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Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by the accumulation of amyloid‐beta (Aβ) proteins and neurofibrillary tangles in the brain. There have been recent advancements in antiamyloid therapy for AD. This narrative review explores the recent advancements and challenges in antiamyloid therapy. In addition, a summary of evidence from antiamyloid therapy trials is presented with a focus on lecanemab. Lecanemab is the most recently approved monoclonal antibody that targets Aβ protofibrils for the treatment of patients with early AD and mild cognitive impairment (MCI). Lecanemab was the first drug shown to slow cognitive decline in patients with MCI or early onset AD dementia when administered as an infusion once every two weeks. In the Clarity AD trial, lecanemab was associated with infusion‐site reactions (26.4%) and amyloid‐related imaging abnormalities (12.6%). The clinical relevance and long‐term side effects of lecanemab require further longitudinal observation. However, several challenges must be addressed before the drug can be routinely used in clinical practice. The drug's route of administration, need for imaging and genetic testing, affordability, accessibility, infrastructure, and potential for serious side effects are some of these challenges. Lecanemab's approval has fueled interest in the potential of other antiamyloid therapies, such as donanemab. Future research must focus on developing strategies to prevent AD; identify easy‐to‐use validated plasma‐based assays; and discover newer user‐friendly, and cost‐effective drugs that target multiple pathways in AD pathology. [ABSTRACT FROM AUTHOR]

Background. Diarrhea is the common gastrointestinal disorder accounting for 2.5 billion episodes and 1.5 million deaths annually. Limitations and inaccessibility of currently available medications are the main problem associated with treatment of diarrhea. Hence, medicinal plants are usually preferred to manage diarrhea because they may contain constituents with high activity and fewer side effects. Even though the dose, safety, and efficacy of Colocasia esculenta (L.) Schott are not substantiated scientifically, several societies use it for the treatment of diarrhea. Objective. This study was targeted at exploring the in vivo antidiarrheal activities of 80% methanol extract and solvent fractions of peels of Colocasia esculenta (L.) Schott in Swiss albino mice. Methods. The plant was collected and extracted with 80% methanol, followed by fractionation with distilled water, chloroform, and diethyl ether. Castor oil‐induced diarrhea, enteropooling, and motility tests were used to evaluate antidiarrheal activity. The test groups received graded doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg. Negative controls received 10 ml/kg of 2% Tween 80 while positive controls received loperamide (3 mg/kg) or atropine (5 mg/kg). Results. The crude and solvent fractions of the plant extract have induced significant effects in reduction of the number and weight of wet stools at all tested doses. However, delay in onset of diarrhea was observed only at 400 mg/kg (P < 0.001) for both crude extract and solvent fractions. In antienteropooling test, 80% methanol extract and solvent fractions have significantly reduced the weight and volume of intestinal contents, especially at 200 mg/kg and 400 mg/kg. Regarding the antimotility test, the crude extract reduced motility at all tested doses, whereas the solvent fractions reduced intestinal motility mainly at 400 mg/kg (P < 0.001). Conclusion. The study has revealed that the 80% methanol extract and solvent fractions of the plant possess antidiarrheal activities supporting the traditional antidiarrheal claims of the plant. [ABSTRACT FROM AUTHOR]

Objective. During in vitro fertilization-embryo transfer (IVF-ET) treatment, the reproductive endocrine regulatory mechanisms hold pivotal importance. Specifically, the serum estradiol ( E 2 ) level during ovulation emerges as a critical factor influencing pregnancy outcomes. This retrospective study aimed to comprehensively compare two common clinical regimens based on the grouping of serum E 2 levels and the number of oocytes retrieved on the trigger day. Our objective was to evaluate the pregnancy outcomes in IVF-ET patients across different ovarian response groups, exploring the efficacy of the dual-trigger and single-trigger regimens to provide valuable insights for optimizing clinical strategies in the context of IVF-ET. Methods. A retrospective analysis was conducted on the clinical data of 2778 infertile patients who underwent ART (IVF/ICSI). Subsequently, a detailed statistical analysis was performed on 1032 patients following an antagonist regimen. Participants were categorized into single-trigger and dual-trigger groups based on real-world trigger protocols, considering different ovarian responses. Comprehensive statistical assessments were conducted on baseline characteristics, ovulation induction, and pregnancy outcomes. Results. Baseline characteristics and cycle parameters among the three patient groups (high ovarian response, normal response, and poor response) exhibited no significant differences between the dual-trigger and single-trigger regimen groups. Despite the dual-trigger regimen utilizing a significantly lower HCG dose, no notable discrepancies were observed in laboratory results and pregnancy outcomes (embryo transfer rate, pregnancy rate, and live birth rate) for normal and high responders. Remarkably, E 2 levels were higher in the dual-trigger group compared to the single-trigger group. In high and normal responders, the dual-trigger regimen demonstrated increased oocyte counts and oocyte acquisition rates, coupled with decreased transfer cancellation rates attributed to ovarian hyperstimulation syndrome (OHSS). Intriguingly, patients with a poor ovarian response experienced no graft cancellations due to OHSS prevention in either group. Conclusion. For patients with high and normal ovarian responses, the utilization of a dual-trigger regimen on the trigger day effectively mitigates the risk of OHSS. Our large sample study supports the substitutability of the dual-trigger regimen over the single-trigger regimen without compromising pregnancy outcomes. However, this conclusion is not applicable to patients with poor ovarian responses. The results of this study highlight the necessity of adopting a customized and individualized treatment approach that should be based on the patient's ovarian response. Additionally, recognizing the pivotal role of the endocrine environment in influencing pregnancy outcomes and the occurrence of OHSS, further exploration of the effects of different triggering regimens on endocrine parameters is warranted. Such investigations will contribute to enhancing the reproductive outcomes of IVF-ET technology. [ABSTRACT FROM AUTHOR]

Heart‐Protecting Musk Pill (HMP) is a Traditional Chinese Medicine (TCM) that has been used for the prevention and treatment of coronary heart disease in clinic. The current study investigated the effect of HMP on the concentrations of interleukin‐6 (IL‐6) and tumor necrosis factor‐alpha (TNF‐α) and observed the relationship between level changes of inflammatory cytokines and ventricular remodeling in rats with acute myocardial infarction (AMI). Animal models of AMI were made by coronary artery ligation in Sprague‐Dawley (SD) rats. AMI rats showed increased levels of IL‐6 and TNF‐α. Treatment with HMP decreases IL‐6 and TNF‐α concentrations in rats with AMI. Histopathological and transmission electron microscopic findings were also essentially in agreement with biochemical findings. The results of our study revealed that inflammatory cytokines IL‐6 and TNF‐α induce cardiac remodeling in rats after AMI; HMP improves cardiac function and ameliorates ventricular remodeling by downregulating the expression of IL‐6 and TNF‐α and further suppressing the ultrastructural changes of myocardial cells. [ABSTRACT FROM AUTHOR]

Objective. Matrix metalloproteinase-2 (MMP2) overexpression has been considered as a hallmark of tumor aggressiveness. The significant roles of MMP2 in other human disorders, such as cardiovascular diseases and dental caries, have also been demonstrated. Herein, we used in silico approaches to evaluate the binding affinity of selected cinnamic acids to the MMP2 catalytic domain. The obtained findings were subsequently juxtaposed with those attributed to oleandrin, utilized as a reference pharmaceutical agent. Methods. This research employed the AutoDock software to assess the affinity of 19 herbal compounds derived from cinnamic acid to the catalytic cleft of MMP2. The ligands attaining the most negative scores, as determined by the Gibbs free binding energy assessments, were accorded the highest rankings. The interactions between the MMP2 and cinnamic acids ranked highest were elucidated using the Discovery Studio Visualizer tool. Molecular dynamics simulations were performed to investigate the structural stability of MMP2 backbone atoms when forming complexes with both the top-ranked inhibitor from this study and a standard drug. Results. Eight cinnamic acids were indicated with Δ G binding values less than −10 kcal/mol. Cynarin emerged as the most potent inhibitor of the enzyme, with the Δ G binding score and inhibition constant value of −15.19 kcal/mol and 7.29 pM, respectively. The MMP2 backbone atoms achieve stability around the 20 ns mark, displaying a root mean square deviation of approximately 3.2 Å when influenced by the top-ranked cinnamic acid, the standard drug, or in their free form. Conclusion. The inhibition of MMP2 by cinnamic acids, particularly cynarin, holds promise as a valuable therapeutic strategy for various human disorders, encompassing cancer, cardiovascular conditions, and dental caries. [ABSTRACT FROM AUTHOR]

Purpose. Basal cell carcinoma (BCC) is the most frequent malignant periocular tumor. It is associated with exposure to ultraviolet radiation, and its incidence is gradually increasing. It may occasionally display more aggressive behavior and result in orbital or intracranial invasion. Mortality from periocular BBC with orbital invasion is very low, but the associated morbidity can be significant, from disfigurement to blindness. Traditionally, these cases have been treated with orbital exenteration or with radiotherapy (RT), but in recent years, hedgehog pathway inhibitors (HPIs) have emerged, are effective in more serious cases, and are used primarily or combined with surgery, changing our perspective on the management of these patients. Methods. We studied 24 cases of periocular BCC with orbital invasion, some primary and others recurrent, which were treated between 2011 and 2021 in the same hospital. All patients had clinical or radiological evidence of orbital invasion. Orbital exenteration was performed on 9/24 of the patients (1 received vismodegib after surgery), and 12/24 were treated, surgically preserving the eyeball, with 3 of them receiving adjuvant vismodegib. Three of the twenty-four patients were treated exclusively with vismodegib (Erivedge®, Genentech). Results. One patient died due to poor tumor evolution, but the rest evolved favorably and they have had no recurrences. Vismodegib was generally well tolerated, except for in one patient who discontinued treatment due to the side effects. Conclusions. In advanced BBC with orbital invasion, mutilating surgical treatments such as exenteration or potentially vision-threatening treatments such as RT remain as options. In recent years, however, very promising new medical therapies have emerged, such as HPI, which can be used effectively instead of surgery or in combination with it, preserving the eye and vision, which implies a new approach to treatment. [ABSTRACT FROM AUTHOR]

Aim. The present study evaluated the therapeutic effects of luteolin in alleviating pulpitis of dental pulp- (DP-) derived microvesicles (MVs) via the inhibition of protein kinase R- (PKR-) mediated inflammation. Methodology. Proteomic analysis of immortalized human dental pulp (DP-1) cell-derived MVs was performed to identify PKR-associated molecules. The effect of luteolin on PKR phosphorylation in DP-1 cells and the expression of tumor necrosis factor-α (TNF-α) in THP-1 macrophage-like cells were validated. The effect of luteolin on cell proliferation was compared with that of chemical PKR inhibitors (C16 and 2-AP) and the unique commercially available sedative guaiacol-parachlorophenol. In the dog experimental pulpitis model, the pulps were treated with (1) saline, (2) guaiacol-parachlorophenol, and (3) luteolin. Sixteen teeth from four dogs were extracted, and the pulp tissues were analyzed using hematoxylin and eosin staining. Immunohistochemical staining was performed to analyze the expression of phosphorylated PKR (pPKR), myeloperoxidase (MPO), and CD68. Experimental endodontic-periodontal complex lesions were established in mouse molar through a silk ligature and simultaneous MV injection. MVs were prepared from DP-1 cells with or without pretreatment with 2-AP or luteolin. A three-dimensional microcomputed tomography analysis was performed on day 7 (n = 6). Periodontal bone resorption volumes were calculated for each group (nonligated–ligated), and the ratio of bone volume to tissue volume was measured. Results. Proteomic analysis identified an endogenous PKR activator, and a protein activator of interferon-induced PKR, also known as PACT, was included in MVs. Luteolin inhibited the expressions of pPKR in DP-1 cells and TNF-α in THP-1 cells with the lowest suppression of cell proliferation. In the dog model of experimental pulpitis, luteolin treatment suppressed the expression of pPKR-, MPO-, and CD68-positive cells in pulp tissues, whereas guaiacol-parachlorophenol treatment caused coagulative necrosis and disruption. In a mouse model of endodontic-periodontal complex lesions, luteolin treatment significantly decreased MV-induced alveolar bone resorption. Conclusion. Luteolin is an effective and safe compound that inhibits PKR activation in DP-derived MVs, enabling pulp preservation. [ABSTRACT FROM AUTHOR]

Background. Anti-vascular endothelial growth factor (anti-VEGF) therapy via intravitreal injection is an effective treatment for patients with abnormal ocular neovascularization, such as age-related macular degeneration (AMD) and diabetic macular edema (DME). However, prolonged and frequent anti-VEGF treatment is associated with a risk of local and systemic adverse events, including geographic atrophy, cerebrovascular disease, and death. Furthermore, some patients do not adequately respond to anti-VEGF therapy. Hypoxia-inducible factor (HIF) is a transcription factor that controls the expression of hypoxia-responsive genes involved in angiogenesis, inflammation, and metabolism. The HIF/VEGF pathway plays an important role in neovascularization, and the inhibition of HIF activation could be an effective biomolecular target for neovascular diseases. The demand for disease prevention or treatment using functional foods such as superfoods has increased in recent years. Few reports to date have focused on the antineovascular effects of superfoods in the retinal pigment epithelium (RPE). In light of the growing demand for functional foods, we aimed to find novel HIF inhibitors from superfoods worked in RPE cells, which could be an adjuvant for anti-VEGF therapy. Methods. Seven superfoods were examined to identify novel HIF inhibitor candidates using luciferase assay screening. We used the human RPE cell line ARPE-19 and fetal human RPE (fhRPE) to investigate the biomolecular actions of novel HIF inhibitors using quantitative PCR and western blotting. Results. Under CoCl2-induced pseudohypoxic condition and 1% oxygen hypoxic incubation, camu-camu (Myrciaria dubia) showed HIF inhibitory effects determined by luciferase assays. Camu-camu downregulated HIF-1α and VEGFA mRNA expressions in a concentration-dependent manner. Camu-camu also inhibited HIF-1α protein expressions, and its inhibitory effect was greater than that of vitamin C, which is present at high levels in camu-camu. Conclusion. The camu-camu extract suppressed the activation of HIF and VEGF in RPE cells. This could assist anti-VEGF therapy in patients with abnormal ocular neovascularization. [ABSTRACT FROM AUTHOR]

Objective. The bromodomain-containing 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family, which is an important epigenetic reader. It is currently a promising oncology target. In some tumors, BET bromodomain inhibitors have demonstrated promising results. Proteolysis-targeting methods (PROTAC), which rapidly and effectively degrade BRD4, have displayed considerable potential in the treatment of tumors in recent years. The purpose of this study is to examine the potential impact of BRD4 PROTAC compounds ARV-825 on oncogene BRD4-NUT fused protein in NUT carcinoma. Methods. The effectiveness of ARV-825 was evaluated at the cellular level using the cell counting kit 8 test, wound healing, cell transfection, western blotting analysis, and RNA sequencing. The effectiveness of ARV-825 was also examined in vivo using a xenograft model. Results. The BRD4-NUT fusion gene was overexpressed in 3T3 cells, and the pathogenic fusion gene was simulated. The results showed that the overexpression of BRD4-NUT could promote the proliferation and migration of 3T3 cells, but the expression of BRD4 protein was degraded after the addition of the novel cereblon-based PROTAC compound ARV-825 against BRD4, resulting in inhibition of BRD4-NUT 3T3 cell proliferation and migration. Further RNA-seq analysis showed that overexpression of BRD4-NUT was accompanied by increased expression of gene (e.g., Myc, E2F, TRAFs, Wnt, Gadd45g, and Sox6) with significantly enriched pathway (e.g., small cell lung cancer, NF-kappa B signaling pathway, and breast cancer), promoted cell cycle from G 1 phase to S phase, and increased cell proliferation and migration, activated the antiapoptosisi signal, led to abnormal cell growth, and ultimately led to tumorigenesis. The addition of ARV-825 effectively rescued this process and effectively inhibited cell vitality, proliferation, and migration. In vivo studies demonstrated that treatment with ARV-825 greatly suppressed tumor growth without causing harmful side effects and downregulated the BRD4-NUT expression level. Conclusion. Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event. [ABSTRACT FROM AUTHOR]

In order to highlight the activities of bioactive compounds present in the stem of sweet cherries, four different cultivars (Van, Burlat, Napoleon, and Cœur pigeon) were collected in Sefrou city in Morocco and were studied. Several assays were performed for this purpose, such as the quantification of phenolic compounds (TPC, TFC, and CTC) and the evaluation of the antioxidant activity using DPPH, ABTS, and FRAP assays. The phenolic profile of each extract was characterized by UHPLC-DAD/MS analysis. The antidiabetic (α-amylase inhibition) and antigout (xanthine oxidase inhibition) activities were also investigated. The results showed high levels of phenolic compounds, with the values of 340 ± 12.06, 244 ± 10.20, 232 ± 5.07, and 19 ± 3.10 mg gallic acid equivalent/g extract for the cultivars Napoleon, Coeur de pigeon, Van, and Burlat, respectively. According to the same order, the flavonoids showed amounts of 34.31 ± 2.08, 23.75 ± 1.02, 24.37 ± 1.20, and 23.31 ± 0.90 mg (rutin equivalent) RE/g extract. These values were correlated with the results of the antioxidant assays, where the Napoleon cultivar proved to be the most potent using the DPPH (IC50 = 2.51 µg/mL) and ABTS (IC50 = 55.38 µg/mL) assays. The phenolic profile of each extract resulted in the identification of twenty-two compounds belonging to five distinct groups. The major phenolic compounds identified were sakuranetin and dihydrowgonin with their glucosides. Antidiabetic activity assays showed that only stem extracts from Burlat and Napoleon cultivars were able to inhibit the α-amylase enzyme with values of 85.57 ± 1.09% and 68.01 ± 3.52%, respectively. All stem extracts proved their ability to inhibit the xanthine oxidase enzyme which is directly linked to the gout disease, with a high value for Van cultivar (40.63 ± 2.37%). These new findings could provide new opportunities for the valorization of cherry stems for the pharmaceutical application of their active phytochemicals. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the anti-inflammatory effects of EU-Idd both in vivo and in vitro. In vivo, we used the collagen-induced arthritis (CIA) rat model to investigate the efficacy of EU-Idd on rheumatoid arthritis. Hematoxylin-eosin staining and Safranin O-fast green staining were used to evaluate the pathological status of the ankle joints in CIA rats. Micro-CT scanning was used to investigate bone erosion of the ankle joints. In vitro, the effect of EU-Idd on Th17 cell differentiation was identified by flow cytometry. TRAP staining was used to detect osteoclast cells. HFLS-RA model cells, induced by tumor necrosis factor-α(TNF-α), were used to evaluate the anti-inflammatory effects of EU-Idd while the levels of related inflammatory cytokines and JAK2/STAT3 proteins were detected by RT-qPCR and western blotting. EU-Idd alleviated joint inflammation in CIA rats and exerted protective effects on the ankle joints. EU-Idd also prevented the differentiation of CD4+ T cells into Th17 cells, reduced the number of osteoclasts, and improved the expression levels of bone metabolism-related proteins including OPG and RANKL. Moreover, EU-Idd inhibited the invasion and migration of HFLS-RA cells and downregulated the expression of related inflammatory cytokine genes and the protein expression levels of p-JAK2 and p-STAT3, both in vivo and in vitro. EU-Idd exerts anti-inflammatory and osteoprotective effects by regulating the JAK2/STAT3 pathway in rheumatoid arthritis. These results are beneficial to excavate new pharmaceutical ingredients for rheumatoid arthritis from iridoid. [ABSTRACT FROM AUTHOR]

The prognosis of patients with colorectal cancer (CRC) is affected by invasion and metastasis. Leucyl-tRNA synthetase (LARS) was shown to be related to the growth and migration of lung cancer cells. Dickkopf 4 (DKK4) is known as a Wnt/β-catenin pathway inhibitor, and its upregulation was reported in several cancers. However, the clinical significance of LARS and DKK4 in human CRC has not been clearly defined. We investigated the expression of LARS and DKK4 by immunohistochemical staining in tissue microarrays from 642 primary CRC patients and analyzed the relationship between their expression and the clinicopathological characteristics of CRC patients. LARS and DKK4 expressions were not related to gender, age at surgery, histologic grade, size, tumor location, tumor invasion, or metastasis, but LARS expression was significantly correlated with TNM stage, N stage, and lymph node metastasis. DKK4 expression was inversely related to the TNM stage and N stage. Survival analysis demonstrated that the OS and DFS in the LARS high expression group were not different compared to the LARS low expression group. OS and DFS in the DKK4 high expression group were significantly higher than in the DKK4 low expression group. In addition, OS and DFS in the group with the combination of the LARS high/DKK4 low expression were significantly lower than in the LARS high/DKK4 high expression group. The low expression of DKK4 alone can be used as a predictor of relapse in CRC patients. In addition, DKK4 low expression in the case of LARS high expression can be used as a poor prognostic factor in CRC patients. Thus, our findings suggest that DKK4 alone or in combination with LARS at diagnosis may be a useful prognostic factor for CRC. [ABSTRACT FROM AUTHOR]

Chronic and acute stress caused by emotional or physical insults can affect the function of other organs via the brain-body axis. As one of the smallest organs in mammalian, hair follicles are highly susceptible to stress. Under stress, the sympathetic nerves release norepinephrine (NA), which acts directly on the β-2 adrenergic receptors on melanocyte stem cells (MeSCs) within the hair follicles, causing the MeSCs to lose quiescence and enter a rapid proliferation state followed by differentiation and migration, leading to rapid loss of MeSCs and, ultimately, grey hair. Here, we screened out β-2 blockers forming the ZINC 15 compound database, found a natural product isoliensinine, and was effective in preventing stress-induced hair greying in mice. The study sheds light on the development of products that use natural compounds to prevent stress-induced hair greying. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a global health issue that lacks effective treatments. Dysfunction and/or death of pancreatic β-cells (PBCs) are considered a major cause of T2DM. Therefore, elucidating the mechanisms underlying the death of PBCs might be helpful to develop novel strategies to treat T2DM. Ferroptosis is a newly identified form of cell death that has distinct features. However, knowledge regarding the role of ferroptosis in the death of PBCs remains limited. In the current study, we used high glucose (10 mM) (HG) levels to induce ferroptosis in PBC. We also observed that hispidin, a polyphenol compound that can be isolated from Phellinus linteus, could attenuate ferroptosis induced by HG in PBCs. Mechanistic investigations showed that hispidin led to the upregulation of miR-15b-5p, which directly inhibits the expression of glutaminase (GLS2) which plays an essential role in the glutamine metabolism. In addition, we found that overexpression of GLS2 could abrogate the protective effect of hispidin against ferroptosis caused by HG in PBCs. Therefore, our study provides novel insights into the mechanisms that regulate the death of PBCs. [ABSTRACT FROM AUTHOR]

Extensive peritoneal spread and capacity for distant metastasis account for the majority of mortality from epithelial ovarian cancer (EOC). Accumulating evidence shows that interleukin-6 (IL-6) promotes tumor invasion and migration in EOC, although the molecular mechanisms remain to be fully elucidated. Meanwhile, the hypoxic microenvironment has been recognized to cause metastasis by triggering epithelial–mesenchymal transition (EMT) in several types of cancers. Here, we studied the synergy between IL-6 and hypoxia in inducing EMT in two EOC cell lines, A2780 cells and SKOV3 cells. Exogenous recombination of IL-6 and autocrine production of IL-6 regulated by plasmids both induced EMT phenotype in EOC cells characterized by downregulated E-cadherin as well as upregulated expression of vimentin and EMT-related transcription factors. The combined effects of IL-6 and hypoxia were more significant than those of either one treatment on EMT. Suppression of hypoxia-inducible factor-1α (HIF-1α) before IL-6 treatment inhibited the EMT phenotype and invasion ability of EOC cells, indicating that HIF-1α occupies a key position in the regulatory pathway of EMT associated with IL-6. EMT score was found positively correlated with mRNA levels of IL-6, signal transducer and activator of transcription 3 (STAT3), and HIF-1α, respectively, in 489 ovarian samples from The Cancer Genome Atlas dataset. Next, blockade of the abovementioned molecules by chemical inhibitors reversed the alteration in the protein levels of EMT markers induced by either exogenous or endogenous IL-6. These findings indicate a positive feedback loop between IL-6 and HIF-1α, and induce and maintain EMT phenotype through STAT3 signaling, which might provide a novel rationale for prognostic prediction and therapeutic targets in EOC. [ABSTRACT FROM AUTHOR]

Objective. This study was conducted to compare the efficacy of standard therapy (radiotherapy/RT/CT) with that of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibody (NPC) therapy in patients with advanced nasopharyngeal cancer. Methods. A meta-analysis was performed to meet the objective of this study. The English databases PubMed, Cochrane Library, and Web of Science were searched. The literature review compared anti-EGFR-targeted therapy with conventional therapy practices. The main outcome measure was overall survival (OS). Secondary goals were progression-free survival (PFS), locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and adverse events (grade 3). Results. The database search resulted in 11 studies, with a total of 4219 participants. It was found that combining an anti-EGFR regimen with conventional therapy did not enhance OS (hazard ratio HR = 1.18 ; 95 % confidence interval CI = 0.51 – 2.40 ; p = 0.70) or PFS appreciably (HR = 0.95 ; 95 % CI = 0.51 – 1.48 ; p = 0.88) in patients with nasopharyngeal carcinoma. While LRRFS increased considerably (HR = 0.70 ; 95 % CI = 0.67 – 1.00 ; p = 0.01), the combined regimen did not improve DMFS (HR = 0.86 ; 95 % CI = 0.61 – 1.12 ; p = 0.36). Treatment-related adverse events included haematological toxicity (RR = 0.2 ; 95 % CI = 0.08 – 0.45 ; p = 0.01), cutaneous reactions (RR = 7.05 ; 95 % CI = 2.15 – 23.09 ; p = 0.01), and mucositis (RR = 1.96 ; 95 % CI = 1.58 – 2.09 ; p = 0.01). Conclusions. Individuals who have nasopharyngeal cancer do not have an increased chance of surviving until a local recurrence of their disease if they get normal therapy in addition to an anti-EGFR regimen. However, this combination does not enhance overall survival. On the other hand, this factor adds to an increase in the number of adverse effects. [ABSTRACT FROM AUTHOR]

Background. Tuberculosis (TB) of the spine is a highly disruptive disease, especially in underdeveloped and developing countries. This condition requires standard TB treatment for 9–18 months, which increases patient risk of drug-resistant TB. Consequently, this raises the concern of adopting additional therapies to shorten the treatment duration, improve the efficacy of anti-TB drugs, and further decrease damage in the affected tissues and organs. Matrix metalloproteinase- (MMP-) 1 is a key regulator of the destruction of the extracellular matrix and associated proteins and is a new potential target for TB treatment research. In the present study, we investigated the effects of doxycycline as an MMP-1 inhibitor in patients with spondylitis TB. Methods. Seventy-two New Zealand white rabbits with spondylitis TB were divided into 12 different groups based on incubation period (2, 4, 6, and 8 weeks) and doxycycline administration (without, 1 mg/kg body weight (BW), and 5 mg/kg BW). We observed the course of infection through the blood concentration changes and immunohistochemical examination of MMP-1, in addition to BTA staining, culture, polymerase chain reaction (PCR), and histopathological examination. Results. Treatment with once daily 5 mg/kg BW doxycycline significantly improved the blood MMP-1 level (p < 0.05) compared with the placebo and 1 mg/kg BW doxycycline. A significantly reduced ongoing infection and a higher healing rate were demonstrated in rabbits with a higher doxycycline dose through BTA staining, culture, PCR, and histopathology. Various degrees of vertebral endplates, vertebral body, and intervertebral disc destruction were observed in 32 rabbits with positive histopathological findings, in addition to positive inflammatory cell infiltration, characterized by numerous lymphocytes, macrophages, and epithelial cells, as well as abundant granulation tissue and necrotic substances proximal to the inoculated vertebral area. Bone and intervertebral disc destructions were more apparent in the untreated rabbits. Conclusion. Our study demonstrated the potential of doxycycline as an adjunctive treatment in spondylitis TB. However, limitations remain regarding the differences in the pathogenesis and virulence of Mycobacterium tuberculosis between rabbit and human systems, sample size, and the dose-dependent effect of doxycycline. Further studies are needed to address these issues. [ABSTRACT FROM AUTHOR]

We aim to investigate the effect of overexposure to blue light on the rat ocular surface and explore the potential mechanisms. 450 nm light-emitting diode (LED) derived light at 1000 lux was used to irradiate SD rats, 12 hours a day, for consecutive 28 days. Rats in the control group were exposed to 400 lux white light at the same time (in an indoor environment). Tear film breakup time (TBUT), tear volume, and corneal fluorescein staining scores were used to measure the changes to the ocular surface. Expressions of nuclear factor-κB (NF-κB), inhibitor-κB (I-κB), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) were measured by real-time PCR, and the activation of the NF-κB pathway was detected by Western blotting, respectively. Cornea ultrastructure was examined by TEM and optical microscope on day 28. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB signaling pathway, was used to measure the inhibition of blue light injury. The above indexes were detected again when compared with the solvent-treated group. On day 28, compared with day 0, the TBUT of the blue light group was significantly shorter, and the score was significantly higher. The amount of tear secretion changed slightly with time. HE and PAS staining revealed significantly decreased corneal epithelial cell layers and increased goblet cells after 28-day irradiation of blue light. Disarranged stromal cells, vacuoles in the basal nuclei, and decreased desmosomes were also found in the blue light group. Significantly increased levels of NF-κB, IL-6, TNF-α, and the ratio of phosphorylated NF-κB p65 (pNF-κB p65) to total NF-κB p65 implied blue light-induced damage and pathway activation. In addition, PDTC significantly reduced the phosphorylation of NF-κB activated in blue light-treated corneas and alleviated the ocular surface changes caused by blue light. Finally, our results demonstrated that long-term blue light exposure in rats could cause ocular surface changes and manifest as dry eye. Inflammation and activation of the NF-κB pathway may play a role in the pathogenesis. [ABSTRACT FROM AUTHOR]

Anlotinib is a small-molecule RTK inhibitor that has achieved certain results in further-line treatment, but many patients do not respond to this drug and lack effective methods for identification. Although radiomics has been widely used in lung cancer, very few studies have been conducted in the field of antiangiogenic drugs. This study aims to develop a new model to predict the efficacy of patients receiving anlotinib by combining pretreatment computed tomography (CT) radiomic characters with clinical characters, in order to assist precision medicine of pulmonary cancer. 254 patients from seven institutions were involved in the study. Lesions were selected according to the RECIST 1.1 criteria, and the corresponding radiomic features were obtained. We constructed prediction models based on clinical, NCE-CT, and CE-CT radiomic features, respectively, and evaluated the prediction performance of the models for training sets, internal validation sets, and external validation sets. In the RAD score only model, the area under curve(AUC) of the NCE-CT cohort was 0.740 (95% CI: 0.622, 0.857) for the training set, 0.711 (95% CI: 0.480, 0.942) for the internal validation set, and 0.633(95% CI: 0.479, 0.787) for the external validation set, while that of the CE-CT cohort was 0.815 (95% CI: 0.705, 0.926) for the training set, 0.771 (95% CI: 0.539, 1.000) for the internal validation set, and 0.701 (95% CI: 0.489, 0.913) for the external validation set. In the RAD score-combined model, the AUC of the NCE-CT cohort was 0.796 (95% CI: 0.691, 0.901) for the training set, 0.579 (95% CI: 0.309, 0.848) for the internal validation set, and 0.590 (95% CI: 0.427, 0.753) for the external validation set, while that of the CE-CT cohort was 0.902 (95% CI: 0.828, 0.977) for the training set, 0.865 (95% CI: 0.696, 1.000) for the internal validation set, and 0.837 (95% CI: 0.682, 0.992) for the external validation set. In conclusion, radiomics has accurate predictions for the efficacy of anlotinib. CE-CT-based radiomic models have the best predictive potential in predicting the efficacy of anlotinib, and model predictions become better when they are combined with clinical characteristics. [ABSTRACT FROM AUTHOR]

Background. Diabetic retinopathy (DR), including retinal angiogenesis and endothelial cell proliferation and migration, is a serious complication in diabetic patients. It has been reported that ginsenoside Rg1 can prevent retinal damage. However, the mechanism by which Rg1 prevents retinal damage is unknown. Therefore, the aim of the present study was to investigate the mechanism by which Rg1 inhibits high glucose-induced complications through the regulation of the lncRNA SNHG7/miR-2116-5p/SIRT3 axis. Methods. Under high glucose (HG) conditions, human retinal endothelial cells (HRECs) were cultured to simulate a DR environment, and Rg1 was added after 48 h. Negative control (NC), miR-2116-5p mimic, si-SNHG7, pc-DNA SIRT3, and miR-2116-5p inhibitor were transfected into HRECs, and CCK-8 assay was used to detect the cell viability. Angiogenesis and transwell assays were used to evaluate angiogenesis and cell migration, respectively. qRT–PCR and Western blot were used to detect the expression of related genes and proteins. Luciferase reporter assays and bioinformatics were used to analyze the target binding sites of miR-2116-5p to lncRNA SNHG7 and SIRT3. Results. The proliferation, migration and angiogenesis of HRECs were induced by HG. As expected, HG upregulated miR-2116-5p and VEGF expression but downregulated lncRNA SNHG7 and SIRT3 expression. Importantly, Rg1 inhibited HG-induced HREC proliferation, migration, and angiogenesis by upregulating the lncRNA SNHG7, and miR-2116-5p had a target regulatory relationship with both lncRNA SNHG7 and SIRT3. Conclusion. Rg1 inhibits HG-induced proliferation, migration, angiogenesis, and VEGF expression in retinal endothelial cells through the lncRNA SNG7/miR-2116-5p/SIRT3 axis. This finding provides theoretical evidence for the clinical application of Rg1 in DR. [ABSTRACT FROM AUTHOR]

Tocilizumab (Actemra®), as the first human interleukin‐6 receptor (IL‐6R) antagonist, has been used in treating moderate to severe active rheumatoid arthritis (RA) patients who were undertreatment with one or more disease‐modifying anti‐rheumatic drugs (DMARDs) and did not improve significantly. Tocilizumab also has been administrated and confirmed in several inflammatory‐based diseases. Recently, tocilizumab has been prescribed to treat patients with advanced coronavirus disease (COVID‐19) and is used as one of the effective drugs in reducing the increased inflammation in these patients. On the other hand, cancer treatment has been considered by researchers one of the most important challenges to human health. Regarding inflammatory‐associated malignancies, it has been shown that inflammatory mediators such as interleukin‐1 beta (IL‐1β), IL‐6, and tumour necrosis factor‐alpha (TNF‐α) may play a role in tumorigenesis, thus targeting these cytokines as evidence suggested can be useful in the treatment of these types of cancers. This review summarized the role of the IL‐6/IL‐6R axis in inflammation‐based cancers and discussed the effectiveness and challenges of treating cancer with tocilizumab. [ABSTRACT FROM AUTHOR]

Isoschaftoside is a C-glycosyl flavonoid extracted from the root exudates of Desmodium uncinatum and Abrus cantoniensis. Previous studies suggested that C-glycosyl flavonoid has neuroprotective effects with the property of reducing oxidative stress and inflammatory markers. Microglia are key cellular mediators of neuroinflammation in the central nervous system. The aim of this study was to investigate the effect of isoschaftoside on lipopolysaccharide-induced activation of BV-2 microglial cells. The BV-2 cells were exposed to 10 ng/ml lipopolysaccharide and isoschaftoside (0–1000 μM). Isoschaftoside effectively inhibited lipopolysaccharide-induced nitric oxide production and proinflammatory cytokines including iNOS, TNF-α, IL-1β, and COX2 expression. Isoschaftoside also significantly reduced lipopolysaccharide-induced HIF-1α, HK2, and PFKFB3 protein expression. Induction of HIF-1α accumulation by CoCl2 was inhibited by isoschaftoside, while the HIF-1α specific inhibitor Kc7f2 mitigated the metabolic reprogramming and anti-inflammatory effect of isoschaftoside. Furthermore, isoschaftoside attenuated lipopolysaccharide-induced phosphorylation of ERK1/2 and mTOR. These results suggest that isoschaftoside can suppress inflammatory responses in lipopolysaccharide-activated microglia, and the mechanism was partly due to inhibition of the HIF-1α-mediated metabolic reprogramming pathway. [ABSTRACT FROM AUTHOR]

Background. Roxadustat is a newly listed oral hypoxia-inducible factor-proline enhancing enzyme inhibitor (HIF-PHI) in recent years. There have been some studies that have proved the efficacy of roxadustat on the treatment of renal anemia in patients with chronic kidney disease (CKD), but there are still different conclusions on its safety. Methods. PubMed, Embase, Cochrane, and ClinicalTrials were searched for randomized controlled trials (RCTs) that assess efficacy and safety of roxadustat treatment for anemia in CKD patients. The Cochrane Literature Quality Evaluation Scale was used to evaluate the quality of included literature. We choose fixed-effects model or random effects model for data processing based on heterogeneity. It was considered statistically significant when p value <0.05. Results. A total of 842 articles were retrieved, and 16 trials in the 15 articles were finally included. Roxadustat treatment significantly increased Hb levels. Iron (SMD 1.43, 95% CI 0.31 to 2.55), total iron-binding capacity (SMD 2.06, 95% CI 0.91 to 3.22), ferritin (WMD 21.33, 95% CI 3.04 to 39.62), transferrin saturation (SMD 4.17, 95% CI 3.90 to 4.45), and LDL-cholesterol (SMD -0.64, 95% CI -0.73 to -0.55) showed statistical significance in dialysis-dependent (DD) study. And hepcidin (SMD -1.56, 95% CI -2.63 to -0.50), transferrin (SMD 1.80, 95% CI 1.53 to 2.06), total iron-binding capacity (SMD 1.62, 95% CI 1.39 to 1.86), total cholesterol (SMD -0.88, 95% CI -1.68 to -0.09), ferritin (WMD -52.68, 95% CI -62.68 to -42.67), transferrin saturation (SMD -5.57, 95% CI -7.47 to -3.68), and LDL-cholesterol (SMD -0.85, 95% CI -1.37 to -0.34) showed statistical significance in not dialysis-dependent (NDD) study. In terms of safety, roxadustat treatment did not increase risk of total adverse events either in dialysis-dependent or not dialysis-dependent patients. Conclusion. Roxadustat can effectively improve anemia in patients with chronic kidney disease. There was no significant difference in total adverse events compared with the control group. [ABSTRACT FROM AUTHOR]

Objective. As a highly malignant tumour, malignant rhabdoid tumours of the kidney (MRTK) are prone to metastasis and invasion, while tumour metastasis and invasion are inseparable from matrix metalloproteinases (MMPs) and epithelial-mesenchymal transformation (EMT). Moreover, the key to EMT is remodelling of the cytoskeleton. Therefore, our study is aimed at investigating whether doxycycline hydrochloride (DCH), an inhibitor of MMPs, could reverse EMT in MRTK to exert an antitumour effect by regulating MMPs and the cytoskeleton. Methods. The existence of EMT in MRTK cells was verified by bioinformatics analysis, immunofluorescence, and western blotting (WB). In vitro, the proliferation, migration, and invasion abilities of G401 cells were examined by Cell Counting Kit-8 (CCK-8), scratch, and Transwell assays, respectively. The effect of DCH on tumour growth in tumour-bearing mice was explored in in vivo experiments, and the expression of MMP2 and MMP9 and EMT correlation indexes was measured by immunofluorescence and WB, and the changes in cytoskeletal F-actin and β-tubulin were measured by fluorescence. Results. The altered extracellular matrix (ECM) composition, EMT, and high expression of MMP2 and MMP9 existed in MRTK. DCH inhibited the proliferation, migration, and invasion of G401 cells in vitro. In vivo, DCH inhibited tumour growth in mice, downregulated the expression of MMP2 and MMP9, and partially reversed EMT. Alternatively, DCH resulted in cytoskeletal rearrangements of G401 cells. Conclusions. DCH, as an MMP inhibitor, is used for the first time in MRTK research, showing good antitumour effects by reversing EMT and potentially providing new therapeutic measures for MRTK treatment. [ABSTRACT FROM AUTHOR]

Food browning is an undesirable phenomenon caused by the enzyme polyphenol oxidase that led to food wastage and eventually deteriorates the market value. In this study, the effect of natural inhibitors including red grapefruit, key lime, red chili pepper, and pineapple on polyphenol oxidase extracted from pearl brinjal was investigated. As for the effects of chemical inhibitors, L‐cysteine exhibited stronger inhibition (IC50: 0.29 mM), as compared to citric acid (IC50: 50.73 mM). Meanwhile, red chili pepper was found to be the best natural inhibitor (IC50: 65.78 mg/ml), followed by red grapefruit, key lime, and lastly pineapple (IC50: 145.90, 206.78, and 216.86 mg/ml, respectively). All the natural inhibitors showed an increase in inhibition percentage along with an increase in inhibitor concentration (13.33 ± 3.82–48.93 ± 3.05%). The present findings suggested the potential of red grapefruit, key lime, red chili pepper, and pineapple to replace chemical inhibitors in the future to inhibit browning. Novelty impact statement: The use of natural inhibitors does safeguard health‐concerned consumers on obtaining both browning and chemical‐free food. Red chili pepper was found to be a potential natural inhibitor to replace chemical inhibitors to inhibit the browning of pearl brinjal. Both red chili pepper and pearl brinjal are also compatible in terms of palatability, which makes them a good combination for food industries to produce for consumers to taste with minimal browning. [ABSTRACT FROM AUTHOR]

Hyperuricemia is a common disease caused by a high level of uric acid. Urate transporter 1 (URAT1) is an important protein and mediates approximately 90% of uric acid reabsorption. Therefore, the URAT1 inhibitor is a class of uricosuric medicines widely used in the clinic for the treatment of hyperuricemia. To find the new medicine with stronger URAT1 inhibition and lower toxicity, researchers have been exploring natural products. This study systematically summarizes the natural products with URAT1 inhibition. The results show that many natural products are potential URAT1 inhibitors, such as flavonoids, terpenoids, alkaloids, coumarins, stilbenes, and steroids, among which flavonoids are the most promising source of URAT1 inhibitors. It is worth noting that most studies have focused on finding natural products with inhibition of URAT1 and have not explored their activities and mechanisms toward URAT1. By reviewing the few existing studies of the structure-activity relationship and analyzing common features of natural products with URAT1 inhibition, we speculate that the rigid ring structure and negative charge may be the keys for natural products to produce URAT1 inhibition. In conclusion, natural products are potential URAT1 inhibitors, and exploring the mechanism of action and structure-activity relationship will be an important research direction in the future. [ABSTRACT FROM AUTHOR]

San-Jiu-Wei-Tai granules (SJWTG) are a significant Chinese patent medicine for the treatment of chronic gastritis (CG), having outstanding advantages in long-term treatment; however, the chemical composition and potential mechanism have not been investigated until now. In this study, a rapid separation and identification method based on UPLC-QE-Orbitrap-MS was established, and 95 chemical components from SJWTGs were identified, including 6 chemical components of an unknown source that are not derived from the 8 herbs included in SJWTGs. The identified chemical components were subsequently analysed by network pharmacology, suggesting that the core targets for the treatment of CG with SJWTGs were EGFR, SRC, AKT1, HSP90AA1, MAPK1, and MAPK3 and thus indicating that SJWTGs could reduce the inflammatory response of gastric epithelial cells and prevent persistent chronic inflammation that induces cancerization by regulating the MAPK signalling pathway and the C-type lectin receptor signalling pathway as well as their upstream and downstream pathways in the treatment of CG. The key bioactive components in SJWTGs were identified as 2,6-bis(4-ethylphenyl)perhydro-1,3,5,7-tetraoxanaphth-4-ylethane-1,2-diol, a chemical component of an unknown source, murrangatin, meranzin hydrate, paeoniflorin, and albiflorin. The results of molecular docking showed the strong binding interaction between the key bioactive components and the core targets, demonstrating that the key bioactive components deserve to be further studied and considered as Q-markers. By acting on multiple targets, SJWTG is less susceptible to drug resistance during the long-term treatment of CG, indicating the advantage of Chinese patent medicines. Furthermore, the preventive effect of SJWTGs on gastric cancer also demonstrates the superiority of preventive treatment of disease with traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

Cell cycle-related kinase (CCRK) is most closely related to cyclin-dependent protein kinase, which may activate cyclin-dependent kinase 2 and is associated with the growth of human cancer cells. However, the expression and function of CCRK in the pathogenesis of clear cell renal cell cancer (ccRCC) are unclear. Herein, this research aimed to explore the potential mechanism of the targeted regulation of CCRK by miR-335-5p on the proliferation and tumorigenicity of human ccRCC cells. The results showed that CCRK was significantly overexpressed in ccRCC tissues and cells, and knockdown of the CCRK expression by shRNA inhibited cell proliferation in vitro and in vivo and enhanced cell apoptosis in vitro, which indicated that CCRK could be a potential target for antitumour drugs in the treatment of ccRCC. Moreover, miR-335-5p was found to bind directly to the 3′ untranslated region of CCRK, was expressed at markedly low levels in ccRCC cells, and was closely associated with the tumour stage. The overexpression of CCRK partially reversed the inhibitory effects of miR-335-5p on the cell growth of ccRCC, which implied that miR-335-5p could serve as a promising tumour inhibitor for ccRCC. In summary, CCRK could serve as an alternative antitumour drug target, and miR-335-5p could be a promising therapeutic tumour inhibitor for ccRCC treatment. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common cancers globally. There are currently few effective chemotherapeutic drugs available for GC patients. The inhibitors of phosphatidylinositol kinase containing an FYVE finger structure (PIKfyve) have shown significant anticancer effects in several types of cancers, but their effectiveness in GC remains unknown. In this study, we investigate the effect of APY0201, an inhibitor of PIKfyve, on GC tumor growth and its mechanism of action. It was found that APY0201 inhibited GC cell proliferation in in vitro GC cell model, organoid model, and in vivo xenograft tumor model. Through analyzing cell autophagy, we found that APY0201 might block autophagic flux by impairing lysosome degradation function of GC cells, inducing the accumulation of autophagosomes, thus causing the inhibition of GC cell proliferation. We also found that APY0201 induced G1/S phase arrest in GC cells. Importantly, APY0201 was also effective in inducing repression of autophagy and cell cycle arrest in the mouse tumor xenograft. Our results suggest that APY0201 could be a new promising therapeutic option for GC. [ABSTRACT FROM AUTHOR]

The aim of the present study was to evaluate the antioxidant and antidiabetic potential of Indian olive seed extracts. Plant seeds were sequentially extracted with n-hexane, chloroform, methanol, and water. 2,2-Diphenyl-1-picrylhydrazyl (DPPH) scavenging and alpha-amylase inhibitory activities of extracts were carried out. Olea europaea methanolic extract (MEOE) and aqueous extract (AEOE) were orally administered to normoglycemic and alloxan-treated diabetic rats so as to determine their hypoglycemic effect. High-performance liquid chromatography (HPLC) analysis showed gallic acid, ferulic acid, quercetin, and vanillic acid in MEOE. It was found that the methanolic and aqueous extracts exhibited the maximum DPPH and alpha-amylase inhibition activities, respectively. MEOE and AEOE exerted a significant decline in the fasting blood sugar in diabetic animals (p < 0.05); however, they did not cause hypoglycemia in nondiabetic animals. Treatment with MEOE and AEOE reduced the aggravated liver and kidney function biomarkers. Aggravated levels of oxidative stress biomarkers including superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and malondialdehyde (MDA) were restored by treatment with MEOE. Moreover, MEOE improved the count of islets of Langerhans in the pancreas, fatty changes, and enlarged sinusoidal spaces in the liver and necrosis of the glomerulus and tubular cells of the kidney in diabetic rats. This study showed that the African olive seed extract effectively managed experimental diabetes and restored the normal functions and histology of the liver and kidney in diabetic rats through the reduction of oxidative stress. [ABSTRACT FROM AUTHOR]

Background. Transarterial chemoembolization (TACE) is a first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Owing to differences in its efficacy across individuals, determining the indicators of patient response to TACE and finding approaches to reversing nonresponse thereto are necessary. Methods. Transcriptome data were obtained from the GSE104580 dataset, in which patients were marked as having TACE response or nonresponse. We identified differentially expressed genes (DEGs) and performed Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. We screened genes with a prognostic value for TACE in the HIF-1 signaling pathway by univariate regression analysis. By using least absolute shrinkage and selection operator (LASSO) Cox regression, we established a multigene signature in GSE14520, which we verified using a drug sensitivity test. The Connectivity Map (CMap) database was used to find potential drugs to reverse nonresponse to TACE. Results. We constructed a prognostic signature consisting of three genes (erythropoietin (EPO), heme oxygenase 1 (HMOX1), and serine protease inhibitor 1 (SERPINE1)) that we validated by drug sensitivity test. After dividing patients treated with TACE into high- and low-risk groups based on this new signature, we showed that overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group and that the risk score was an independent predictor of OS in patients treated with TACE. Based on our CMap findings, we speculated that PD-184352, an inhibitor of mitogen-activated protein kinase (MEK), had potential as a drug treatment to reverse nonresponse to TACE. We confirmed this speculation by using PD-184352 in a cell promotion experiment in a TACE environment. Conclusion. We constructed a TACE-specific three-gene signature that could be used to predict HCC patients' responses to and prognosis after TACE treatment. PD-184352 might have potential as a drug to improve TACE efficacy. [ABSTRACT FROM AUTHOR]

Rytigynia senegalensis (Rubiaceae) is a plant used in African medicine for the treatment of diabetes. The aim of this study was to evaluate the in vitro antioxidant, enzyme inhibitory, and hypoglycemic effects of Rytigynia senegalensis extract (RSE). The contents of phenols, tannins, and flavonoids were determined by phytochemical screening. 2,2-Azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) and 2,2-diphenylpicrylhydrazyl (DPPH) were determined to evaluate the free radical scavenging capacity of the RSE. The inhibitory activity of α-amylase and α-glucosidase was evaluated in vitro using the α-amylase and α-glucosidase inhibition methods and in vivo using the sucrose and starch tolerance tests. The glucose tolerance test was performed on normal rats using doses of 50, 100, and 200 mg/kg of RSE. RSE contains total phenols (36.35 mg GAE/g of extract), flavonoids (11.91 mg QE/g of extract), and tannins (13.01 mg CE/g of extract). RSE exhibits significant radical scavenging activity on DPPH and ABTS radicals with an IC50 of 17.51 and 21.89 μg/mL, respectively. RSE showed an inhibitory effect on the activity of α-amylase and α-glucosidase with an IC50 of 308.93 and 354.13 μg/mL, respectively. RSE (100 and 200 mg/kg) caused a significant decrease in area under the curve and postprandial glycemia at 60, 90, and 120 min following the administration of starch or sucrose. Regarding the glucose tolerance test, RSE (100 and 200 mg/kg) significantly reduced postprandial hyperglycemia from the 90th min posttreatment. RSE lowered postprandial hyperglycemia and has antioxidant properties. These effects would be due to the presence of bioactive compounds in the RSE. [ABSTRACT FROM AUTHOR]

Juniperus thurifera is a native species to the mountains of the western Mediterranean region. It is used in traditional medicine as a natural treatment against infections. The present study aimed to carry out the chemical analysis and evaluate the antioxidant, antimicrobial, as well as in silico inhibition studies of the essential oils from Juniperus thurifera bark (EOEJT). Chemical characterization of EOEJT was done by gas chromatography (GC-MS). We have performed three antioxidant assays (Reducing power (FRAP), 2, 2-diphenylpicrylhydrazyl (DPPH), and total antioxidant capacity (TAC)) of the EOEJT. We next evaluated the antimicrobial activity against in silico study, which was carried out to help evaluate the inhibitory effect of EOEJT against NADPH oxidase. Results of the GC/MS analysis revealed seven major compounds in EOEJT wherein muurolol (36%) and elemol (26%) were the major components. Moreover, EOEJT possessed interesting antioxidant potential with an IC50 respectively of 21.25 ± 1.02 μg/mL, 481.02 ± 5.25 μg/mL, and 271 μg EAA/mg in DPPH, FRAP, and total antioxidant capacity systems. Molecular docking of EOEJT in NADPH oxidase active site showed inhibitory activity of α-cadinol and muurolol with a glide score of −6.041 and −5.956 Kcal/mol, respectively. As regards the antibacterial and antifungal capacities, EOEJT was active against all tested bacteria and all fungi, notably, against Escherichia coli K12 with an inhibition diameter of 21 mm and a MIC value of 0.67 mg/mL, as well as against Proteus mirabilis ATCC 29906 with an inhibition diameter of 18.33 ± 1.15 mm and a MIC value of 1.34 mg/mL. A more pronounced effect was recorded for the fungal pathogens Fusarium oxysporum MTCC 9913 with inhibition of 37.44 ± 0.28% and MIC value of 6.45 mg/mL, as well as against Candida albicans ATCC 10231 with an inhibition diameter of 20.33 ± 1.15 mm and a MIC value of 0.67 ± 0.00 mg/mL. Altogether, these results highlight the importance of EOEJT as a source of natural antibacterial and antioxidant drugs to fight clinically important pathogenic strains. [ABSTRACT FROM AUTHOR]

With the increase of obesity incidence, the development of antiobesity drugs has aroused extensive interest. In this study, a simple and portable personal glucose meter (PGM) method based on the lipase-mediated reaction combined with molecular docking was developed for the screening of lipase inhibitors. Lipase can catalyse the hydrolysis of 4-acetamidophenyl acetate to form acetaminophen, which can directly trigger the reduction of K3[Fe(CN)6] to K4[Fe(CN)6] in the glucose test strips and generate an electrical signal that can be detected by the PGM. When lipase inhibitors exist, the yield of acetaminophen will be reduced and results in a corresponding decrease of the PGM signal. Therefore, the activity of lipase can be measured by the PGM. After optimization of the experimental conditions, the inhibitory activity of fourteen small-molecule compounds and fifteen natural product extracts on lipase were evaluated by the developed PGM method. The results indicate that tannic acid, (-)-epigallocatechin gallate, (-)-epigallocatechin, (-)-epicatechin gallate, and epicatechin have good inhibitory effect on lipase (% of inhibition higher than 40.0%). Besides, the natural product extracts of Galla Chinensis, lemon, and Rhei Radix et Rhizoma have a good inhibitory effect on lipase with % of inhibition of (97.5 ± 0.6)%, (88.1 ± 0.7)%, and (79.1 ± 1.6)%, respectively. Finally, the binding sites and modes of six small-molecule compounds on lipase were investigated by the molecular docking study. The results show that the developed PGM method is an effective approach for the discovery of potential lipase inhibitors. [ABSTRACT FROM AUTHOR]

Oroxylum indicum (L.) Kurz (Bignoniaceae), a traditional Chinese herbal medicine, possesses various biological activities including antioxidant, anti-inflammatory, antibacterial, and anticancer. In order to guide the practical application of O. indicum in the pharmaceutical, food, and cosmetic industries, we evaluated the effects of five different extraction techniques (maceration extraction (ME), oxhlet extraction (SOXE), ultrasound-assisted extraction (UAE), tissue-smashing extraction (TSE), and accelerated-solvent extraction (ASE)) with 70% ethanol as the solvent on the phytochemical properties and biological potential. The UHPLC-DAD Orbitrap Elite MS technique was applied to characterize the main flavonoids in the extracts. Simultaneously, the antioxidant and enzyme inhibitory activities of the tested extracts were analyzed. SOXE extract showed the highest total phenolic content (TPC, 50.99 ± 1.78 mg GAE/g extract), while ASE extract displayed the highest total flavonoid content (TFC, 34.92 ± 0.38 mg RE/g extract), which displayed significant correlation with antioxidant activity. The extract obtained using UAE was the most potent inhibitor of tyrosinase (IC50: 16.57 ± 0.53 mg·mL−1), while SOXE extract showed the highest activity against α-glucosidase (IC50: 1.23 ± 0.09 mg·mL−1), succeeded by UAE, ME, ASE, and TSE extract. In addition, multivariate analysis suggested that different extraction techniques could significantly affect the phytochemical properties and biological activities of O. indicum. To sum up, O. indicum displayed expected biological potential and the data collected in this study could provide an experimental basis for further investigation in practical applications. [ABSTRACT FROM AUTHOR]

Background. This study aimed to investigate the molecular mechanism of Tongfengding capsule (TFDC) in treating immune-inflammatory diseases of gouty arthritis (GA) and interleukin-1-beta (IL-1β) inhibitors by using network pharmacology, molecular docking, and cell experiments. Methods. In this study, the compounds of TFDC and the potential inflammatory targets of GA were obtained from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), Online Mendelian Inheritance in Man (OMIM), and GeneCards databases. The TFDC-GA-potential targets interaction network was accomplished by the STRING database. The TFDC-active compound-potential target-GA network was constructed using Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used to further explore the GA mechanism and therapeutic effects of TFDC. Quantitative real-time PCR (qPCR) was used to verify whether the TFDC inhibited IL-1β in GA. Molecular docking technology was used to analyze the optimal effective compounds from the TFDC for docking with IL-1β. Result. 133 active compounds and 242 targets were screened from the TFDC, and 25 of the targets intersected with GA inflammatory targets, which were considered as potential therapeutic targets. Network pharmacological analysis showed that the TFDC active compounds such as quercetin, stigmasterol, betavulgarin, rutaecarpine, naringenin, dihydrochelerythrine, and dihydrosanguinarine had better correlation with GA inflammatory targets such as PTGS2, PTGS1, NOS2, SLC6A3, HTR3A, PPARG, MAPK14, RELA, MMP9, and MMP2. The immune-inflammatory signaling pathways of the active compounds for treating GA are IL-17 signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, HIF-1 signaling pathway, etc. The TFDC reduced IL-1β mRNA expression in GA by qPCR. Molecular docking results suggested that rutaecarpine was the most appropriate natural IL-1β inhibitor. Conclusion. Our findings provide an essential role and bases for further immune-inflammatory studies on the molecular mechanisms of TFDC and IL-1β inhibitors development in GA. [ABSTRACT FROM AUTHOR]

Khellin and visnagin are natural furanochromones that photoreact with DNA. Khellin has been used in the treatment of vitiligo and psoriasis, as well as in the treatment of angina pectoris and asthma due to its potent action as a coronary vasodilator and antispasmodic agent. The present study aimed to investigate whether the compounds khellin and visnagin act as inhibitors of NorA protein, an efflux pump overproduced by the strain of Staphylococcus aureus SA-1199B that confers resistance to the fluoroquinolones, such as norfloxacin and ciprofloxacin. These substances alone did not show antibacterial activity against the strain tested. On the other hand, when these compounds were added to the culture medium at subinhibitory concentration, they were able to reduce the minimum inhibitory concentration (MIC) of norfloxacin, ethidium bromide, as well as berberine, suggesting that these compounds are modulating agents of norfloxacin resistance, possibly due to NorA inhibition. Molecular docking analysis showed that both khellin and visnagin form hydrogen bonds with Arg310, an important residue in the interaction between NorA and its substrates, supporting the hypothesis that these compounds are NorA inhibitors. These results suggest a possible application of khellin and visnagin as adjuvants to norfloxacin in the treatment of infections caused by strains of S. aureus that overproduce NorA. [ABSTRACT FROM AUTHOR]

An ulcer is an erosion of the gastric mucosa that occurs following an imbalance between the aggression and protective factors and/or an infection with Helicobacter pylori (H. pylori). About 90-100% of duodenal ulcers and 70-80% of gastric ulcers are caused by H. pylori. The objective of this work was to evaluate in vitro the anti-H. pylori activity and then the anti-inflammatory and antioxidant properties of aqueous and methanol extracts of Alstonia boonei. The anti-H. pylori tests (CMI and antiureasic activity) were determined using the agar well diffusion method, the microbroth dilution method, and the measurement of ammonia production by the indophenol method; the anti-inflammatory properties were evaluated by inhibition of proteinases, denaturation of albumin, production of NO by macrophages, cell viability, and hemolysis of red blood cells by heat; then, the antioxidant properties were evaluated by the FRAP method (ferric reducing antioxidant power) and the DPPH (1,1-diphenyl-2-picrylhydrazyl) test. The results show that the best trapping of the DPPH radical was obtained with the methanol extract (EC50 = 8.91 μg/mL) compared to the aqueous extract (EC50 = 19.86 μg/mL). The methanol extract also showed greater iron-reducing activity than the aqueous extract and vitamin C. Furthermore, at the concentration of 200 μg/mL, the methanol extract showed a percentage (96.34%) strains of H. pylori higher than that of the aqueous extract (88.52%). The MIC90 of the methanol extract was lower than that of the aqueous extract. The methanol extract showed a higher percentage inhibition (85%) of urease than the aqueous extract (73%). The methanol extract at a concentration of 1000 μg/mL showed the greatest ability to inhibit proteinase activity, albumin denaturation, and red blood cell hemolysis; on the other hand, maximum cell viability and greater production of nitrite oxide by macrophages were obtained with the aqueous extract. Aqueous and methanol extracts of Alstonia boonei possess anti-H. pylori which would probably be linked to their antioxidant and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

The galls of Pistacia integerrima are used in folk medicine for curing diabetes. The main aim of this study was the purification of flavonoids from galls of P. integerrima. The methanolic extract was subjected to column chromatographic analysis which afforded six flavonoids, namely, 3,5,7,4 ′ -tetrahydroxy-flavanone (1), naringenin (2), 3,5,4 ′ -trihydroxy,7-methoxy-flavanone (3), sakuranetin (4), spinacetin (5), and patuletin (6). These isolated compounds (1–6) were tested against α-glycosidase. The maximum antagonistic effect was noted against compound 6 (97.65%) followed by compound 5 (90.42%) and compound 1 (90.01%) at the same concentration (0.2 μg). The inhibitory potential of all tested compounds was significant with a degree of variation from each other. Docking studies showed that all studied compounds interact with the active site residues via hydrogen bond interactions with hydroxyl groups, and thus, inhibition was enhanced. Hence, this finding would be the first screening of isolated flavonoids for α-glycosidase activity and with the mechanism of action. These flavonoids should be further investigated as candidate drugs for combating diabetes mellitus. [ABSTRACT FROM AUTHOR]

Objective. Acute lung injury (ALI) is a severe respiratory disorder causing alveolar-capillary barrier, leading to a high rate of morbidity and death in critically ill individuals. microRNAs (miRNAs)-mediated mechanism in the pathogenesis of ALI has attracted much interest. Herein, we attempt to characterize a candidate miRNA and its downstream target that is linked to the pathogenesis of ALI. Methods. LPS-conditioned MH-S cells were treated with miR-29a-1-5p mimic, inhibitor, and RNT4 expression vector, and the ALI animal model was injected with agomir and antagomir of miR-29b-1-5p and RNT4 expression vector, in which the pro-inflammatory cytokine production, cell viability and apoptosis, myeloperoxidase (MPO) activity, wet/dry (W/D) ratio, and expression of TGF-β1, α-smooth muscle actin (α-SMA), E-cadherin, and vimentin were examined. miR-29a-1-5p inhibition of RTN4 translation was confirmed by luciferase activity assays. Results. An elevated miR-29a-1-5p expression was demonstrated in LPS-conditioned MH-S cells. miR-29a-1-5p inhibitor transfection attenuated the production of pro-inflammatory cytokines and MH-S cell viability but enhanced the apoptosis. miR-29a-1-5p inhibition of RTN4 translation was demonstrated in the setting of LPS-induced ALI. LPS-induced murine models demonstrated upregulated miR-29a-1-5p. Intravenous injection of miR-29b-1-5p agomir attenuated mouse lung injury and pulmonary fibrosis. RTN4 overexpression resisting to miR-29a-1-5p overexpression was demonstrated in LPS-induced murine models. Conclusion. The findings obtained from the study that disturbing the action of miR-29a-1-5p may be a novel therapeutic strategy for preventing ALI. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha (TNF-α) plays an important role in coronary heart disease (CHD), a chronic inflammatory process. Meanwhile, this pro-inflammatory factor is also involved in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA). Patients with RA correspond to a higher risk of CHD. TNF-α antagonist, one of the main treatments for RA, may reduce the risk of CHD in patients with RA. This review summarizes the pathogenesis of TNF-α in CHD and discusses the relationship between TNF-α antagonist and CHD in patients with RA. [ABSTRACT FROM AUTHOR]

Purpose. Aurantiamide acetate (AA) is a dipeptide derivative with complex pharmacological activities and remarkable effects on preventing and treating various diseases. In the current study, we aimed to investigate whether AA can exert protective effects in a mouse model of ALI induced by LPS. Materials and Methods. In this model, mice were given intranasal LPS for 3 days prior to receiving AA (2.5, 5, and 10 mg/kg) via oral gavage. An assessment of histopathological changes was performed by hematoxylin and eosin (HE). Proinflammatory cytokines were detected in bronchoalveolar lavage fluids (BALFs) by enzyme-linked immunosorbent assays (ELISAs). The effects of AA on protein expression of NF-κB and PI3K/AKT signaling pathways were determined by Western blot. In addition, lung wet/dry (W/D) weight ratio, myeloperoxidase (MPO) activity, cell counts, and protein content were also measured. Results. According to results, AA pretreatment significantly reduced lung pathological changes, W/D ratio, MPO activity, and protein content. Additionally, AA resulted in a significant reduction in the number of total cells, neutrophils, and proinflammatory cytokines in the BALF after LPS stimulation. The subsequent study revealed that pretreatment with AA dose dependently suppressed LPS-induced activation of NF-κB as well as PI3K/AKT phosphorylation. Conclusion. The results indicated that the AA had a protective effect on LPS-induced ALI in mice and could be a potential drug for ALI. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is one of the most common forms of diabetes. We are living in the middle of a global diabetes epidemic. Emerging pieces of evidence are suggesting the increased expression of protein tyrosine phosphatase 1B (PTP1B) in the pancreas and adipose tissues during T2DM. The negative regulation of the insulin signaling pathway by PTP1B helps the researchers to consider it as a potential therapeutic target for the treatment of insulin resistance and its associated complications. From the literature, we found that compound 5,7-dihydroxy-3,6-dimethoxy-2-(4-methoxy-3-(3-methyl-2-enyl)phenyl)-4H-chromen-4-one (Viscosol) extracted from Dodonaea viscosa can inhibit PTP1B in vitro. Therefore, in this study, we aimed to evaluate the antidiabetic effect of this compound in a high-fat diet (HFD) and low-dose streptozotocin- (STZ-) induced T2DM mouse model. For this purpose, T2DM was induced in C57BL/6 male mice by using an already established protocol with minor modification. The compound-treated T2DM mice showed improvements in biochemical parameters, i.e., decrease in the fasting blood glucose level, increased body weight, improved liver profile, and reduction in oxidative stress. Furthermore, to elucidate the inhibition of PTP1B, the expression level of PTP1B was also measured at mRNA and protein levels by real-time PCR and western blot, respectively. Additionally, downstream targets (INSR, IRS1, PI3K, and GLUT4) were examined for confirming the inhibitory effect of PTP1B. Our results suggest that the compound can specifically inhibit PTP1B in vivo and might have the ability to improve insulin resistance and insulin secretion. Based on our experiment, we can confidently state that this compound can be a new PTP1B drug candidate for the treatment of T2DM in the coming future. [ABSTRACT FROM AUTHOR]

Zika virus is a member of the Flaviviridae family and genus Flavivirus, which has a phylogenetic relationship with spondweni virus. It spreads to humans through a mosquito bite. To identify potential inhibitors for the Zika virus with biosafety, we selected natural antiviral compounds isolated from plant sources and screened against NS3 helicase of the Zika virus. The enzymatic activity of the NS3 helicase is associated with the C-terminal region and is concerned with RNA synthesis and genome replication. It serves as a crucial target for the Zika virus. We carried out molecular docking for the target NS3 helicase against the selected 25 phytochemicals using AutoDock Vina software. Among the 25 plant compounds, we identified NS3 helicase-ellagic acid (-9.9 kcal/mol), NS3 helicase-hypericin (-9.8 kcal/mol), and NS3 helicase-pentagalloylglucose (-9.5 kcal/mol) as the best binding affinity compounds based on their binding energies. To understand the stability of these complexes, molecular dynamic simulations were executed and the trajectory analysis exposed that the NS3 helicase-ellagic acid complex possesses greater stability than the other two complexes such as NS3 helicase-hypericin and NS3 helicase-pentagalloylglucose. The ADMET property prediction of these compounds resulted in nontoxicity and noncarcinogenicity. [ABSTRACT FROM AUTHOR]

Ruan jian qing mai recipe (RJQM) is an empirical prescription for treating arteriosclerosis obliterans (ASO). However, the mechanism of RJQM recipe-mediated ASO attenuation has not yet been elucidated. Therefore, this study aimed to explore the mechanism by which the RJQM recipe relieves ASO in a mouse model of lower limb ischemia, which was established by ligating and breaking the femoral artery of the left lower limb. The surgical groups were divided into the ischemic group, beraprost sodium group, low-dose RJQM group, medium-dose RJQM group, and high-dose RJQM group. Normal mice were set as the control group. The blood flow of the lower limb was examined on days 7 and 14. At the end of animal procedures, blood samples were collected, and the rectus femoris of the left lower limb were harvested. Results revealed that mice in the ischemic group demonstrated low blood flow. Additionally, hematoxylin and eosin, and Masson staining results showed that inflammation of the rectus femoris was obvious in the ischemia group, and the level of fibrosis was increased. Blood flow was recovered in all treatment groups compared to the ischemic group, and the inflammatory infiltration and fibrosis of the rectus femoris were relieved after RJQM treatment. The serum levels of interleukin (IL)-17A and IL-21 were decreased, and the expression of JAK2/STAT3 proteins was inhibited in all RJQM treatment groups compared to the ischemia group. Furthermore, the improvement of IL-17A, IL-21, and rectus femoris fibrosis was more obvious with increasing treatment time. In conclusion, RJQM can effectively alleviate ASO and promote the recovery of lower limb blood flow by regulating the JAK2/STAT3 signaling pathway to reduce the inflammatory response. [ABSTRACT FROM AUTHOR]

What is known and objective: This study aimed to determine the results of INR monitoring in patients on vitamin K antagonists (VKAs) and the time in therapeutic range (TTR) in 'real‐world' settings. Methods: Retrospective analysis of 836,857 INR measurements performed in adults from February 2010 to August 2015 in two districts in the French Brittany region. Results: Of the 836,857 INR measurements, 94.9% were ordered by general practitioners and 2.0% by cardiologists. The number of tests increased by 10‐year age categories up to the age‐group of 80–90 years. The number of INR measurements increased from 169,636 in 2011 to 176,184 in 2012, but then decreased slightly to 162,597 in 2013 and 164,427 in 2014. Mean coefficient of variation of INR was 19.0%, and mean TTR was 29.0%. TTR was higher in women than in men (31% vs. 18%), in older than in younger patients (19.1% at 40 years and 38.6% at 100 years) and in patients with arrhythmias than in those with deep vein thrombosis/pulmonary embolism (44.4% versus 19.4%) (p < 10−5 for each comparison). Median interval between INR measurements was 14 days [7–28]; it was prolonged in men vs women, rural vs urban regions, older vs younger patients and when requested by GPs vs cardiologists. The interval was shorter for patients with INR outside the therapeutic range versus patients with INR within the therapeutic range (9 days [5–21] vs. 18 days [10–29], p < 10−10). What is new and conclusion: VKAs are still frequently prescribed in this era of direct oral anticoagulants. The low TTR cannot be explained by inadequate INR monitoring. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is used as the standard chemotherapeutic agent for GBM but with limited success, and treatment failure is mainly due to tumor resistance. One of the leading causes of TMZ resistance is the upregulation of the DNA repair mechanism. Therefore, targeting the DNA damage response (DDR) is proposed to be an effective strategy to sensitize tumor cells to TMZ. In the present study, we demonstrated that the combined use of the PI3K inhibitor ZSTK474 and TMZ showed synergetic anticancer effects on human GBM cells in vitro and in vivo. The combination treatment led to significantly increased cell apoptosis and DNA double strand breaks (DSBs). In addition, a mechanistic study indicated that TMZ enhanced the homologous recombination (HR) repair efficiency in GBM cells, while ZSTK474 impaired HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51, thereby sensitizing GBM cells to TMZ. Moreover, TMZ activated the PI3K signaling pathway through upregulation of the PI3K catalytic subunits p110α and p110β and the phosphorylation of Akt. Meanwhile, ZSTK474 blocked the activity of the PI3K/Akt pathway. Taken together, our findings suggested that the combination of ZSTK474 and TMZ might be a potential therapeutic option for GBM. [ABSTRACT FROM AUTHOR]

Streptomyces is amongst the most amenable genera for biotechnological applications, and it is extensively used as a scaffold for drug development. One of the most effective therapeutic applications in the treatment of cancer is targeted therapy. Small molecule therapy is one of them, and it has gotten a lot of attention recently. Streptomyces derived compounds namely streptenols A, C, and F–I and streptazolin were subjected for ADMET property assessment. Our computational studies based on molecular docking effectively displayed the synergistic effect of streptomyces-derived compounds on the gynecological cancer target PIK3CA. These compounds were observed with the highest docking scores as well as promising intermolecular interaction stability throughout the molecular dynamic simulation. Molecular docking and molecular dynamic modeling techniques were utilized to investigate the binding mode stability of drugs using a pharmacophore scaffold, as well as physicochemical and pharmacokinetic aspects linked to alpelisib. With a root mean square fluctuation of the protein backbone of less than 0.7 nm, they demonstrated a steady binding mode in the target binding pocket. They have also prompted hydrogen bonding throughout the simulations, implying that the chemicals have firmly occupied the active site. A comprehensive study showed that streptenol D, streptenol E, streptenol C, streptenol G, streptenol F, and streptenol B can be considered as lead compounds for PIK3CA-based inhibitor design. To warrant the treatment efficacy against cancer, comprehensive computational research based on proposed chemicals must be assessed through in vitro studies. [ABSTRACT FROM AUTHOR]

Background. Ankylosing spondylitis (AS) is a common immune-related systemic chronic inflammatory osteoarthropathy. Previous studies have proven that biologic agents, including IL-17A inhibitors (IL17Ai), TNF-α inhibitor FC fusion protein (TNFiFCP), or fully human monoclonal antibody (TNFiNMA) and JAK inhibitor (JAKi), are effective for AS treatment. Our study is aimed at comparing the clinical efficacy, tolerability, and safety of different biological agents, including novel IL-6 inhibitor (IL6i), IL-23 inhibitor (IL23i), and IL-17 A/F dual variable domain inhibitor (IL17AFi) in AS. Method. PubMed, Scopus, Embase, CNKI, and the Cochrane Library were systematically searched. A frequentist framework network meta-analysis with a random-effects model was performed. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA) and cluster-rank analysis. Results. IL17AFi reported both the highest ASAS40 (SUCRA = 91.4 %) and ASAS20 (SUCRA = 92.5 %) response, while IL6i and IL23i reported the lowest responses (SUCRA = 6.6 % and 19.9%, respectively). With the exceptions of IL6i (RR 0.60, 95% CI (0.22 to 1.67) for ASAS40 and 1.36 (0.71 to 2.58) for ASAS20) and IL23i (0.98 (0.68 to 1.40) for ASAS40 and 0.91 (0.70 to 1.19) for ASAS20), all biological drugs demonstrated statistically superior ASAS responses than placebo. TNFiFMA performed best in the suppression of disease activity (SUCRA = 77.4 %, SMD 2.35, and 95% CI (1.11 to 3.59)) and functional improvement (SUCRA = 68.8 %, SMD 1.67, and 95% CI (0.59 to 2.74)). There were no significant differences in tolerability or safety between biologic drugs and placebo. Conclusions. The novel IL-17 A/F dual variable domain inhibitor, bimekizumab, may be an ideal future treatment choice for AS, while IL-23 and IL-6 inhibitors demonstrate little potential in the treatment of AS. For patients with rapid disease progression and severe functional limitation, TNF-α inhibitors, especially infliximab, are safe and effective and could be a first-line treatment choice. [ABSTRACT FROM AUTHOR]

Background. Breast cancer is one of the most common types of cancer diagnosed and the second leading cause of death among women. Breast cancer susceptibility proteins of type 1 and 2 are human tumor suppressor genes. Genetic variations/mutations in these two genes lead to overexpression of human breast tumor suppressor genes (e.g., BRCA1, BRCA2), which triggers uncontrolled duplication of cells in humans. In addition, multidrug resistance protein 1 (MDR1), an important cell membrane protein that pumps many foreign substances from cells, is also responsible for developing resistance to cancer chemotherapy. Aim of the Study. The aim of this study was to analyze some natural compounds or their derivatives as part of the development of strong inhibitors for breast cancer. Methodology. Molecular docking studies were performed using compounds known in the literature to be effective against BRCA1 and BRCA2 and MDR1, with positive control being 5-fluorouracil, an antineoplastic drug as a positive control. Results. The binding affinity of the compounds was analyzed, and it was observed that they had a better binding affinity for the target proteins than the standard drug 5-fluorouracil. Among the compounds analyzed, α-hederin, andrographolide, apigenin, asiatic acid, auricular acid, sinularin, curcumin, citrinin, hispolon, nerol, phytol, retinol palmitate, and sclareol showed the best binding affinity energy to the BRCA1, BRCA2, and MDR1 proteins, respectively. Conclusions. α-Hederin, andrographolide, apigenin, asiatic acid, auricular acid, hispolon, sclareol, curcumin, citrinin, and sinularin or their derivatives can be a good source of anticancer agents in breast cancer. [ABSTRACT FROM AUTHOR]