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The phytoecdysteroids (PEs) comprise a large group of biologically-active plant steroids, which have structures similar to those of insect-molting hormones. PEs are distributed in plants as secondary metabolites that offer protection against phytophagus (plant-eating) insects. When insects consume the plants containing these chemicals, they promptly molt and undergo metabolic destruction; the insects eventually die. Chemically, ecdysteroids are a group of polyhydroxylated ketosteroids that are structurally similar to androgens. The carbon skeleton of ecdysteroids is termed as cyclopentanoperhydro-phenanthrene with a β -side chain at carbon-17. The essential characteristics of ecdysteroids are a cis -(5 β -H) junction of rings A and B, a 7-en-6-one chromophore, and a trans -(14 α -OH) junction of rings C and D. Plants only synthesize PEs from mevalonic acid in the mevalonate pathway of the plant cell using acetyl-CoA as a precursor; the most common PE is 20-hydroxyecdysone. So far, over 400 PEs have been identified and reported, and a compilation of 166 PEs originating from 1998 has been previously reviewed. In the present review, we have summarized 212 new PEs reported between 1999 and 2019. We have also critically analyzed the biological, pharmacological, and medicinal properties of PEs to understand the full impact of these phytoconstituents in health and disease. Phytoecdysteroids (PEs) have shown a wide range of biological, pharmacological, and medicinal properties implicated in the prevention and therapy of acute and chronic diseases. PEs are effective against different types of cancer due to their anti-inflammatory and antioxidant mechanisms. It also has shown antidiabetic antimicrobial and hepatoprotective abilities. [Display omitted] [ABSTRACT FROM AUTHOR]

Novel nanomaterials for the intracellular transport of therapeutic cargos have been actively sought to effectively breach cell-membrane barriers. In this study we developed novel self-micellizing anticancer lipid (SMAL)-based pro-apoptotic nanoparticles (NPs) that enhance the accumulation and chemotherapeutic efficacy of oxaliplatin (OL) in colorectal cancer cells (CRCs). We demonstrated that NPs with special affinity to caveolae could be designed and based on this specificity, NPs effectively differentiated between endothelial cells (tumor cells) and epithelial cells, without the need for a cell-specific targeting moiety. We demonstrated a remarkable uptake of OL-loaded SMAL NPs (SMAL-OL) in HCT116 and HT-29 cells via the caveolae-mediated endocytosis (CvME) pathway. The higher accumulation of SMAL-OL in the intracellular environment resulted in a significantly elevated anticancer effect compared to that of free OL. Cell cycle analysis proved G2/M phase arrest, along with substantial presence of cells in the sub-G1 phase. An immunoblot analysis indicated an upregulation of pro-apoptotic markers (Bax; caspase-3; caspase-9; and PARP1) and downregulation of Bcl-xl and the PI3K/AKT/mTOR complex, indicating a possible intrinsic apoptotic signaling pathway. Overall, the ability of SMAL NPs to confer preferential specificity towards the cell surface domain could offer an exciting means of targeted delivery without the need for receptor-ligand-type strategies. Statement of Significance In this work, we developed a novel self-micellizing anticancer lipid (SMAL)-based pro-apoptotic nanoparticles (NPs) that enhance the accumulation and chemotherapeutic efficacy of oxaliplatin (OL) in colorectal cancer cells. We demonstrated that NPs with special affinity to caveolae could be realized and based on this specificity, NPs effectively differentiated between endothelial cells (tumor cells) and epithelial cells, without the need for a cell-specific targeting moiety. In addition, oxaliplatin-loaded SMAL were efficiently endocytosed by the cancer cells and represent a significant breakthrough as an effective drug delivery system with promising potential in cancer therapy. We believe this work holds promising potential for the development of next generation of multifunctional nanocarriers for an exciting means of targeted delivery without the need for receptor-ligand-type strategies. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Chaga mushroom (Inonotus obliquus) has been used in folk medicine to treat several disorders through its various biological functions. I. obliquus is claimed to produce general immune-potentiating and strengthening, antiinflammatory, and antitumor properties, but its effects on intestinal inflammation (ulcerative colitis) are clearly not understood. Aim of the study: To determine the effects and mode of action of an aqueous extract of I. obliquus (IOAE) on experimental colitis in mice induced by dextran sulfate sodium (DSS). Materials and methods: Female 5-week-C57BL/6 mice were randomized into groups differing in treatment conditions (prevention and treatment) and doses of IOAE (50 and 100mg/kg body weight). Mice were exposed to DSS (2%) in their drinking water over 7 day to induce acute intestinal inflammation. In colon tissues, we evaluated histological changes by hematoxylin and eosin staining, levels of iNOS by immuno-histochemical staining, and neutrophil influx by myeloperoxidase assay. mRNA expression of pro-inflammatory mediators TNF-α, IL-1β, IL-6, and IFN-γ was determined by RT-PCR. Results: Histological examinations indicated that IOAE suppressed edema, mucosal damage, and the loss of crypts induced by DSS. IOAE markedly attenuated DSS-induced iNOS levels and myeloperoxidase accumulation in colon tissues, demonstrating its suppressive effect on infiltration of immune cells. In addition, IOAE significantly inhibited mRNA expression of pro-inflammatory cytokines induced by DSS in colon tissues. Conclusion: Our results suggest anti-inflammatory effect of IOAE at colorectal sites due to down-regulation of the expression of inflammatory mediators. Suppression of TNF-α and iNOS together with IL-1β by IOAE denotes that it might be a useful supplement in the setting of inflammatory bowel disease. [Copyright &y& Elsevier]

• Novel machine learning algorithm based on physics informed neural networks (PINNs) for approximating solutions of forward and inverse problems for radiative transfer. • Fast, robust and accurate approach, independent of the equation dimensionality. • Estimates on the generalization error of PINNs for the unsteady and steady forward problem. • Extensive numerical experiments demonstrating the accuracy and efficiency of the proposed algorithm. We propose a novel machine learning algorithm for simulating radiative transfer. Our algorithm is based on physics informed neural networks (PINNs), which are trained by minimizing the residual of the underlying radiative transfer equations. We present extensive experiments and theoretical error estimates to demonstrate that PINNs provide a very easy to implement, fast, robust and accurate method for simulating radiative transfer. We also present a PINN based algorithm for simulating inverse problems for radiative transfer efficiently. [ABSTRACT FROM AUTHOR]

We derive bounds on the error, in high-order Sobolev norms, incurred in the approximation of Sobolev-regular as well as analytic functions by neural networks with the hyperbolic tangent activation function. These bounds provide explicit estimates on the approximation error with respect to the size of the neural networks. We show that tanh neural networks with only two hidden layers suffice to approximate functions at comparable or better rates than much deeper ReLU neural networks. • Explicit bounds for function approximation in Sobolev norms by tanh neural networks. • Tanh networks with 2 hidden layers are at least as expressive as deeper ReLU networks. • Improved convergence rate for neural network approximation of analytic functions. [ABSTRACT FROM AUTHOR]

Aim of the study In this study, we examined the effect of different fractions and components of Chaga mushroom (Inonotus Obliquus) on viability and apoptosis of colon cancer cells. Among them, one component showed the most effective growth inhibition and was identified as ergosterol peroxide by NMR analysis. We investigated the anti-proliferative and apoptosis mechanisms of ergosterol peroxide associated with its anti-cancer activities in human colorectal cancer (CRC) cell lines and tested its anti-tumor effect on colitis-induced CRC developed by Azoxymethane (AOM)/Dextran sulfate sodium (DSS) in a mouse model. Materials and methods We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, Western blot analysis, colony formation assays, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and AOM/DSS mouse models to study the molecular mechanism of metastatic activities in CRC cells. Results Ergosterol peroxide inhibited cell proliferation and also suppressed clonogenic colony formation in HCT116, HT-29, SW620 and DLD-1 CRC cell lines. The growth inhibition observed in these CRC cell lines was the result of apoptosis, which was confirmed by FACS analysis and Western blotting. Ergosterol peroxide inhibited the nuclear levels of β-catenin, which ultimately resulted in reduced transcription of c-Myc, cyclin D1, and CDK-8. Ergosterol peroxide administration showed a tendency to suppress tumor growth in the colon of AOM/DSS-treated mice, and quantification of the IHC staining showed a dramatic decrease in the Ki67-positive staining and an increase in the TUNEL staining of colonic epithelial cells in AOM/DSS-treated mice by ergosterol peroxide for both prevention and therapy. Conclusion Our data suggest that ergosterol peroxide suppresses the proliferation of CRC cell lines and effectively inhibits colitis-associated colon cancer in AOM/DSS-treated mice. Ergosterol peroxide down-regulated β-catenin signaling, which exerted anti-proliferative and pro-apoptotic activities in CRC cells. These properties of ergosterol peroxide advocate its use as a supplement in colon cancer chemoprevention. [ABSTRACT FROM AUTHOR]

• Cardiac arrhythmias, atrial filtration and ventricular tachycardia, mainly caused by the autonomic nervous system. • Conventional strategies have been overcome using parasympathetic and sympathetic stimulation. • Therapeutic modalities associated with VNS, tragus stimulation, RDN, BAT and CSD may be promising. • Heart rate variability, skin sympathetic nerve activity using microneurography, and alternans are a few autonomic tone evaluation techniques. The pathophysiology of atrial fibrillation and ventricular tachycardia that result in cardiac arrhythmias is related to the sustained complicated mechanisms of the autonomic nervous system. Atrial fibrillation is when the heart beats irregularly, and ventricular arrhythmias are rapid and inconsistent heart rhythms, which involves many factors including the autonomic nervous system. It's a complex topic that requires careful exploration. Cultivation of speculative knowledge on atrial fibrillation; the irregular rhythm of the heart and ventricular arrhythmias; rapid oscillating waves resulting from mistakenly inconsistent P waves, and the inclusion of an autonomic nervous system is an inconceivable approach toward clinical intricacies. Autonomic modulation, therefore, acquires new expansions and conceptions of appealing therapeutic intelligence to prevent cardiac arrhythmia. Notably, autonomic modulation uses the neural tissue's flexibility to cause remodeling and, hence, provide therapeutic effects. In addition, autonomic modulation techniques included stimulation of the vagus nerve and tragus, renal denervation, cardiac sympathetic denervation, and baroreceptor activation treatment. Strong preclinical evidence and early human studies support the annihilation of cardiac arrhythmias by sympathetic and parasympathetic systems to transmigrate the cardiac myocytes and myocardium as efficient determinants at the cellular and physiological levels. However, the goal of this study is to draw attention to these promising early pre-clinical and clinical arrhythmia treatment options that use autonomic modulation as a therapeutic modality to conquer the troublesome process of irregular heart movements. Additionally, we provide a summary of the numerous techniques for measuring autonomic tone such as heart rate oscillations and its association with cutaneous sympathetic nerve activity appear to be substitute indicators and predictors of the outcome of treatment. [ABSTRACT FROM AUTHOR]

Epilepsy is a neurological disease affecting people of all ages worldwide. Side effects of antiepileptic drugs and their association with oxidative stress stimulate the search for new drugs, which would be more affordable with fewer adverse effects. Accordingly, the aim of the present work is to evaluate the anticonvulsant effect of anacardic acid (AA), a natural compound extracted from cashew liquid ( Anacardium occidentalis ), in murine models, as well as its antioxidant actions in Saccharomyces cerevisiae . AA (>90% purity) was tested, in vivo , in male Swiss mice (25–30 g) with four convulsive models, (1) pentylenetetrazole, (2) pilocarpine, (3) electroshock, and (4) kainic acid, at doses of 25, 50, and 100 mg/kg, body weight (B.W.) Additionally, the effective dose, toxic dose, and protective index studies were also performed. Results revealed that AA exhibits anticonvulsive effects in models 1, 3, and 4, with a mean effective dose (ED 50 ) of 39.64 (model 1) >100 mg/kg, B.W. (model 2), and 38.36 (model 3); furthermore, AA displays a protection index of 1.49 (model 1), <0.6 (model 2, and 1.54 (model 3). In addition, AA showed antioxidant activities in S. cerevisiae mutated for superoxide dismutases (SOD). In conclusion, these results show that AA exhibits significant anticonvulsant and antioxidant activities and may be used as a promising natural product for the treatment of epilepsy. [ABSTRACT FROM AUTHOR]

Omeprazole (OME) is a proton pump inhibitor used for the treatment of various gastric and intestinal disease; however, studies on its effects on the genetic materials are still restricted. The present study aimed to evaluate possible toxicogenic effects of OME in Allium cepa meristems with the application of cytogenetic biomarkers for DNA damage, mutagenic, toxic and cytotoxic effects. Additionally, retinol palmitate (RP) and ascorbic acid (AA) were also co-treated with OME to evaluate possible modulatory effects of OME-induced cytogenetic damages. OME was tested at 10, 20 and 40 μg/mL, while RP and AA at 55 μg/mL and 352.2 μg/mL, respectively. Copper sulphate (0.6 μg/mL) and dechlorinated water were used as positive control and negative control, respectively. The results suggest that OME induced genotoxicity and mutagenicity in A. cepa at all tested concentrations. It was noted that cotreatment of OME with the antioxidant vitamins RP and/or AA significantly (p < 0.05) inhibited and/or modulated all toxicogenic damages induced by OME. These observations demonstrate their antigenotoxic, antimutagenic, antitoxic and anticitotoxic effects in A. cepa . This study indicates that application of antioxidants may be useful tools to overcome OME-induced toxic effects. [ABSTRACT FROM AUTHOR]

Citrinin (CIT) is a mycotoxin which causes contamination in the food and is associated with different toxic effects. A web search on CIT has been conducted covering the timespan since 1946. The accumulated data indicate that CIT is produced by several fungal strains belonging to Penicillium, Aspergillus and Monascus genera, and is usually found together with another nephrotoxic mycotoxin, ochratoxin A. Although, it is evident that CIT exposure can exert toxic effects on the heart, liver, kidney, as well as reproductive system, the mechanism of CIT-induced toxicity remains largely elusive. It is still controversial what are the genotoxic and mutagenic effects of CIT. Until now, its toxic effect has been linked to the CIT-mediated oxidative stress and mitochondrial dysfunction in biological systems. However, the toxicity strongly depends on its concentration, route, frequency and time of exposure, as well as from the used test systems. Besides the toxic effects, CIT is also reported to possess a broad spectrum of bioactivities, including antibacterial, antifungal, and potential anticancer and neuro-protective effects in vitro. This systematic review presents the current state of CIT research with emphasis on its bioactivity profile. [ABSTRACT FROM AUTHOR]

• [6]-Gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone] is a phenolic substance with several pharmacological properties. • [6]-Gingerol showed antitumoral effects in primary cells of Sarcoma 180 as well as in peripheral blood lymphocytes of mice. • [6]-Gingerol induced cytogenetic changes in S-180 cells, biomarkers of genotoxicity, mutagenicity, apoptosis and necrosis. • [6]-Gingerol may be an antitumoral agent with mechanisms associated with reducing genetic instability inducing apoptosis. [6]-Gingerol [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone] is a phenolic substance reported for several ethnopharmacological usage by virtue of its antioxidant, antiemetic, anti-inflammatory and anticancer properties. This study assessed the antitumoral effects of [6]-Gingerol in primary cells of Sarcoma 180 as well as in peripheral blood lymphocytes of mice. The effect of [6]-Gingerol was assessed by applying cytogenetic biomarkers as indicative of genotoxicity, mutagenicity and apoptosis. Ascitic liquid cells were treated with [6]-Gingerol at concentrations of 21.33, 42.66 and 85.33 μM and subjected to the cytotoxicity assays using Trypan blue test and the comet assay, as well as the cytokinesis-block micronucleus assay. Doxorubicin (6 μM) and hydrogen peroxide (85.33 μM) were used as positive controls. [6]-Gingerol, especially at concentrations of 42.66 and 85.33 μM, showed notable cytotoxicity in Sarcoma 180 cells by reducing cell viability and cell division rates via induction of apoptosis. Genotoxicity at the concentrations used was punctuated by the increase in the index and frequency of DNA damage in tested groups. [6]-Gingerol, at all concentrations tested, did not induce significant aneugenic and/or clastogenic effects. It did, however, induced other nuclear abnormalities, such as nucleoplasmic bridges, nuclear buds and apoptosis. The genotoxic effects observed in the cotreatment with H 2 O 2 (challenge assay) employing neoplastic and healthy cells, indicated that [6]-Gingerol may induce oxidative stress. Observations suggest that [6]-Gingerol may be a candidate for pharmaceutical antitumoral formulations due to its cytotoxicity and to mechanisms associated with genetic instability generated by nuclear alterations especially by apoptosis. [ABSTRACT FROM AUTHOR]