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Background: Immune checkpoint inhibitors (ICIs) have advanced the therapeutic landscape for malignant melanoma patients. However, they can cause permanent and irreversible dermatologic immune‐related adverse events (irAEs) that may lead to interruption of ICI treatment or become life‐threatening. To assess the risk of severe dermatologic irAEs (grade 3 or higher) among ICIs for advanced melanoma, we conducted a network meta‐analysis (NMA). Methods: Phase II/III randomized controlled clinical trials (RCTs) involving ICIs were retrieved from various databases, including PubMed, Embase, Cochrane Library, and Web of Science. These trials were published from the inception of databases to October 15, 2022. In addition, the risk of severe dermatologic irAEs associated with ICI types and doses was evaluated and compared by NMA. Results: This study included 20 Phase II/III RCTs with a total of 10 575 patients. The results indicated that ICIs carry a higher risk of severe dermatologic irAEs compared to chemotherapy. Additionally, the combinational therapy of Nivolumab + Ipilimumab was associated with a higher risk than ICI monotherapy. Comparatively, the latest treatment option involving dual ICI therapy with Relatlimab + Nivolumab showed a lower toxicity risk, but higher than Ipilimumab alone. Lastly, Nivolumab, at a dose of 3 mg/kg every 2 weeks, was observed as the lowest‐risk dosing regimen for severe dermatologic irAEs in patients with advanced melanoma. Conclusion: The findings suggest that Nivolumab (1 mg/kg) + Ipilimumab (3 mg/kg) administered every 3 weeks should be used cautiously in patients with advanced melanoma at high risk for dermatologic irAEs. While we recommend the preferred regimen of Nivolumab (dose = 3 mg/kg, every 2 weeks). [ABSTRACT FROM AUTHOR]

BACKGROUND: Chemical fungicides are the mainstay of plant disease control in agricultural production, but there are a very limited number of drugs that can effectively control plant diseases. Two series of secondary amine derivatives were synthesized using the diamine skeleton combined with saturated aromatic and aliphatic aldehydes, and their antibacterial and antifungal activities against plant pathogens were determined. In addition, the antimicrobial mechanism of the highly active compound A26 was preliminarily examined against Xanthomonas oryzae (Xoo). RESULTS: Compound A26 exhibited the highest antibacterial potency among all the target compounds, with MIC values of 3.12, 3.12 and 12.5 μg mL−1 against Xoo, Xanthomonas axonopodis pv. Citri and Pseudomonas sollamacearum, respectively. In addition, compound A26 had powerful curative and protective effects against Xoo at 200 μg mL−1, and was better than the control agent Xinjunan. Preliminary mechanistic studies showed that compound A26 reduced the bacterial pathogenicity by targeting cell membranes and inhibiting the secretion of extracellular polysaccharides. Meanwhile, the toxicity of compound A26 to Human Embryonic Kidney 293 cells and Human Liver‐7702 was similar to that of Xinjunan, and it had moderate toxicity according to the World Health Organization classification standard of oral exogenous toxicity, with an LD50 of 245.47 mg kg−1. CONCLUSION: Secondary amines have efficient and broad‐spectrum antibacterial activity against plant pathogenic bacteria and are expected to be a new class of candidate compounds for antibacterial drugs. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: The unreasonable use of chemical fungicides causes common adverse consequences that not only affect the environment, but also cause resistance and resurgence problems of plant pathogens, which are extremely harmful to human health, the economy, and the environment. Based on the rich biological activities of boron‐based compounds, 82 phenylboronic acid derivatives were selected and their antifungal activities against six agricultural plant pathogens were determined. Combined with transcriptomics tools, the mechanism of action of compound A49 (2‐chloro‐5‐trifluoromethoxybenzeneboronic acid) against Botrytis cinerea Pers (B. cinerea) was studied. Results: The EC50 values of compounds A24, A25, A30, A31, A36, A41, A49 and B23 against all six fungi were under 10 μg/mL. Compound A49 displayed significant activity against B. cinerea (EC50 = 0.39 μg/mL), which was better than that of commercial fungicide boscalid (EC50 = 0.55 μg/mL). A49 not only inhibited the germination of B. cinerea spores, but also caused abnormal cell morphology, loss of cell membrane integrity, enhanced cell membrane permeability, and accumulation of intracellular reactive oxygen species. Further findings showed that A49 reduced cellular antioxidant activity, and peroxidase and catalase activities. Transcriptomic results indicated that A49 could degrade intracellular redox processes and alter the metabolism of some amino acids. Meanwhile, A49 showed obvious activity in vivo and low cytotoxicity to mammal cells. Conclusion: The boron‐containing small molecule compounds had high efficiency and broad‐spectrum antifungal activities against six plant pathogens, and are expected to be candidate compounds for a new class of antifungal drugs. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

BACKGROUND: The resistance of traditional chemical fungicides to plant pathogenic fungi and the threats to the safety of humans and the environment highlight an urgent need to find safe and efficient alternatives to chemical fungicides. Owing to the wide spectrum of antifungal activities, low persistence and nontoxicity to mammals and aquatic life, essential oils have considerable potential as low‐risk pesticides. In this study, the essential oil and the main components of Angelica sinensis (Oliv.) Diels (Danggui) were extracted, analyzed by GC–MS, and evaluated for their antifungal activities against six plant pathogenic fungi. RESULTS: 3‐butylidenephthalide (3‐BPH) showed the best antifungal activity against Fusarium graminearum with an EC50 value of 14.35 μg mL−1. The antifungal mechanistic studies revealed that 3‐BPH induced the generation of endogenous ROS to cause lipid peroxidation of the cell membrane and inhibited the biosynthesis of ergosterol, thereby causing the cell membrane damaged to exert its fungicidal activity. Significantly, 3‐BPH could reduce deoxynivalenol production compared to the control. CONCLUSION: This study demonstrated the potent fungicidal activity of natural phthalide compound 3‐BPH and highlighted its potential as an alternative agent to control F. graminearum. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Phytopathogenic fungi infections have become a major threat to reduce crop yields and dampen human health globally. The mycelium growth inhibition method was adopted to evaluate the antifungal activity of commercially available natural and natural‐like phenols, bioassay results showed that most phenolic compounds exhibited excellent fungicidal activity against Fusarium graminearum, Rhizoctonia solani, Botrytis cinerea, Fusarium oxysporum f. sp. Vasinfectum, Sclerotinia sclerotiorum, and Magnaporthe oryzae. Particularly, compound Z‐5 exhibited an excellent inhibition rate of 100.00 % at 100 μg/mL and EC50 value of 3.20 μg/mL against Fusarium graminearum. In addition, compound Z‐5 displayed the best efficacy and superior fungicidal activity compared to azoxystrobin (EC50=9.78 μg/mL) based on mycelial growth and spore germination. Significantly, compound Z‐5 at 200 μg/mL reduced 4‐deoxynivalenol production by over 98 % compared to the control, through down‐regulation of the gene expression of Tri5 and Tri6. Preliminary mechanism studies revealed that compound Z‐5 might exert its fungicidal activity by inducing accumulation of reactive oxygen species and lipid peroxidation, and causing cell membrane destruction and DNA synthesis interference. This study demonstrated the potent fungicidal activity of the natural‐like phenolic compound Z‐5 and highlighted its potential as an alternative agent to control F. graminearum. [ABSTRACT FROM AUTHOR]

BACKGROUND: The abuse of chemical fungicides not only leads to toxic residues and resistance in plant pathogenic fungi, but also causes environmental pollution and side effects on in humans and animals. Based on the antifungal activities of berberine, seven different types of berberine derivatives (A1–G1) were synthesized, and their antifungal activities against six plant pathogenic fungi were evaluated (Rhizoctonia solani, Botrytis cinerea, Fusarium graminearum, Phytophthora capsici, Sclerotinia sclerotiorum, and Magnaporthe oryzae). RESULTS: The results for antifungal activities in vitro showed that berberine derivative E1 displayed good antifungal activity against R. solani with a median effective concentration (EC50) of 1.77 μg ml−1, and berberine derivatives F1 and G1 demonstrated broad‐spectrum antifungal activities with EC50 values ranging from 4.43 to 42.23 μg ml−1 against six plant pathogenic fungi. Berberine derivatives (E2–E29, F2–F18, and G2–G9) were further synthesized to investigate the structure–activity relationship (SAR), and compound E20 displayed significant antifungal activity against R. solani with an EC50 value of 0.065 μg ml−1. Preliminary mechanism studies showed that E20 could cause mycelial shrinkage, cell membrane damage, mitochondrial abnormalities and the accumulation of harmful reactive oxygen species, resulting in cell death in R. solani. Moreover, in vivo experimental results showed that the protective effect of E20 was 97.31% at 5 μg ml−1, which was better than that of the positive control thifluzamide (50.13% at 5 μg ml−1). CONCLUSION: Berberine derivative E20 merits further development as a new drug candidate with selective and excellent antifungal activity against R. solani. © 2022 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

The coexistence mechanism of Eu2+ and Eu3+ ions in YAl3(BO3)4 host under different reducing conditions is investigated and confirmed in great detail, which can be described by three aspects as following. First, Eu3+ is protected by the layered structure of YAl3(BO3)4. Second, the number of the interstitial defects ((Al)i...,(Y)i...) increases with increasing Eu2+ to maintain the charge balance of the system. And these defects can capture free electrons which are used for the reduction of Eu3+. Finally, free holes become more and more with the number of nonequivalent substitution defects (EuY') increasing, which make the 5d electrons of Eu2+easily escape to the conduction band and Eu2+ convert to Eu3+. This work will be of great significance to research coexistence of multiple valence ions in the structure of borate and defect motion with nonequivalent substitution. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) has recorded knowledge of diabetes for over 2000 years. Because a considerable number of TCM studies exhibit design defects, such as limited intervention duration, small sample sizes and inconsistent efficacy evaluations, the role of TCM in the treatment of diabetes cannot be fully elucidated. In this review, we evaluate randomized controlled trials of prediabetes, diabetes and diabetic complications published in the past decade. We found that TCM could significantly improve glucose control and clinical indices in patients with diabetes and effectively delay the progression of diabetes. We also summarize potential pharmacological mechanisms underlying the efficacy of TCM medication/herbs and their active ingredients for treating diabetes. More rigorously designed experiments and long‐term evaluation of TCM for diabetes will allow for more effective diabetes management. [ABSTRACT FROM AUTHOR]

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Aim Partial hepatectomy ( PH) induces robust hepatic regenerative and metabolic responses that are considered to be triggered by humoral factors. The aim of the study was to identify plasma protein factors that potentially trigger or reflect the body's immediate-early responses to liver mass reduction. Methods Male C57BL/6 mice were subjected to sham operation, 70% PH or 90% PH. Blood was collected from the inferior vena cava at 20, 60 and 180 min after surgery. Results Using a label-free quantitative mass spectrometry-based proteomics approach, we identified 399 proteins exhibiting significant changes in plasma expression between any two groups. Of the 399 proteins, 167 proteins had multiple unique sequences and high peptide ID confidence (>90%) and were defined as priority 1 proteins. A group of plasma proteins largely associated with metabolism is enriched after 70% PH. Among the plasma proteins that respond to 90% PH are a dominant group of proteins that are also associated with metabolism and one known cytokine (platelet factor 4). Ninety percent PH and 70% PH induces similar changes in plasma protein profile. Conclusion Our findings enable us to gain insight into the immediate-early response of plasma proteins to liver mass loss. Our data support the notion that increased metabolic demands of the body after massive liver mass loss may function as a sensor that calibrates hepatic regenerative response. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we have identified 876 polymorphism sites in 145 complete or partial genomes of SARS-CoV available in the NCBI GenBank. One hundred and seventy-four of these sites existed in two or more SARS-CoV genome sequences. According to the sequence polymorphism, all SARS-CoVs can be divided into three groups: (I) group 1, animal-origin viruses (such as SARS-CoV SZ1, SZ3, SZ13 and SZ16); (II) group 2, all viruses with clinical origin during first epidemic; and (III) group 3, SARS-CoV GD03T0013. According to 10 special loci, group 2 again can be divided into genotypes C and T, which can be further divided into sub-genotypes C1–C4 and T1–T4. Positive Darwinian selections were identified between any pair of these three groups. Genotype C gives neutral selection. Genotype T, however, shows negative selection. By comparing the death rates of SARS patients in the different regions, it was found that the death rate caused by the viruses of the genotype C was lower than that of the genotype T. SARS-CoVs might originate from an unknown ancestor. [Copyright &y& Elsevier]