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Two efficient, scalable routes to bis-1,2,4-oxadiazole have been developed by tandem Staudinger/aza-Wittig reaction from the same starting material diaziglyoxime, isocyanates and triphenylphosphonium in good yields. Background: Two convenient and efficient routes for the synthesis of diamino derivatives of bis-1,2,4-oxadiazoles were described. Objective: This study provides a simple protocol for the synthesis of bis-1,2,4-oxadiazoles. Methods: The two procedures were based on tandem Staudinger/aza-Wittig reaction from the same starting material diaziglyoxime, isocyanates and triphenylphosphorus. Results: In synthesis method I, diaziglyoxime 1 was treated with various aromatic or aliphatic isocyanates to give diazioxalimides 2 a high yield. Diazioxalimides 2 reacted with Ph3P to produce the iminophosphoranes 4; the reaction was directly heated from room temperature to 115 ℃ to get the desired diamino derivatives of bis-1,2,4-oxadiazole 4 in 72-92% yields. In synthesis method II, the same target compounds 4 were synthesized in a one-pot reaction by Ph3P and aromatic or aliphatic isocyanates in toluene for 10 h under 115 ℃ in 53-71% yields. Conclusion: The two procedures provide proficient methods of making nitrogen-containing heterocyclic rings. The structures of target compounds 4 were identified by IR, 1HNMR, 13CNMR and HRMS.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Current treatments, including surgery, radiotherapy, and chemotherapy, are limited by severe side effects and the development of resistance. Objective: Therefore, it is important to find additional therapies to combat the problem. Ginsenoside Rb1 is the main active ingredient of ginseng, which is a well-known herb in traditional Chinese medicine. Ginsenoside is reported to play an important role in the prevention and treatment of cancer. Methods: We established Azoxymethane (AOM)/Dextran sodium sulfate (DSS) colon cancer model based on inflammation, observed the beneficial effect of ginsenoside Rb1, and detected the changes in gut microbiota. Results: Our experimental results showed that ginsenoside Rb1 significantly reduced the levels of TNF-α, IL-6, IL- 17A, IL-33, IL-1β, and IL-22, increased the level of IL-10, and also changed the gut microbiota composition. These results suggested that ginsenoside Rb1 can be used to prevent inflammation-associated CRC development and may provide an effective therapeutic strategy for CRC by relieving chronic inflammation and restoring the gut microenvironment in the AOM/DSS-induced model of colitis-associated colorectal cancer in mice. Conclusion: Ginsenoside Rb1 significantly attenuated AOM/DSS-induced colon carcinogenesis.

As a traditional Chinese medicine, Lianhua Qingwen capsules have been widely used to treat Coronavirus Disease 2019 (COVID-19). This study was aimed to demonstrate the association between treatment with Lianhua Qingwen capsules and the clinical outcomes of hospitalized patients with COVID-19. This retrospective study was conducted at four hospitals in Central China. Data of hospitalized COVID-19 patients were collected between December 19, 2019 and April 26, 2020. Based on whether Lianhua Qingwen capsules were used, patients were classified into Lianhua Qingwen and non-Lianhua Qingwen (control) groups. To control for confounding factors, we used conditional logistic regression in a propensity-score matched (PSM) cohort (1 : 1 balanced), as well as logistic regression without matching as sensitivity analysis. A total of 4918 patients were included, 2760 of whom received Lianhua Qingwen capsules and 2158 of whom did not. In the PSM model, after adjusting for confounders, the in-hospital mortality was similar between the Lianhua Qingwen group and the control group (6.8% vs. 3.3%, adjusted OR, 0.66 [95% CI, 0.38-1.15], p = 0.138 ). The negative conversion rate of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection was higher in the Lianhua Qingwen group (88.3% vs. 96.1%, adjusted OR, 4.02 [95% CI, 2.58-6.25], p < 0.001 ). The incidence of acute liver injury was comparable between the two groups (14.0% vs. 11.5%, adjusted OR: 0.85 [95% CI, 0.71-1.02], p = 0.083 ), and the incidence of acute kidney injury was lower in the Lianhua Qingwen group (5.3% vs. 3.0%, adjusted OR: 0.71 [95% CI, 0.50-1.00], p = 0.048 ). Treatment with Lianhua Qingwen capsules was not significantly associated with in-hospital mortality in COVID-19 patients. In the Lianhua Qingwen group, the negative conversion rate of SARS-CoV-2 infection was higher and the incidence of acute kidney injury was lower than in the control group.

A cuprous iodide tetrahedral chain hybrid undergoes a two-step phase transition, leading to switchable dielectrics, and displays thermochromism and piezochromism.

To compare homoleptic [2]catenanes and single rings consisting of gold(i) thiolates, the geometric and electronic structures, absorption spectra, binding energy, interaction energy and composition of intramolecular forces were studied theoretically.

The basic Grey Wolf Optimizer (GWO) has some shortcomings, for example, the convergence speed is slow, it is easy to fall into local extremum, and high-dimensional optimization ability is poor and so on. In response to these shortcomings, an improved grey wolf algorithm which combines flower pollination mechanism, teaching mechanism and polynomial variation is proposed in this study. The flower pollination mechanism is integrated with GWO algorithm, Levy distribution is introduced into the global search of grey wolf population. And the double random mechanism is added in the local search, for these improvements, this algorithm’s overall optimization performance is improved. The teaching mechanism is added to wolf to improve the algorithm’s convergence speed. Polynomial mutation is applied to the individuals with poor optimization effect to improve the algorithm’s accuracy and its ability to jump out of local extremum. Theoretical analysis shows that the time complexity of the improved algorithm is the same as that of the basic algorithm. The test results of five representative comparison algorithms on multiple different characteristics and different dimensions of CEC2017 benchmark functions and two classical engineering problems show that FMGWO algorithm has high optimization accuracy, convergence speed and solution stability. Therefore, it has obvious advantages in global optimization. &nbsp

Acquired immunodeficiency syndrome (AIDS) caused by Human immunodeficiency virus type 1 (HIV-1) has a high tendency among illicit drug abusers. Recently, it is reported that abuse of fentanyl, a potent synthetic μ receptor-stimulating opioid, is an independent risk factor for HIV-1 infection. However, the mechanism of action in augmenting HIV-1 infection still remains elusive. In this study, we found that fentanyl enhanced infection of HIV-1 in MT2 cells, primary macrophages and Jurkat C11 cells. Fentanyl up-regulated CXCR4 and CCR5 receptor expression, which facilitated the entry of virion into host cells. In addition, it down-regulated interferon-β (IFN-β) and interferon-stimulated genes (APOBEC3F, APOBEC3G and MxB) expression in MT2 cells. Our findings identify an essential role of fentanyl in the positive regulation of HIV-1 infection via the upregulation of co-receptors (CXCR4/CCR5) and downregulation of IFN-β and ISGs, and it may have an important role in HIV-1 immunopathogenesis.

Cathepsin B (CTSB), a member of lysosomal cathepsin, is involved in cell autophagy and apoptosis. We previously reported that CTSB increased cardiomyocyte apoptosis in mice heart during pressure overload, while the role of CTSB on diabetic cardiomyopathy has not been fully elucidated. The aim of this study is to explore the role and the underlying mechanism of CTSB on diabetic cardiomyopathy. Mice were subjected to streptozotocin injection to induce a diabetes model. Neonatal rat cardiomyocytes were isolated and cultured with high glucose (33.3 mM) to establish an

Patients with advanced gastric cancer experience rapid disease progression with limited survival, high mortality, and a lack of surgical options. Thus, radiochemotherapy or a combination of chemotherapeutics with targeted therapy is the mainstay of treatment. In comparison to the treatment of other malignant tumors, in gastric cancer, the development of molecularly targeted drugs has been relatively slow. Currently, there are two major classes of molecularly targeted drug regimens that have achieved a certain efficacy in clinical practice: anti-vascular endothelial growth factor (anti-VEGF) therapy and anti-epidermal growth factor receptor (anti-EGFR) therapy. Trastuzumab has been approved as the standard of care for first-line treatment in advanced human epidermal growth factor receptor 2 (HER2)-positive gastric cancer. Ramucirumab in combination with paclitaxel is the recommended regimen for second-line treatment, and apatinib is recommended as third-line treatment. This review summarizes the current status of targeted therapies in the treatment of gastric cancer and gives a perspective on the future.

Background: The Bosniak classification system based on contrast-enhanced computed tomography (CECT) is commonly used for the differential diagnosis of cystic renal masses. Contrastenhanced ultrasound (CEUS) is a relatively novel technique, which has gradually played an important role in the diagnosis of cystic renal cell carcinoma (CRCC) due to its safety and lowest price. Objective: The aim of the study is to investigate the application value of CEUS and Bosniak classification into the diagnosis of cystic renal masses. Method: 32 cystic masses from January 2018 to December 2019 were selected. The images of conventional ultrasound (US), CEUS and CECT from subjects confirmed by surgical pathology were retrospectively analyzed. The Bosniak classification system of cystic renal masses was implemented using CEUS and CECT, and the diagnostic ability was compared. Results: For the 32 cystic masses, postoperative pathology confirmed 11 cases of multilocular CRCC, 15 cases of clear cell carcinoma with hemorrhage, necrosis and cystic degeneration, 5 cases of renal cysts, and 1 case of renal tuberculosis. The Bosniak classification based on CEUS was higher than that based on CECT, and the difference was statistically significant (P = .024). The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of CEUS were comparable to CECT. There was no significant difference observed in the diagnosis of CRCC (P >.05). Conclusion: CEUS combined with Bosniak classification greatly improves the diagnosis of CRCC. CEUS shows a comparable diagnostic ability to CECT. In daily clinical routine, patients who require multiple examinations and present contraindications for CECT can particularly benefit from CEUS.

3-Isothiocyanato oxindoles are a class of important building blocks which have been widely used in the synthesis of structurally diverse enantioenriched spirooxindoles. In this short review, it is attempted to cover the recent synthetic aspects of 3-isothiocyanato oxindoles participated cascade cyclizations in the last few years (i.e., from 2017 to 2022), with an emphasis on formal [3+2] cycloaddition reactions.1 Introduction2 Organocatalyzed Formal [3+2] Cycloaddition of 3-Isothiocyanato Oxindoles3 Lewis Acid Catalyzed Formal [3+2] Cycloaddition of 3-Isothiocyanato Oxindoles4 Conclusions

Ionotropic γ-aminobutyric acid (GABA) receptor (GABAR) in an insect is the major inhibitory receptor and is one of the most important targets for insecticides. Due to the high spatiotemporal resolution of GABAR, the photopharmacological ligands acting on it in vertebrates but not insect have been developed.In this study, two types of photochromic ligands (PCLs) including DTFIPs (DTFIP1 and DTFIP2) and ABFIPs (p-, m-, and o-ABFIP) were synthesized by incorporating photoswitch azobenzene or dithienylethene into fipronil (FIP), which is the antagonist of insect GABAR. Their photomodulation was measured by mosquito larval behavior, and their potential action mechanism was explored by the two-electrode voltage clamp (TEVC) technique in vitro. DTFIP1 and m-ABFIP exhibited the most significant difference of insecticidal activity by about 90- and 5-fold to mosquito larvae between non-irradiated and irradiated formation, respectively, and allowed for optical control of mosquito swimming activity. TEVC assay results indicated that m-ABFIP and DTFIP1 enable optical control over the homomeric LsRDL-type GABAR, which is achieved by regulating the chloride channel of resistance to dieldrin (RDL)-type GABAR by photoisomerization.Our results suggested that PCLs synthesized from fipronil provide an alternative and precise tool for studying insect ionotropic GABARs and GABA-dependent behavior. © 2022 Society of Chemical Industry.

Combinational therapy such as taking tranexamic acid while using laser treatment has been proved potential efficacy by many experiments. However, there is few research which contains large samples and consistent observations.We evaluated clinical efficacy and safety of a new systemic treatment of drug-laser-photon therapy.Retrospective and randomized investigator-blinded study of 75 patients with mixed type melasma was analyzed. At each visit, standardized photographs were taken using VISIA. Modified melasma area and severity index (mMASI) scores were marked using photographs by two dermatologists.The mMASI score decreased significantly from 6.92 to 3.84 after the treatment. The VISIA analyze right cheek data shows: Spots (from 49.67 ± 3.43 to 56.09 ± 3.31), UV spots (from 41.39 ± 24.45 to 44.56 ± 25.86), and Brown spots (from 23.97 ± 17.89 to 28.16 ± 21.28) are statistically increased (p = 0.035, p = 0.018, p = 0.07). All patients feel varying degrees of improvement, about 10.17% felt very much improved, 30.51% felt much improved (51%-75%), 45.76% felt moderately improved (26%-50%), and 13.56% felt little improved (1%-25%).This study was no control group.The efficacy and safety profile of the combination of drug-laser-photon therapy systemic treatment in melasma patients has been proved. It has potential possibility to become a new, reliable, widely suitable therapy strategy.

Metalloenzymes are attractive research targets in fields of chemistry, biology, and medicine. Given that metalloenzymes can manifest conservation of metal-coordination and ligand binding modes, the excavation and expansion of metalloenzyme-specific knowledge is of interest in bridging metalloenzyme-related fields. Building on our previous metalloenzyme-ligand association database, MeLAD, we have expanded the scope of metalloenzyme-specific knowledge and services, by forming a versatile platform, termed the Metalloenzyme Data Bank and Analysis (MeDBA). The MeDBA provides: (i) manual curation of metalloenzymes into different categories, that this M-I, M-II and M-III; (ii) comprehensive information on metalloenzyme activities, expression profiles, family and disease links; (iii) structural information on metalloenzymes, in particular metal binding modes; (iv) metalloenzyme substrates and bioactive molecules acting on metalloenzymes; (v) excavated metal-binding pharmacophores and (vi) analysis tools for structure/metal active site comparison and metalloenzyme profiling. The MeDBA is freely available at https://medba.ddtmlab.org.

Natural products (NPs) and their structural analogs represent a major source of novel drug development for disease prevention and treatment. The development of new drugs from NPs includes two crucial aspects. One is the discovery of NPs from medicinal plants/microorganisms, and the other is the evaluation of the NPs in vivo at various physiological and pathological states. The heterogeneous spatial distribution of NPs in medicinal plants/microorganisms or in vivo can provide valuable information for drug development. However, few molecular imaging technologies can detect thousands of compounds simultaneously on a label-free basis. Over the last two decades, mass spectrometry imaging (MSI) methods have progressively improved and diversified, thereby allowing for the development of various applications of NPs in plants/microorganisms and in vivo NP research. Because MSI allows for the spatial mapping of the production and distribution of numerous molecules in situ without labeling, it provides a visualization tool for NP research. Therefore, we have focused this mini-review on summarizing the applications of MSI technology in discovering NPs from medicinal plants and evaluating NPs in preclinical studies from the perspective of new drug research and development (RD). Additionally, we briefly reviewed the factors that should be carefully considered to obtain the desired MSI results. Finally, the future development of MSI in new drug RD is proposed.

Unprecedented advances have been achieved in hepatobiliary cancer treatment with immune checkpoint blockade (ICB). However, the efficacy of ICB in patients with hepatobiliary malignancies is still limited. Resistance to immunotherapies is often orchestrated by complicated tumor-host-microenvironment interactions but could also occur after initial efficacy, mostly when only partial responses are obtained. Clarification of cancer-resistance mechanisms will be beneficial to provide the rationale for the administration of personalized drugs. Here, we review the factors related to resistance to immune-targeted therapies in hepatobiliary malignancies and discuss the potential strategies for overcoming resistance and future directions of immunotherapy development.

Hepatitis A virus (HAV) live-attenuated vaccine H2 strain has been approved for clinical use for decades with ideal safety profiles in nonhuman primate models and humans. Recently, type I interferon (IFN) receptor-deficient mice were shown to be susceptible to HAV infection. Herein, we sought to determine the infection and replication dynamics of the H2 in Ifnar

Zika virus (ZIKV) is primarily transmitted through mosquito bites and sexual contact, and vertical transmission of ZIKV has also been observed in humans. In addition, ZIKV infection via unknown transmission routes has been frequently reported in clinical settings. However, whether ZIKV can be transmitted via aerosol routes remains unknown. In this study, we demonstrated that aerosolized ZIKV is fully infectious in vitro and in vivo. Remarkably, intratracheal (i.t.) inoculation with aerosolized ZIKV led to rapid viremia and viral secretion in saliva, as well as robust humoral and innate immune responses in guinea pigs. Transcriptome analysis further revealed that the expression of genes related to viral processes, biological regulation and the immune response was significantly changed. Together, our results confirm that aerosolized ZIKV can result in systemic infection and induce both innate and adaptive immune responses in guinea pigs, highlighting the possibility of ZIKV transmission via aerosols.

Integrating metal-organic framework (MOF)-covalent organic framework (COF) allows versatile engineering of hybrid materials with properties superior to pristine components, especially COFs suffered from aggregation-caused quenching (ACQ), unlocking more possibilities to improve the luminescence of COFs. In this work, we prepared various MOF@COF composites with different COF layer thicknesses, in which stable UiO-66-NH

Small-diameter artery disease is the most common clinical occurrence, necessitating the development of small-diameter artificial blood vessels. In this study, seven types of poly(-caprolactone)-cellulose acetate (PCL-CA) composite nanofiber membranes were prepared with different proportions of PCL and CA. The adhesion and growth of Mc3t3-e1 cells were considered to confirm the in vitro cytocompatibility of PCL-CA membranes. A smooth stainless-steel mandrel with a diameter of 4 mm was used to roll up the prepared nanofiber membranes to produce the tubular scaffold with 50 °C hot water. The tubular scaffolds were subjected to axial and circumferential tensile tests. The mechanical performance of the PCL-CA tubular scaffold could be improved by increasing the layers. In addition, the burst pressure (BP) of the tubular scaffolds was increased with the layers, and the BPs of six-layer (2380 ± 36.8 mmHg) and eight-layer (3720 ± 80.5 mmHg) tubular scaffolds were much higher than that of the human saphenous vein (2000 mmHg). The compression shape memory performances of the PCL-CA tubular scaffold with different layers were also investigated to simulate and analyze the contraction and expansion of tubular scaffolds. The experimental results showed that the compression strain of the tubular scaffold in the diameter direction reached 35%, and the ultimate shape recovery rate reached 87%. However, the shape fixity rate and shape recovery rate increased, demonstrating that the optimum number of layers can improve the compression shape memory performance of the tubular scaffold. The results of this study, including comprehensive morphological and mechanical properties and cytocompatibility, indicated the potential applicability of PCL-CA tubular scaffolds as tissue engineering grafts.