Effect of resveratrol on herpesvirus encephalitis: Evidences for its mechanisms of action.

BACKGROUND: Herpes simplex virus type 1 (HSV-1)-induced herpes simplex encephalitis (HSE) has a high mortality rate in clinically immunocompromised patients, while recovered patients often experience neurological sequelae due to neuroinflammation. Nucleoside drugs and nucleoside analogues such as acyclovir and ganciclovir are mainly used in clinical treatment, and the emergence of resistant viral strains makes the development of new anti-herpesvirus encephalitis drugs urgent. Resveratrol is a multifunctional, plant-derived bioactive compound and its antiviral potential is attracting much attention. PURPOSE: This study aimed to investigate the anti-HSV-1 mechanism of resveratrol in microglial cells and in the HSE mouse model. METHODS: The antiviral effect of resveratrol on HSV-1 infection was investigated by plaque assay, virus titer, immunofluorescence, Western blot and time-of-addition assay. The influence of resveratrol on stimulator of interferon gene (STING)/Nuclear Factor kappa B (NF-κB) signaling pathway-mediated neuroinflammation was examined by Western blot, RT-qPCR and ELISA. The interaction between resveratrol and STING/heat shock protein 90 beta (HSP90ß) was evaluated by molecular modeling, co-immunoprecipitation, and drug affinity responsive target stability assay. The therapeutic effect of resveratrol on HSE was evaluated in the HSE mouse model by analyzing weight loss, neurodegenerative symptoms and histopathological scores. RESULTS: Resveratrol inhibited the early process of HSV-1 infection, and interfered with the STING/NF-κB signaling pathway to attenuate HSV-1-induced neuroinflammation and microglial M1 polarization, independent of its classical target Sirtuin1. Mechanistically, resveratrol completely bound to Glu515 and Lys491 of HSP90ß, thus disrupting the HSP90ß-STING interaction and promoting STING degradation. Resveratrol also significantly alleviated viral encephalitis and neuroinflammation caused by HSV-1 in the HSE mouse model. CONCLUSION: Resveratrol acted as a non-classical HSP90ß inhibitor, binding to the STING-HSP90ß interaction site to promote STING degradation and attenuate HSV-1-induced encephalitis and neuroinflammation. These findings suggest the alternative strategy of targeting HSP90ß and resveratrol-mediated inhibition of HSP90ß as a potential antiviral approach.

Activity-guided isolation and identification of antiherpesvirus and antineuroinflammatory active terpenoids from Artemisia vulgaris L. based on the LC-MS/MS molecular network.

Seven undescribed terpenoids, comprising two guaiane-type sesquiterpene lactones (1-2), one eucalyptol-type sesquiterpene (3), one monolactone (4), and three triterpenoids (5-7), along with 35 known analogues, were isolated from the leaves of Artemisia vulgaris L. Their structures and configurations were analysed by extensive spectroscopy. Compounds 1, 2, 8-10, 13, 17, 19, and 28 showed antineuroinflammatory activity, and compounds 1 and 2 revealed remarkable antineuroinflammatory effects, with an IC50 value of 2.2 ± 0.1 and 1.6 ± 0.1 µM, more potent than the positive control drug dexamethasone. Furthermore, compounds 1 and 2 could inhibit the expression of BV-2 inflammatory genes (IL-6, TNF-α, IL-1ß) induced by LPS, downregulate the critical inflammatory protein production of iNOS and COX-2. The anti-HSV-1 activity screening revealed that compounds 28, 29 and 38 exhibited inhibitory activity against HSV-1 proliferation. Particularly, compound 28 exhibited a significant anti-HSV-1 effect, inhibiting the proliferation of HSV-1 and acyclovir-resistant strains of HSV-1/153 and HSV-1/Blue. Our research identified compounds 1, 2, and 28 from A. vulgaris., which could potentially serve as lead compounds for antineuroinflammatory and anti-HSV-1 activities.

Sesquiterpenoids and triterpenoids with anti-inflammatory effects from Artemisia vulgaris L.

In this study, eight undescribed sesquiterpenoids (artemvulactone A-G and artemvulemdiol A), and two undescribed triterpenoids, (3S)-dammar-20,25-diene-3-hydroxy-24-one and (3S,23E)-dammar-20,23-diene-25- methoxy-3-ol were isolated from the leaves of Artemisia vulgaris L., together with ten known sesquiterpenoids and three known triterpenoids. The structures of these undescribed terpenoids were determined by extensive spectroscopy methods, including 1D and 2D-NMR, HRESIMS, IR, UV, X-ray diffraction, and ECD. The absolute configurations of artemvulactone A, artemvulactone D, and artemvulactone E were determined by X-ray diffraction (Cu Kα). All isolates were evaluated for their anti-inflammatory efficacy by detecting the expression of inflammatory mediator NO in LPS-induced RAW264.7 cells, and the results indicated that artemvulactone E exhibited significant anti-inflammatory effect with an IC50 value of 0.9 ± 0.2 µM. Furthermore, artemvulactone E could reduce LPS-induced COX-2 protein expression dose-dependently by western blotting experiments.

The Effects of AT-533 and AT-533 gel on Liver Cytochrome P450 Enzymes in Rats.

BACKGROUND AND OBJECTIVES: AT-533 is a novel heat shock protein 90 inhibitor, which exhibits various biological activities in vitro and in vivo. Cytochrome P450 (CYP) enzymes in the liver are involved in the biotransformation of drugs and considered to be essential indicators of liver toxicity. The aim of this study was to assess the effect of AT-533, either as active pharmaceutical ingredient or in gel form, on liver CYP enzymes. METHODS: The effect of AT-533 or AT-533 gel on rat liver cytochrome P450 enzymes, including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, was analyzed using LC-MS/MS. RESULTS: AT-533 and AT-533 gel did not significantly increase or reduce the enzymatic activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 at any treatment dose. CONCLUSIONS: AT-533 and AT-533 gel did not have any effect on CYP activity and may be considered safe for external use in gel form, as an alternative to conventional treatment.

New Atypical Manifestations and Prognostic Factors of Vibrio vulnificus Infection: a 10-Year Retrospective Study.

Vibrio vulnificus (V. vulnificus) infection is rare but potentially fatal. This study explored new atypical manifestations and prognostic factors of V. vulnificus-infected patients during hospitalization. We retrospectively reviewed the medical records of 33 patients diagnosed with V. vulnificus infection in Guangdong Province, China between 2010 and 2020. Multiple logistic regression and receiver operating characteristic (ROC) curve analyses were performed. The new atypical manifestations included cholangitis, urinary tract infection, and suppurative otitis media. Eleven of the 33 (33.3%) V. vulnificus-infected patients eventually died. Univariate analysis showed that patients with cardio-cerebrovascular diseases, lower platelet counts, and higher levels of C-reactive protein and procalcitonin (PCT) had statistically higher mortality. However, multivariate analysis showed that only the PCT level (P = 0.036) was statistically significant. In addition, the area under the ROC value estimate for PCT was 0.8816 (95% confidence interval (CI), 0.759-1.000; P = 0.0009). More than half of the patients with V. vulnificus infection died when PCT was > 20 ng/mL, while no patient died when PCT was ≤ 20 ng/mL. This study found new atypical manifestations of V. vulnificus infection. In addition, PCT was an effective and independent predictor of mortality in patients with V. vulnificus infection, allowing clinicians to conduct early risk stratification and determine the best therapeutic strategies.

MicroRNA-195 acts as a tumor suppressor by directly targeting Wnt3a in HepG2 hepatocellular carcinoma cells.

MicroRNAs (miRNAs) are a class of small, non­coding, endogenous RNAs that are important in tumor cell biological processes as they regulate gene expression. miR-195 has been demonstrated to be a tumor repressor in numerous types of human cancer. However, the mechanism by which miR­195 suppresses tumor development remains to be elucidated. The aim of this study was to investigate the effect of miR-195 on the biological functions of HepG2 hepatocellular carcinoma (HCC) cells and identify the association between miR-195 and Wnt3a in HCC. miR-195 mRNA expression levels in HCC tissues and cell lines were measured by reverse transcription polymerase chain reaction analysis. miR-195 function was measured with cell proliferation, cell cycle and apoptosis assays following transfection with miR­195 and anti­miR­195 sequences, and the respective controls. Luciferase reporter assay was used to determine whether Wnt3a was a target of miR-195. In addition, Wnt3a expression levels were determined in HCC cells using western blot analysis. The miR-195 expression levels were found to be reduced in HCC tissues and cell lines. miR-195 overexpression resulted in a reduction in cell proliferation. In addition, the overexpression of miR-195 in HCC cells induced G1 phase cell cycle arrest and promoted apoptosis. Furthermore, Wnt3a was demonstrated to be directly targeted by miR-195. These findings suggest that miR-195 is key in regulating cell proliferation, cell cycle and apoptosis through targeting Wnt3a. In addition, overexpression of miR-195 may be a potential therapeutic strategy in the treatment of HCC.

Downregulation of miR-145 expression in oral squamous cell carcinomas and its clinical significance.

BACKGROUND: MicroRNAs have been reported to play roles as oncogenes or tumor suppressor genes in human cancers. However, the expression levels of miR-145 in oral squamous cell carcinoma (OSCC) are unclear. The purpose of this study was to investigate the status of miR-145 expression in OSCC and determine its clinical significance. PATIENTS AND METHODS: We examined miR-145 levels in 62 OSCC tissue samples and cell lines by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). The relationship between miR-145 expression and clinicopathologic factors of OSCC patients was analyzed. RESULTS: The proportion of miR-145 low expression was 82.26% (51/62) among the 62 OSCC patients, and expression levels of miR-145 in OSCC tissue samples and cell lines were significantly lower than in non-tumor controls. miR-145 expression levels were not significantly associated with age (p = 0.607), sex (p = 0.213), location (p = 0.952), histology (p = 0.603), pT stage (p = 0.305), pTNM stage (p = 0.471), and lymphatic metastasis (p = 1.000). CONCLUSION: miR-145 may be involved in the early tumorigenesis of oral squamous cells, and might be a potential biomarker in the early diagnosis of OSCC.

Growth performance, vitamin E status, and proximate and fatty acid composition of channel catfish, Ictalurus punctatus, fed diets containing various levels of fish oil and vitamin E.

A study was conducted to determine the effect of increasing dietary levels of fish oil on vitamin E requirement and their effect on growth performance, liver vitamin E status, and tissue proximate and fatty acid compositions of channel catfish. Basal purified diets (42% protein and 3,800 kcal DE/kg) supplemented with 6, 10, and 14% menhaden fish oil were each supplemented with 50, 100, and 200 mg vitamin E/kg (3×3 factorial experiment). Each diet was fed to juvenile channel catfish in three random aquaria to apparent satiation twice daily for 12 weeks. Weight gain, feed intake, and feed efficiency ratio were not affected by dietary levels of fish oil, vitamin E, or their interaction. Survival rate at the end of week 12 was significantly lower for fish fed diets containing 14% fish oil, regardless of vitamin E content. Whole-body moisture significantly decreased and lipid increased when dietary lipid levels were increased to 10 or 14%. Dietary vitamin E levels had no effect on body proximate composition. Lipid content of liver was not influenced by dietary levels of fish oil and vitamin E or their interaction. Hepatosomatic index significantly decreased with increasing lipid levels but was not affected by dietary levels of vitamin E. Liver vitamin E increased with increasing dietary vitamin E but decreased with increasing fish oil levels. Fatty acid composition of whole body and liver reflected that of dietary lipid but was not influenced by dietary levels of vitamin E. Whole-body saturates increased, whereas MUFA decreased with increasing dietary levels of fish oil. Liver saturates were not affected by fish oil levels, but MUFA and n-6 decreased and increased, respectively, with increasing fish oil levels. Total n-3 and n-3 HUFA in both tissues increased with increasing fish oil levels in diets, but liver stored much higher levels of these fatty acids.

Effects of variable periods of food deprivation on the development of enteric septicemia in channel catfish.

Enteric septicemia of catfish (ESC), caused by the bacterium Edwardsiella ictaluri, is the most significant bacterial disease affecting channel catfish Ictalurus punctatus. Withholding feed during outbreaks of ESC is a widely accepted industry practice used to control losses from the disease. Scientific evidence concerning the validity of the practice is contradictory. Two studies were conducted to further evaluate the survival of channel catfish fingerlings following variable periods of feed deprivation before and after exposure to E. ictaluri in controlled aquarium experiments. In the first study, feed was withheld for varying time periods before bacterial challenge. After bacterial challenge, feed was either withheld or fish were fed daily. The second study utilized fish fed daily or fish deprived of feed 7 d before bacterial challenge. Daily feeding was resumed 4, 48, and 96 h after fish were exposed to E. ictaluri. In both experiments, the prechallenge feed treatments did not affect mortality. In contrast, withholding feed after bacterial challenge reduced mortalities by 52% in experiment 1 and by 45% in experiment 2. The highest mortality was observed when fish were fed immediately after immersion exposure and the lowest when fish were completely denied feed or fed daily starting 96 h after challenge. This reduction in mortality occurred when the concentration of E. ictaluri in aquarium water was negligible. These data suggest that when E. ictaluri is present in the water, feeding fish increases mortality by enhancing oral exposure to the pathogen.

Bollgard II cotton: compositional analysis and feeding studies of cottonseed from insect-protected cotton (Gossypium hirsutum L.) producing the Cry1Ac and Cry2Ab2 proteins.

Bollgard II cotton event 15985 producing the Cry1Ac and Cry2Ab2 proteins has been developed by genetic modification to broaden the spectrum of insects to which the plant is tolerant and to provide an insect resistance management tool to impede the onset of resistance. The purpose of this study was to evaluate the composition and nutrition of Bollgard II cotton, relative to the use for food and animal feed, compared to that of conventional cotton varieties. Compositional analyses were conducted to measure proximate, fiber, amino acid, fatty acid, gossypol, and mineral contents of cottonseed from a total of 14 U.S. field sites over two years. Compositional analysis results showed that the cottonseed and cottonseed oil from Bollgard II cotton were comparable in their composition to those of the conventional control cotton line and other commercial varieties. The composition data are supported by nutritional safety studies conducted with dairy cows, catfish, and quail. Results from these studies showed that Bollgard II performed similarly to the conventional control cotton varieties. These data demonstrate that Bollgard II cotton is compositionally and nutritionally equivalent to conventional cotton varieties. These data support the conclusion that Bollgard II cotton is as safe and nutritious as conventional cotton for food and feed use.