatment effects of DBD.

OBJECTIVES To perform a systematic review and meta-analysis to investigate pretreatment collaterals and outcomes of mechanical thrombectomy in patients with acute ischemic stroke of large-vessel occlusion in anterior circulation. METHODS We systematically searched Embase, PubMed, and the Cochrane Library from their dates of inception to March 5, 2020, and also manually searched reference lists of relevant articles. Pooled relative risk with 95% confidence interval on the association between good collaterals and functional independence (in terms of mRS 0-2), symptomatic intracranial hemorrhage, mortality, and successful reperfusion were synthesized using a random-effects model. RESULTS Thirty-four studies enrolling 5768 patients were included in analysis. Good collaterals were significantly associated with functional independence (RR 1.93, 95%CI 1.64-2.27, P

The tumor necrosis factor (TNF)-α- induced protein 8 (TNFAIP8/TIPE) family is a death effector domain (DED)-containing protein family with four identified members: TNFAIP8 (TIPE), TNFAIP8L1 (TIPE1), TNFAIP8L2 (TIPE2), and TNFAIP8L3 (TIPE3). These proteins were found to play crucial roles in the regulation of immune homeostasis, inflammation, and cancer development. Intensive research in the past two decades revealed a strong correlation of TIPE proteins with the development of various cancers including cancers of the bladder, blood, bone, breast, cervix, colon, esophagus, endometrium, stomach, liver, lung, ovary, pancreas, prostate, and thyroid gland. Also, deregulation of these proteins was found to promote the essential hallmarks of cancer such as survival, tumor growth, proliferation, inhibition of apoptosis, angiogenesis, invasion, migration, and metastasis. Further, differential expression of these proteins in normal and cancer tissues and their association with tumor progression and prognosis signifies the potential diagnostic and prognostic values of TIPE proteins and their importance in cancer therapy. The current review summarizes the literature available thus far on the expression, function, and role of TIPE proteins in the development and maintenance of various cancers.

Background There is no current consensus on the treatment of Rectus abdominis diastasis (RAD). This study aimed to assess the recurrence rates and adverse events after operative or non-operative intervention.Methods We performed a retrospective study and a systematic review. Patients with a diagnosis of RAD who underwent the mesh placement procedure were eligible. Data were collected from The Research Patient Data Registry. Then, a systematic literature search of Pubmed, Embase, and The Cochrane Library databases was performed. A modified Downs and Black checklist for randomized and non-randomized studies of healthcare interventions (DB) was used to evaluate the methodological quality of the studies.Results Data of 82 patients was collected. The 5-year cumulative incidence of recurrence of abdominal hernia was high (females 37.0% vs males 43.4%, P = 0.557). Of 3908 citations, 27 studies describing 2,372 patients were included into the systematic review. In non-operative group, seven studies (25.93%) with a total of 603 subjects reported no patient relapsed after a follow-up of 12 months; a 40% recurrence rate was reported after a follow-up of 5 years in one study, the adverse events associated with operation mainly included seroma (5.13%), a sensibility disorder of the abdominal skin (2.26%), and minor scarring (1.56%). Muscle strength training, such as training of the pelvic floor muscles, abdominal muscles, rectus abdominis, internal/external oblique, or transverse abdominal muscles, was performed in all included non-surgery studies, neither adverse events nor recurrence was reported.Conclusion Operative intervention may be effective at restoring the functions of the rectus muscles and at improving the stability of abdominal wall in the short-term, while non-operative intervention has a limited effect, especially for those RAD combined with hernia.

Chronic airway inflammation is the key process of bronchial asthma which is a serious disease harmful to human health. This study demonstrated the pharmacological effects of the combination of fish oil and ethanol extract of Spirulina platensis (CFS) on alleviation of asthma induced by ovalbumin (OVA) in mice. BALB/c mice were divided into 6 groups: normal, model, 1 mg/kg of dexamethasone, 0.4, 0.8 and 1.6 g/kg of CFS. All mice were administrated continuously for 84 days. All the groups except normal group were sensitized and challenged with OVA. The results showed that CFS inhibited the infiltration of inflammatory cells into lung and bronchoalveolar lavage fluid (BALF) (P

In this study, a circular porous 5-fluorouracil/ultrahigh-molecular-weight-polyethylene (5-FU/UHMWPE) scaffold with different 5-FU concentration was fabricated using fused deposition molding (FDM) 3D printing technology. In vitro cytotoxicity experiments indicated that 5-FU/UNMWPE scaffold has a high inhibitory effect on 4T1 breast cancer cells together with less toxic damage to normal cells. In vivo Animal experiments revealed that 5-FU/UHMWPE scaffold can effectively treat mice with breast cancer cells 4T1. The tumor inhibition rate of 0.5% 5-FU/UHMWPE scaffold, 3.0% 5-FU/UHMWPE scaffold and injecting groups were 54%, 71% and 92%, respectively. Although the tumor inhibition rate of the scaffold group was smaller than the 5-fu-injection group, anatomical analysis showed that there was no obvious drug toxicity in the heart, liver, spleen, lung and kidney of the scaffold groups. These implantable scaffolds ensure a long-term therapeutic drug level near the tumor site while minimizing the drug's exposure to normal tissues. These results suggested that 3D printed porous 5-FU/UHMWPE scaffolds could be a potential drug delivery system in cancer treatment.

Diabetic nephropathy (DN) is one of the most severe complications of diabetes mellitus. This study aimed to determine the effects and potential mechanism of caffeic acid para-nitro phenethyl ester (CAPE-pNO2), a derivative of caffeic acid phenethyl ester (CAPE), on DN; In vivo, intraperitoneal injections of streptozotocin (STZ) were used to induce diabetes in mice; then, the mice were intraperitoneally injected daily with CAPE or CAPE-pNO2 for 8 weeks. The mice were sacrificed, and blood samples and kidney tissues were collected to measure biological indexes. The results showed that CAPE and CAPE-pNO2 could lower serum creatinine, blood urea nitrogen, 24-h albumin excretion, malondialdehyde and myeloperoxidase levels and increase superoxide dismutase activity in diabetic mice. According to HE, PAS and Masson staining, these two compounds ameliorated structural changes and fibrosis in the kidneys. In addition, the immunohistochemical and western blot results showed that CAPE and CAPE-pNO2 inhibited inflammation through the Akt/NF-κB pathway and prevented renal fibrosis through the TGF-β/Smad pathway. In vitro, CAPE and CAPE-pNO2 inhibited glomerular mesangial cell (GMC) proliferation, arrested cell cycle progression and suppressed ROS generation. These compounds also inhibited ECM accumulation via regulating the TGF-β1, which was a similar effect to that of the NF-κB inhibitor PDTC. More importantly, CAPE and CAPE-pNO2 could up-regulate nitric oxide synthase expression in STZ-induced diabetic mice and HG-induced GMCs. CAPE-pNO2 had stronger effects than CAPE both in vivo and in vitro. These data suggest that CAPE-pNO2 ameliorated DN by suppressing oxidative stress, inflammation, and fibrosis via the Akt/NF-κB/ iNOS pathway.

Pancreatic cancer is one of the most aggressive cancers with a poor prognosis and 5-year low survival rate. In the present study, we report that bruceine A, a quassinoid found in Brucea javanica (L.) Merr. has a strong antitumor activity against human pancreatic cancer cells both in vitro and in vivo. Human proteome microarray reveals that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is the candidate target of bruceine A and both fluorescence measurement and microscale thermophoresis suggest bruceine A binds to PFKFB4. Bruceine A suppresses glycolysis by inhibiting PFKFB4, leading to cell cycle arrest and apoptosis in MIA PaCa-2 cells. Furthermore, glycogen synthase kinase-3 β (GSK3β) is identified as a downstream target of PFKFB4 and an PFKFB4-interacting protein. Moreover, bruceine A induces cell growth inhibition and apoptosis through GSK3β, which is dysregulated in pancreatic cancer and closely related to the prognosis. In all, these findings suggest that bruceine A inhibits human pancreatic cancer cell growth via PFKFB4/GSK3β-mediated glycolysis, and it may serve as a potent agent for curing human pancreatic cancer.

Natural compounds, in recent years, have attracted significant attention for their use in the prevention and treatment of diverse chronic diseases as they are devoid of major toxicities. Boswellic acid (BA), a series of pentacyclic triterpene molecules, is isolated from the gum resin of Boswellia serrata and Boswellia carteri. It proved to be one such agent that has exhibited efficacy against various chronic diseases like arthritis, diabetes, asthma, cancer, inflammatory bowel disease, Parkinson’s disease, Alzheimer’s, etc. The molecular targets attributed to its wide range of biological activities include transcription factors, kinases, enzymes, receptors, growth factors, etc. The present review is an attempt to demonstrate the diverse pharmacological uses of BA, along with its underlying molecular mechanism of action against different ailments. Further, this review also discusses the roadblocks associated with the pharmacokinetics and bioavailability of this promising compound and strategies to overcome those limitations for developing it as an effective drug for the clinical management of chronic diseases.

For the last couple of decades, natural products, either applied singly or in conjunction with other cancer therapies including chemotherapy and radiotherapy, have allowed us to combat different types of human cancers through the inhibition of their initiation and progression. The principal sources of these useful compounds are isolated from plants that were described in traditional medicines for their curative potential. Leelamine, derived from the bark of pine trees, was previously reported as having a weak agonistic effect on cannabinoid receptors and limited inhibitory effects on pyruvate dehydrogenase kinases (PDKs). It has been reported to possess a strong lysosomotropic property; this feature enables its assembly inside the acidic compartments within a cell, such as lysosomes, which may eventually hinder endocytosis. In this review, we briefly highlight the varied antineoplastic actions of leelamine that have found implications in pharmacological research, and the numerous intracellular targets affected by this agent that can effectively negate the oncogenic process.

Formononetin, an isoflavone, is extracted from various medicinal plants and herbs, including the red clover (Trifolium pratense) and Chinese medicinal plant Astragalus membranaceus. Formononetin’s antioxidant and neuroprotective effects underscore its therapeutic use against Alzheimer’s disease. Formononetin has been under intense investigation for the past decade as strong evidence on promoting apoptosis and against proliferation suggests for its use as an anticancer agent against diverse cancers. These anticancer properties are observed in multiple cancer cell models, including breast, colorectal, and prostate cancer. Formononetin also attenuates metastasis and tumor growth in various in vivo studies. The beneficial effects exuded by formononetin can be attributed to its antiproliferative and cell cycle arrest inducing properties. Formononetin regulates various transcription factors and growth-factor-mediated oncogenic pathways, consequently alleviating the possible causes of chronic inflammation that are linked to cancer survival of neoplastic cells and their resistance against chemotherapy. As such, this review summarizes and critically analyzes current evidence on the potential of formononetin for therapy of various malignancies with special emphasis on molecular targets.

Cancer is still a major risk factor to public health globally, causing approximately 9.8 million deaths worldwide in 2018. Despite advances in conventional treatment modalities for cancer treatment, there are still few effective therapies available due to the lack of selectivity, adverse side effects, non-specific toxicities, and tumour recurrence. Therefore, there is an immediate need for essential alternative therapeutics, which can prove to be beneficial and safe against cancer. Various phytochemicals from natural sources have been found to exhibit beneficial medicinal properties against various human diseases. Zerumbone is one such compound isolated from Zingiber zerumbet Smith that possesses diverse pharmacological properties including those of antioxidant, antibacterial, antipyretic, anti-inflammatory, immunomodulatory, as well as anti-neoplastic. Zerumbone has shown its anti-cancer effects by causing significant suppression of proliferation, survival, angiogenesis, invasion, and metastasis through the molecular modulation of different pathways such as NF-κB, Akt, and IL-6/JAK2/STAT3 (interleukin-6/janus kinase-2/signal transducer and activator of transcription 3) and their downstream target proteins. The current review briefly summarizes the modes of action and therapeutic potential of zerumbone against various cancers.

The FBXW7 (F-box with 7 tandem WD40) protein encoded by the gene FBXW7 is one of the crucial components of ubiquitin ligase called Skp1-Cullin1-F-box (SCF) complex that aids in the degradation of many oncoproteins via the ubiquitin-proteasome system (UPS) thus regulating cellular growth. FBXW7 is considered as a potent tumor suppressor as most of its target substrates can function as potential growth promoters, including c-Myc, Notch, cyclin E, c-JUN, and KLF5. Its regulators include p53, C/EBP-δ, Numb, microRNAs, Pin 1, Hes-5, BMI1, Ebp2. Mounting evidence has indicated the involvement of aberrant expression of FBXW7 for tumorigenesis. Moreover, numerous studies have also shown its role in cancer cell chemosensitization, thereby demonstrating the importance of FBXW7 in the development of curative cancer therapy. This comprehensive review emphasizes on the targets, functions, regulators and expression of FBXW7 in different cancers and its involvement in sensitizing cancer cells to chemotherapeutic drugs.

Oxymatrine (OMT) is a quinolizidine alkaloid derived from the roots of the Sophora genus plants. It has been widely used as a treatment for chronic hepatitis infections and inflammatory diseases due to its effective immunomodulatory and anti-inflammatory properties. Recently, the potential anti-cancer effects of OMT have been actively studied in various cancers. It can induce apoptosis and inhibit the proliferation of tumor cells, including those of colorectal cancer, gall bladder carcinoma, and leukemia. Moreover, it reduces tumor growth in different in vivo models as well as augments the anti-cancer effects of existing chemotherapeutics on tumor cells. OMT regulates various oncogenic signaling pathways such as the Akt, epidermal growth factor receptor (EGFR), and nuclear factor kappa B (NF-κB) cascades to exert its cytotoxicity against cancer cells. This review provides an overview of the current knowledge on the potential of OMT as an anti-cancer therapeutic through the modulation of diverse oncogenic molecular targets.

Paraquat (PQ), a highly toxic herbicide, selectively accumulates in the lungs and causes pulmonary damage through oxidative and inflammatory processes after intentional or accidental poisoning. The resulting acute lung injury (ALI) is characterized by neutrophil infiltration and extensive inflammation with rapid respiratory failure. However, effective therapies are lacking. We tested the hypothesis that suppressing neutrophil-derived matrix metalloproteinase 9 (MMP9) would ameliorate the inflammatory milieu and alleviate PQ-induced ALI. Lung injury was assessed in mice intratracheally injected with PQ aerosol by measuring the lung static compliance, cell count and neutrophil percentage of the bronchoalveolar lavage fluid (BALF) and lung, alveolar-capillary permeability, and histopathological lung injury scores. MMP9/2 activity was assessed by gelatin zymography, and the location of neutrophils and MMP9 in the lung was evaluated by immunofluorescence costaining. In the neutrophil depletion experiment, mice received anti-Ly6G antibody intraperitoneally; for the MMP inhibition experiment, an MMP inhibitor, doxycycline (DOX), was administered by gavage. In PQ-induced ALI, the activity of neutrophil-derived MMP9 but not MMP2 increased significantly. Neutrophil depletion reduced the inflammatory burden, improved pulmonary edema, and reduced the PQ-induced overexpression of MMP9. Consistently, oral delivery of DOX to mice decreased the overexpression of MMP9 that was activated by PQ and phenocopied the resolution of PQ-induced ALI observed after neutrophil depletion. Taken together, our results show for the first time that DOX is involved in the resolution of PQ-induced ALI via a mechanism involving reducing the activity of neutrophil-derived MMP9. We speculate that DOX may represent a novel therapeutic strategy for PQ-induced ALI.

Despite tremendous progress made during the last few decades in the treatment options for cancer, compounds isolated from Mother Nature remain the mainstay for therapy of various malignancies. Fangchinoline, initially isolated from the dried root of Stephaniae tetrandrine, has been found to exhibit diverse pharmacological effects including significant anticancer activities both in tumor cell lines and selected preclinical models. This alkaloid appears to act by modulating the activation of various important oncogenic molecules involved in tumorigenesis leading to a significant decrease in aberrant proliferation, survival and metastasis of tumor cells. This mini-review briefly describes the potential effects of fangchinoline on important hallmarks of cancer and highlights the molecular targets modulated by this alkaloid in various tumor cell lines and preclinical models.

Yaqin Ling,1 Xiaoling Ling,2 Lu Fan,1 Yong Wang,3,* Qing Li1,* 1Department of Pathophysiology, College of Basic Medical, Lanzhou University, 2Medical Oncology, Lanzhou University First Hospital, 3Department of Gastroenterology, Lanzhou General Hospital of Lanzhou Military Command of PLA, Lanzhou, Gansu Province, People’s Republic of China *These authors contributed equally to this work Purpose: There are a growing number of reports suggesting that the aberrant expression and mutation of the thyroid hormone receptor β1 (TRβ1) gene is associated with the development of human neoplasms. However, its exact role in the pathogenesis of breast cancer remains elusive. In the present study, we analyzed the mRNA expression and mutations of the TRβ1 gene in the Chinese breast cancer population.Methods: The expression of TRβ1 mRNA was examined by real-time quantitative reverse transcription polymerase chain reaction, and mutations in the TRβ1 gene in the hotspot region that spans exons 7–10 were analyzed by polymerase chain reaction single-strand conformation polymorphism and automated DNA sequencing.Results: TRβ1 mRNA expression was significantly reduced in all 105 breast cancer specimens examined. A total of 20 samples showed truncating mutations within the exons 7–10 of the TRβ1 gene, where eight cases harbored a frame shift mutation (five cases of c.850insA in exon7 and three cases c.1028delA in exon 8), whereas missense mutations were observed in 12 breast cancer cases. The 20 cases with mutation in the TRβ1 gene showed a reduction in TRβ1 mRNA expression compared with that observed in matched normal tissues. The mutation was also correlated with menopausal stage and estrogen receptor status.Conclusion: The findings of the present study suggest that the aberrant expression and mutations of the TRβ1 gene are associated with the development of breast cancer and that the ­mutations in the TRβ1 gene partly serve as the underlying mechanism for TRβ1 inactivation in the Chinese breast cancer population. Keywords: breast cancer, mutation, thyroid hormone receptor β1, biomarker

The World Health Organization (WHO) has documented that cancer is the second foremost reason for death worldwide. Various factors are responsible for cancer, for instance, exposure to different physical, chemical and biological carcinogens, infections, hereditary, poor dietary habits and lifestyle etc. Cancer is a preventable disease if detected at an early stage; however, most of the cases of cancer are diagnosed at an incurable advanced or metastatic stage. According to WHO about 70 % of deaths due to cancer occur in countries with low- or middle-income. The major problems associated with the conventional therapies are cancer recurrence, development of chemoresistance, affordability, late-stage diagnosis, adverse side effects and inaccessible treatment. Thus, there is an urgent need to find alternative treatment modalities, which have easy accessibility and are affordable with minimum side effects. In this article, we reviewed the natural stilbene known as "Piceatannol" for its anticancer properties. Numerous preclinical studies have reported the potential of Piceatannol to prevent or impede the growth of various cancers originating from different organs such as brain, breast, cervical, colon, liver, lung, prostate, skin, etc. The current review primarily emphasises on the insights of Piceatannol source, chemistry, and the molecular mechanisms involved in the regression of the tumor. This review supports Piceatannol as a potential anticancer and chemopreventive agent and suggests that it can be effectively employed as a capable anti-cancer drug.

The past few decades have witnessed widespread research to challenge carcinogenesis; however, it remains one of the most important health concerns with the worst prognosis and diagnosis. Increasing lines of evidence clearly show that the rate of cancer incidence will increase in future and will create global havoc, designating it as an epidemic. Conventional chemotherapeutics and treatment with synthetic disciplines are often associated with adverse side effects and development of chemoresistance. Thus, discovering novel economic and patient friendly drugs that are safe and efficacious is warranted. Several natural compounds have proved their potential against this dreadful disease so far. Magnolol is a hydroxylated biphenyl isolated from the root and stem bark of Magnolia tree. Magnolol can efficiently prevent or inhibit the growth of various cancers originating from different organs such as brain, breast, cervical, colon, liver, lung, prostate, skin, etc. Considering these perspectives, the current review primarily focuses on the fascinating role of magnolol against various types of cancers, and the source and chemistry of magnolol and the molecular mechanism underlying the targets of magnolol are discussed. This review proposes magnolol as a suitable candidate that can be appropriately designed and established into a potent anti-cancer drug.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is responsible for the regulation of a large number of genes that are involved in important physiological processes, including survival, inflammation, and immune responses. At the same time, this transcription factor can control the expression of a plethora of genes that promote tumor cell proliferation, survival, metastasis, inflammation, invasion, and angiogenesis. The aberrant activation of this transcription factor has been observed in several types of cancer and is known to contribute to aggressive tumor growth and resistance to therapeutic treatment. Although NF-κB has been identified to be a major contributor to cancer initiation and development, there is evidence revealing its role in tumor suppression. This review briefly highlights the major mechanisms of NF-κB activation, the role of NF-κB in tumor promotion and suppression, as well as a few important pharmacological strategies that have been developed to modulate NF-κB function.

There is great potential to use free nitrous acid (FNA/HNO2), the protonated form of nitrite, as an antimicrobial agent due to its bacteriostatic and bactericidal effects on a range of microorganisms. Here, we determine the effects of FNA on the opportunistic pathogen Pseudomonas aeruginosa PAO1, a well-studied denitrifier capable of nitrate/nitrite reduction in its anaerobic respiration. It was seen that lower FNA concentrations in the range of 0.1 to 0.2 mg N/L exerted a temporary inhibitory effect on the growth of P. aeruginosa, while respiratory inhibition was not detected until an FNA concentration of 1.0 mg N/L was applied. The FNA concentration of 5.0 mg N/L caused complete cell killing and likely cell lysis. The results suggest concentration-related and multiple antimicrobial effects of FNA. Differential killing of FNA in the P. aeruginosa subpopulations was detected, suggesting intrastrain heterogeneity, and does not support the idea of specific concentrations of FNA bringing about bacteriostatic and bactericidal effects on this species. A delayed recovery from FNA treatment suggested that FNA caused cell damage which required repair prior to the organism showing cell growth. The results of the study provide insight of the inhibitory and biocidal mechanisms of FNA on this important microorganism.

To investigate the relationship between sagittal spinal alignment and the incidence of vertebral fracture in patients with osteoporosis. A cohort of 1,044 postmenopausal women with osteoporosis were prospectively observed for the incidence of lumbar vertebral fracture. Baseline characteristics of the subjects were recorded, including age, year post-menopause, body height and weight, lumbar spine BMD (LSBMD) and femoral neck BMD (FNBMD). Patients with radiologically diagnosed lumbar vertebral fractures were assigned to the fracture group, and 150 randomly selected participants were assigned to the non-fracture group. Parameters depicting sagittal spinal alignment, including sacral slope (SS), pelvic tilt, pelvic incidence (PI), thoracic kyphpsis, lumbar lordosis (LL), lumbar lordosis index (LLI) and sagittal vertical axis, were measured for both groups. Comparison between the two groups was carried out by Student’s t test. Variables showing significant differences were entered into a logistic regression analysis to determine the independent risk factors. Patients with fracture events had significantly lower LSBMD as well as a significantly longer year post-menopause. Besides, patients with vertebral fracture were found to have significantly lower LL, LLI, SS and PI. Regression analysis showed that LSBMD (OR = 0.27), LL (OR = 0.3), LLI (OR = 0.43) and PI (OR = 0.67) had significant associations with the risk of vertebral fracture. Osteoporosis patients with low LL, LLI, and PI could be at high risk of lumbar vertebral fracture. In addition to BMD, the abnormal sagittal spinal profile should also be taken into consideration when predicting the incidence of vertebral fracture in such patients.

Introduction: Osteoporosis is characterised by decreased bone mass and weakened bones, with an increased risk of fractures. Osteoporotic fracture, the most serious complication of osteoporosis, is related not only to lower bone mineral density (BMD), but also falls. Osteoporosis and fractures are associated with a decreased health-related quality of life (HRQL). Zoledronic acid (ZOL) is an intravenous once-yearly bisphosphonate that has been shown to be effective and safe in improving BMD and reducing fracture risk in controlled clinical trials. Material and methods: In this self-controlled, prospective trial, 220 postmenopausal women with osteoporosis (mean age 67 years) received a single infusion of ZOL 5 mg at baseline and month 12. BMD, HRQL and Fall Index (FI) were measured at baseline, and months 12 and 24 (before each use of ZOL). The main outcome measures were the changes in lumbar spine and hip BMD and the changes in HRQL, the Short Form-36 questionnaire (SF-36). Additional comparisons were based on the FI. LSD multiple comparisons were used in the comparisons of BMD, SF-36 domain scores and FI. Results: The patients had significantly higher L1-4, total hip, femoral neck and trochanter BMD (P < 0.05) with improved HRQL (P < 0.05) over two years of treatment of once-yearly ZOL 5mg. FI was reduced (P < 0.05) with oral daily elemental calcium and vitamin D in the treatment course. Conclusions: ZOL improves BMD and HRQL, especially in the physical aspects, over two years of treatment in women with postmenopausal osteoporosis, and can help improve balance ability. (Endokrynol Pol 2014; 65 (2): 96–104)

Histone deacetylases (HDACs) are enzymes that can control transcription by modifying chromatin conformation, molecular interactions between the DNA and the proteins as well as the histone tail, through the catalysis of the acetyl functional sites removal of proteins from the lysine residues. Also, HDACs have been implicated in the post transcriptional process through the regulation of the proteins acetylation, and it has been found that HDAC inhibitors (HDACi) constitute a promising class of pharmacological drugs to treat various chronic diseases, including cancer. Indeed, it has been demonstrated that in several cancers, elevated HDAC enzyme activities may be associated with aberrant proliferation, survival and metastasis. Hence, the discovery and development of novel HDACi from natural products, which are known to affect the activation of various oncogenic molecules, has attracted significant attention over the last decade. This review will briefly emphasize the potential of natural products in modifying HDAC activity and thereby attenuating initiation, progression and promotion of tumors.

Background In the 1990s, China introduced rubella vaccine into the private market using BRD-II virus strain, which is different than the globally used RA27/3 strain. In 2007, BRD-II rubella containing vaccine was introduced into the national immunization program and recommended for routine use. However, to our knowledge, there are no field vaccine effectiveness (VE) studies of BRD-II rubella vaccine. In April 2011, a rubella outbreak was detected in two daycare centers in Harbin city, China. We conducted an investigation to determine VE of BRD-II rubella vaccine. Methods Rubella cases were either laboratory-confirmed or epidemiologically linked to laboratory-confirmed cases. We collected demographic characteristics, migrant status, and history of rubella and measles vaccination from all children in the two daycare centers. Results The first case of rubella was on 22 November, 2010. Among the 143 children in the two daycare centers, 22 acquired rubella, for an overall attack rate (AR) of 15.4% (22/143). The AR in higher-grade classes (21.7%) was higher than in lower grade classes (3.9%). The AR among migrant children (47.8%) was higher than among local children (9.2%). Rubella vaccine coverage was 17% (24/143), while measles vaccine coverage was 100%. The AR among rubella-vaccinated children was 0% (0/24), and the AR among rubella-unvaccinated children was 18.5% (22/119), for a VE of 100% ( P value = 0.025, 95% CI: 35–100%). Rubella vaccine coverage among children born before 2007 was 10.2% (10/98), and was lower than that for children born in 2007 or after (31.1% (14/45), RR = 0.33, 95%CI: 0.16–0.68). Emergency vaccination was conducted on 11 and 12 April 2011, and the outbreak stopped in one week later. Conclusions Domestic BRD-II strain rubella vaccine showed high vaccine effectiveness against rubella. Rubella vaccine coverage through routine immunization was insufficient. Consideration should be given for measuring rubella vaccine coverage to determine the need for catch-up vaccination in China.

Growing evidence indicates that glia atrophy contributes to the pathophysiology and the pathogenesis of major depressive disorder. Magnolol is the main constituent identified in the bark of Magnolia officinalis, which has been used for the treatment of mental disorders, including depression, in Asian countries. In this study, we investigated the antidepressant-like effect and the possible mechanisms of magnolol in rats subjected to unpredictable chronic mild stress (UCMS). The ameliorative effect of magnolol on depression symptoms was investigated through behavior tests, including sucrose preference test, open-field test and forced-swimming test. In addition, the levels of glial fibrillary acidic protein (GFAP), an astrocyte marker, in the hippocampus and prefrontal cortex were determined by immunohistochemistry, Western blot, and reverse transcription-polymerase chain reaction (RT-PCR). Exposure to UCMS resulted in a decrease of behavioral activity, whereas magnolol (20, 40 mg/kg) and fluoxetine (20mg/kg) administration significantly reversed the depressive-like behaviors (P

Background: Previous studies demonstrated dysregulated expression of microRNAs (miRNAs) in the myocardium of patients with dilated cardiomyopathy (DCM). This study investigated levels of miRNAs in the circulation of DCM patients, and the value of miRNAs as biomarkers for DCM. Methods and materials: In 45 DCM patients and 39 age- and sex-matched controls, circulating miR-423-5p, miR-126, miR-361-5p, miR-155, and miR-146a concentrations were measured and correlated to cardiac functional parameters, including left ventricular ejection fraction (LVEF) and N-terminal pro-brain natriuretic peptide (NT-proBNP). Results: Plasma levels of miR-126 and miR-361-5P did not differ between the DCM and control groups (p = 0.331 and p = 0.784, respectively). Plasma levels of the immunity-associated miRNAs, miR-146a and miR-155, did not differ between the DCM and control groups (p = 0.437 and p = 0.702, respectively). Levels of circulating miR-423-5p were significantly greater in the DCM group (p = 0.003). Further, there was a positive correlation between plasma levels of miR-423-5p and NT-proBNP (r = 0.430, p = 0.003). MiR-423-5p distinguished DCM cases from controls with an area under the curve (AUC) receiver operating characteristic (ROC) curve of 0.674 (95% CI, 0.555–0.793). Conclusions: Patients with DCM have elevated plasma miR-423-5p levels. The plasma concentration of miR-423-5p was positively correlated with the level of NT-proBNP. Circulating levels of miR-423-5p could be served as a diagnostic biomarker for heart failure caused by DCM. Plasma levels of immunity-associated miR-146a, -155, and -126 were not significantly different between DCM and control groups.

Reverse-mode activation of the Na(+)/Ca(2+) exchanger (NCX) during reperfusion following ischemia contributes to Ca(2+) overload and cardiomyocyte injury. KB-R7943, a selective reverse-mode NCX inhibitor, reduces lethal reperfusion injury under non-ischemic conditions. However, the effectiveness of this compound under ischemic conditions is unclear. In the present study, we studied the effects of KB-R7943 in an animal model of hyperlipidemia. We further assessed whether the K ATP (+) channels are involved in potential protective mechanisms of KB-R7943. Twelve rats were fed normal chow, while 48 animals were fed a high cholesterol diet. The hearts from the control and hypercholesterolemic rats were subjected to 25 min of global ischemia followed by a 120-min reperfusion. Before this, hearts from hypercholesterolemic rats either received no intervention (cholesterol control group) or were pre-treated with 1 μM KB-R7943 and 0.3 μM of K ATP (+) blocker glibenclamide or glibenclamide alone. The infarction sizes (triphenyltetrazolium assay) were 35 ± 5.0 % in the control group, 46 ± 8.7 % in the cholesterol control group (p0.05 vs. control group), 28.6 ± 3.3 % in the KB-R7943 group (p0.05 vs. cholesterol control group), 44 ± 5 % in the KB-R7943 and glibenclamide group, and 47 ± 8.5 % in the glibenclamide group (p0.05 vs. control group). Further, KB-R7943 attenuated the magnitude of cell apoptosis (p0.05 vs. cholesterol control group). These beneficial effects were abolished by glibenclamide. In conclusion, diet-induced hypercholesterolemia enhances myocardial injury. Selective reverse-mode NCX inhibitor KB-R7943 reduces the infarction size and apoptosis in hyperlipidemic animals through the activation of K ATP (+) channels.

CELADEN was a randomized placebo-controlled trial of 50 patients with confirmed dengue fever to evaluate the efficacy and safety of celgosivir (A study registered at ClinicalTrials.gov, number NCT01619969). Celgosivir was given as a 400 mg loading dose and 200 mg bid (twice a day) over 5 days. Replication competent virus was measured by plaque assay and compared to reverse transcription quantitative PCR (qPCR) of viral RNA. Pharmacokinetics (PK) correlations with viremia, immunological profiling, next generation sequence (NGS) analysis and hematological data were evaluated as exploratory endpoints here to identify possible signals of pharmacological activity. Viremia by plaque assay strongly correlated with qPCR during the first four days. Immunological profiling demonstrated a qualitative shift in T helper cell profile during the course of infection. NGS analysis did not reveal any prominent signature that could be associated with drug treatment; however the phylogenetic spread of patients’ isolates underlines the importance of strain variability that may potentially confound interpretation of dengue drug trials conducted during different outbreaks and in different countries. Celgosivir rapidly converted to castanospermine (Cast) with mean peak and trough concentrations of 5727 ng/mL (30.2 μM) and 430 ng/mL (2.3 μM), respectively and cleared with a half-life of 2.5 (± 0.6) hr. Mean viral log reduction between day 2 and 4 (VLR2-4) was significantly greater in secondary dengue than primary dengue (p = 0.002). VLR2-4 did not correlate with drug AUC but showed a trend of greater response with increasing Cmin. PK modeling identified dosing regimens predicted to achieve 2.4 to 4.5 times higher Cmin. than in the CELADEN trial for only 13% to 33% increase in overall dose. A small, non-statistical trend towards better outcome on platelet nadir and difference between maximum and minimum hematocrit was observed in celgosivir-treated patients with secondary dengue infection. Optimization of the dosing regimen and patient stratification may enhance the ability of a clinical trial to demonstrate celgosivir activity in treating dengue fever based on hematological endpoints. A new clinical trial with a revised dosing regimen is slated to start in 2016 (NCT02569827). Furthermore celgosivir’s potential value for treatment of other flaviruses such as Zika virus should be investigated urgently. Trial Registration: ClinicalTrials.gov NCT01619969, Author Summary Dengue virus is currently threatening 40% of the world’s population. An approximately 60% efficacious vaccine has been registered for use in Mexico, Brazil, the Philippines, Paraguay and El Salvador, but there are no approved antiviral treatments available. We have shown that celgosivir, an endoplasmic reticulum alpha glucosidase inhibitor, has submicromolar activity against all 4 serotypes of dengue virus (DENV) and also efficacious in mouse model of infection. The strong preclinical pharmacology motivated the conduct of an investigator-initiated, Phase 1b randomized, double-blind, placebo-controlled trial of celgosivir in 50 adult dengue patients. Although the trial did not meet the primary endpoints of lowering viremia or fever, the safety profile of the drug prompted extended hematological, pharmacokinetic, immunological and viral sequence profiling. Here we report several non-significant trends of pharmacological effect of celgosivir on platelet count, hematocrit, and NS1 clearance in secondary dengue patients. In addition, pharmacokinetic modeling identified an alternate dosing regimen that is predicted to achieve a 4.5-fold increase in minimum drug concentrations during treatment (Cmin) with only a modest increase in overall dose. A new Phase 2a clinical trial with an optimized dosing regimen of celgosivir (ClinicalTrials.gov number NCT02569827) is scheduled to start in the latter part of 2016.

Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381AC) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381AC variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility, affecting 5-10% of females of reproductive age. Currently, little is known about the changes in whole proteins between PCOS and normal ovaries. In the present study, a proteomic approach comprised two-dimensional gel electrophoresis (2DE) analysis and mass spectroscopy was used to identify proteins and examine expression patterns in three PCOS and normal ovaries. One hundred and ten protein spots were separated and showed different intensities between PCOS and normal ovaries. Sixty-nine proteins associated with cellular metabolism and physiological process were identified from 72 spots. Fifty-four proteins were up-regulated in PCOS ovaries and 15 other proteins were up-regulated in normal ovaries. These data demonstrate, for the first time, the complexity in the regulation of ovarian protein expression in human PCOS, and will provide important insight for a better understanding of the pathogenetic mechanisms underlying this clinical disorder.

Introduction. Esotropia is a form of strabismus that can give the affected individual a “cross-eyed” appearance. Acute onset of esotropia is an uncommon form; in the vast majority of cases, no underlying neurological etiology is found.Case Presentation. A 22-year-old female with a long history of opiate abuse presented with acute onset of diplopia. She noted her eyes were crossing and started seeing double. She stopped using heroin 11 days prior to presentation. There was large inward deviation of her left eye. Convergence was difficult and accompanied by horizontal nystagmus. Diplopia resolved by covering each eye. Further investigations including imaging studies were normal.Discussion. Acute onset esotropia is rare and must be investigated right away to exclude central nervous system pathologies, where no opiates use is reported. Diplopia in the form of acute esotropia may manifest in up to 30% of individuals undergoing heroin withdrawal. Evaluating acute esotropia requires detailed information of medical history with an emphasis on drug use.Conclusion. Acute onset esotropia with double vision can be caused by abrupt withdrawal of opiates. This case should serve to raise awareness among health care professionals, to avoid costly and unnecessary diagnostic evaluations and interventions.

The promyelocytic leukemia-retinoic acid receptor alpha (PML-RARalpha) protein of acute promyelocytic leukemia (APL) is oncogenic in vivo. It has been hypothesized that the ability of PML-RARalpha to inhibit RARalpha function through PML-dependent aberrant recruitment of histone deacetylases (HDACs) and chromatin remodeling is the key initiating event for leukemogenesis. To elucidate the role of HDAC in this process, we have generated HDAC1-RARalpha fusion proteins and tested their activity and oncogenicity in vitro and in vivo in transgenic mice (TM). In parallel, we studied the in vivo leukemogenic potential of dominant negative (DN) and truncated RARalpha mutants, as well as that of PML-RARalpha mutants that are insensitive to retinoic acid. Surprisingly, although HDAC1-RARalpha did act as a bona fide DN RARalpha mutant in cellular in vitro and in cell culture, this fusion protein, as well as other DN RARalpha mutants, did not cause a block in myeloid differentiation in vivo in TM and were not leukemogenic. Comparative analysis of these TM and of TM/PML(-/-) and p53(-/-) compound mutants lends support to a model by which the RARalpha and PML blockade is necessary, but not sufficient, for leukemogenesis and the PML domain of the fusion protein provides unique functions that are required for leukemia initiation.

Aims To investigate CYP3A activity in cancer and noncancer Asian patients using midazolam and to reveal possible alternative traits for phenotyping CYP3A. Methods Intravenous midazolam 2.5 mg or 2.5–8 mg was administered to 27 cancer and 24 noncancer patients, respectively. Plasma was sampled at 0, 0.25, 0.5, 1, 1.5, 2, 3.5 and 5 h after intravenous ultrashort, 30 s infusion. Plasma midazolam and 1′-hydroxymidazolam concentrations were determined using GCMS. The disposition of midazolam and 1′-hydroxymidazolam in these patients was compared. Midazolam clearance was correlated with dose-normalized plasma midazolam concentrations (concentration/per dose). Results Clearance (CL) and steady state volume of distribution (Vss) of midazolam (mean ± SD, 95% confidence level) in cancer (424 ± 155, 61.3 ml min−1; 1.21 ± 0.46, 0.18 l kg−1) and noncancer (407 ± 135, 57.1 ml min−1; 1.15 ± 0.33, 0.155 l kg−1) patients, respectively, were not different and comparable with published data. Clearance variability was 4–5 fold in both groups. Midazolam clearance correlated significantly with all plasma concentration/per dose at and after the 1-h time point, with a minimum correlation coefficient of r = 0.752, P