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Pomegranate (Punica granatum L.) has a rich historical background in traditional medicine and is currently the subject of scientific exploration due to its potential health benefits. In this review, the biological characteristics of pomegranate, with a specific focus on the diverse phytochemicals found in its various parts were investigated. Additionally, the medicinal and therapeutic properties associated with these phytochemicals were explored. Pomegranates are abundant in bioactive compounds, including flavonoids, flavones, flavonols, anthocyanidins, ellagic acid, anthocyanins, ellagitannins, and punicic acid. These compounds are associated with various potential health benefits based on the laboratory data. Chromatography and mass spectrometry are used to identify these phytochemicals. Traditional medicinal uses of pomegranate span a broad spectrum, from treating ailments like diarrhoea to combating parasites, underscoring its historical significance. Furthermore, modern scientific research sheds light on the therapeutic properties of pomegranate, including its roles as an antioxidant, an anticancer agent, an anti-inflammatory substance, and a supporter of cardiovascular health. Notably, pomegranate's potential in mitigating conditions, such as Alzheimer's disease is also attractive. In summary, exploring phytochemicals in pomegranate underscores its value as a natural source of diverse therapeutic compounds with applications in medicine and health. However, future clinical trials are necessary to validate these potential benefits. [ABSTRACT FROM AUTHOR]

Prion diseases are 100% fatal infectious neurodegenerative diseases affecting the brains of humans and other mammals. The disease is caused by the formation and replication of prions, composed exclusively of the misfolded prion protein (PrPSc). We invented and developed the protein misfolding cyclic amplification (PMCA) technology for in vitro prion replication, which allow us to replicate the infectious agent and it is commonly used for ultra-sensitive prion detection in biological fluids, tissues and environmental samples. In this article, we studied whether PMCA can be used to screen for chemical compounds that block prion replication. A small set of compounds previously shown to have anti-prion activity in various systems, mostly using cells infected with murine prions, was evaluated for their ability to prevent the replication of prions. Studies were conducted simultaneously with prions derived from 4 species, including human, cattle, cervid and mouse. Our results show that only one of these compounds (methylene blue) was able to completely inhibit prion replication in all species. Estimation of the IC50 for methylene blue inhibition of human prions causing variant Creutzfeldt-Jakob disease (vCJD) was 7.7 μM. Finally, we showed that PMCA can be used for structure-activity relationship studies of anti-prion compounds. Interestingly, some of the less efficient prion inhibitors altered the replication of prions in some species and not others, suggesting that PMCA is useful for studying the differential selectivity of potential drugs. [ABSTRACT FROM AUTHOR]

Biodegradable aliphatic polyester formulations as carriers for topical drug delivery show the potential to encapsulate structurally different therapeutic compounds. Poly(octamethylene suberate) (POS) nanoparticles (POS-NPs) were used as a matrix to encapsulate four therapeutic molecules used to treat skin disorders: caffeine (CF), quercetin (QR), hydrocortisone (HC), and adapalene (AD). Hydrophobicity and chemical structure of bioactive compounds (BCs) influenced the physicochemical stability of drug-loaded nanoparticles. The particle size of drug-loaded nanoparticles was between 254.9 nm for the CF-POS-NP and 1291.3 for QR-POS-NP. Particles had a negative charge from −27.6 mV (QR) to −49.2 mV (HC). Drug loading content for all BC-POS-NPs varies between 36.11 ± 1.48% (CF-POS-NP) and 66.66 ± 4.87% (AD-POS-NP), and their entrapment efficiency is relatively high (28.30 ± 1.81% and 99.95 ± 0.04%, respectively). Calorimetric analysis showed the appearance of polymorphism for AD- and HC-loaded systems and the drug's complete solubilisation into all nanoparticle formulations. FTIR and NMR spectra showed apparent drug incorporation into the polymer matrix of NPs. The encapsulation of BCs enhanced the antioxidative effect. The prepared POS nanoparticles' cytotoxicity was studied using two dermal cell lines, keratinocyte (HaCaT) cells and fibroblasts (HDFn). The nanoparticle cytotoxic effect was more substantial on HaCaT cell lines. A reconstructed human epidermis (RHE) was successfully used to investigate the penetration of polymeric NPs. Based on permeation and histology studies, HC-POS-NPs and CF-POS-NPs were shown not to be suitable for dermal applications with the explored drug concentrations. AD presents a high permeation rate and no toxic impact on RHE. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a neuroinflammatory disease with limited therapeutic effects, eventually developing into handicap. Seeking novel therapeutic strategies for MS is timely important. Active autophagy/mitophagy could mediate neurodegeneration, while its roles in MS remain controversial. To elucidate the exact roles of autophagy/mitophagy and reveal its in-depth regulatory mechanisms, we conduct a systematic literature study and analyze the factors that might be responsible for divergent results obtained. The dynamic change levels of autophagy/mitophagy appear to be a determining factor for final neuron fate during MS pathology. Excessive neuronal autophagy/mitophagy contributes to neurodegeneration after disease onset at the active MS phase. Reactive nitrogen species (RNS) serve as key regulators for redox-related modifications and participate in autophagy/mitophagy modulation in MS. Nitric oxide (•NO) and peroxynitrite (ONOO−), two representative RNS, could nitrate or nitrosate Drp1/parkin/PINK1 pathway, activating excessive mitophagy and aggravating neuronal injury. Targeting RNS-mediated excessive autophagy/mitophagy could be a promising strategy for developing novel anti-MS drugs. In this review, we highlight the important roles of RNS-mediated autophagy/mitophagy in neuronal injury and review the potential therapeutic compounds with the bioactivities of inhibiting RNS-mediated autophagy/mitophagy activation and attenuating MS progression. Overall, we conclude that reactive nitrogen species could be promising therapeutic targets to regulate autophagy/mitophagy for multiple sclerosis treatment. [Display omitted] • Autophagy/mitophagy mediate neurodegeneration in multiple sclerosis (MS). • Reactive nitrogen species (RNS) serve as key regulators for autophagy/mitophagy via redox-related modifications in MS. • Targeting RNS in the regulation of autophagy/mitophagy could be a promising strategy for developing novel drugs for MS. • The potential MS therapeutic compounds for targeting peroxynitrite (ONOO−) have been summarized in this review. [ABSTRACT FROM AUTHOR]

There is increasing evidence that malignant tumors are initiated and maintained by a sub-population of tumor cells that have similar biological properties to normal adult stem cells. This very small population of Cancer Stem Cells (CSC) comprises tumor initiating cells responsible for cancer recurrence, drug resistance and metastasis. Conventional treatments such as chemotherapy, radiotherapy and surgery, in addition to being potentially toxic and non-specific, may paradoxically increase the population, spread and survival of CSCs. Next-generation sequencing and omics technologies are increasing our understanding of the pathways and factors involved in the development of CSCs, and can help to discover new therapeutic targets against CSCs. In addition, recent advances in nanomedicine have provided hope for the development of optimal specific therapies to eradicate CSCs. Moreover, the use of artificial intelligence and nano-informatics can elucidate new drug targets, and help to design drugs and nanoparticles (NPs) to deal with CSCs. In this review, we first summarize the properties of CSCs and describe the signaling pathways and molecular characteristics responsible for the emergence and survival of CSCs. Also, the location of CSCs within the tumor and the effect of host factors on the creation and maintenance of CSCs are discussed. Newly discovered molecular targets involved in cancer stemness and some novel therapeutic compounds to combat CSCs are highlighted. The optimum properties of anti-CSC NPs, including blood circulation and stability, tumor accumulation and penetration, cellular internalization, drug release, endosomal escape, and aptamers designed for specific targeting of CSCs are covered. Finally, some recent smart NPs designed for therapeutic and theranostic purposes to overcome CSCs are discussed. [Display omitted] [ABSTRACT FROM AUTHOR]

The liver is a critical system for metabolism in human beings, which plays an essential role in an abundance of physiological processes and is vulnerable to endogenous or exogenous injuries. After the damage to the liver, a type of aberrant wound healing response known as liver fibrosis may happen, which can result in an excessive accumulation of extracellular matrix (ECM) and then cause cirrhosis or hepatocellular carcinoma (HCC), seriously endangering human health and causing a great economic burden. However, few effective anti-fibrotic medications are clinically available to treat liver fibrosis. The most efficient approach to liver fibrosis prevention and treatment currently is to eliminate its causes, but this approach's efficiency is too slow, or some causes cannot be fully eliminated, which causes liver fibrosis to worsen. In cases of advanced fibrosis, the only available treatment is liver transplantation. Therefore, new treatments or therapeutic agents need to be explored to stop the further development of early liver fibrosis or to reverse the fibrosis process to achieve liver fibrosis resolution. Understanding the mechanisms that lead to the development of liver fibrosis is necessary to find new therapeutic targets and drugs. The complex process of liver fibrosis is regulated by a variety of cells and cytokines, among which hepatic stellate cells (HSCs) are the essential cells, and their continued activation will lead to further progression of liver fibrosis. It has been found that inhibiting HSC activation, or inducing apoptosis, and inactivating activated hepatic stellate cells (aHSCs) can reverse fibrosis and thus achieve liver fibrosis regression. Hence, this review will concentrate on how HSCs become activated during liver fibrosis, including intercellular interactions and related signaling pathways, as well as targeting HSCs or liver fibrosis signaling pathways to achieve the resolution of liver fibrosis. Finally, new therapeutic compounds targeting liver fibrosis are summarized to provide more options for the therapy of liver fibrosis. [ABSTRACT FROM AUTHOR]

Hypersecretion of gastric acid damages the stomach lining, causing the formation of peptic ulcers. Mucilage from medicinal plants offers a relaxing and soothing effect to the endodermal lining of the gut and has antacid properties, which can protect the mucosal lining from gastric acidity. This is the first report aimed to evaluate the physicochemical characteristics, acid-neutralizing, and cytotoxicity properties of traditionally used aqueous mucilage from Asparagus exuvialis and Sesamum capense. The physicochemical properties were determined by biochemical methods. Acid neutralizing and buffering capacities were determined by titration methods. Normal mouse embryonic fibroblast cells were used for cytotoxicity evaluation by MTT assay. The physicochemical characterization confirmed the presence of carbohydrates, alkaloids, saponins, proteins, tannins, flavonoids, and glycosides. Sesamum capense mucilage exhibited the most potent artificial gastric juice neutralizing capacity pH of 4.62±0.01, 8.0±0.00 acid neutralization capacity per gram of acid, and 30 minutes duration of acid neutralization. The aqueous mucilage from S. capense did not cause any significant cytotoxicity to 3T3 cell lines showing an IC50 value of 91.5 ± 0.06 μg mL-1, confirming the safe nature of the mucilage. These findings revealed that S. capense has the potential to neutralize gastric acid responsible for ulceration and can be safely consumed.

The SH-SY5Y cell line is a simple and inexpensive in vitro experimental model for studying Parkinson disease (PD). This experimental model is a useful tool for elucidating pathophysiological mechanisms of PD and in the development of new pharmacological therapies. In this review, we aim to summarize current protocols for SH-SY5Y cell culturing and differentiation and PD experimental designs derived from the SH-SY5Y cell line. The most efficient protocol for differentiation of the SH-SY5Y cell line into dopaminergic neurons seems to be the addition of retinoic acid to the growth medium, followed by 12-O-tetradecanoylphorbol-13-acetate (TPA) addition in a low concentration of fetal bovine serum. PD pathological changes, such as neuronal apoptosis and the intraneuronal alpha-synuclein aggregation, can be reproduced in the SH-SY5Y cell line either by the use of neurotoxic agents [such as rotenone, 1-methyl-4-phenylpyridinium (MPP+), 6-hydroxydopamine] or by genetic modification (transfection of the alpha-synuclein wild-type or mutant gene, genetic manipulation of other genes involved in PD). In addition, compounds with a potential neuroprotective role may be tested on neurotoxicity-induced SHSY5Y models. The cell line can also be used for testing PD pathophysiological mechanisms such as the prion-like neuronal transmission of alpha-synuclein or the microbiota influence in PD. In conclusion, the use of the SH-SY5Y cell line represents a basic but consistent first step in experiments related to PD, but which must be followed by the confirmation of the results through more complex in vitro and in vivo experimental models. [ABSTRACT FROM AUTHOR]

Hypersecretion of gastric acid damages the stomach lining, causing the formation of peptic ulcers. Mucilage from medicinal plants offers a relaxing and soothing effect to the endodermal lining of the gut and has antacid properties, which can protect the mucosal lining from gastric acidity. This is the first report aimed to evaluate the physicochemical characteristics, acid-neutralizing, and cytotoxicity properties of traditionally used aqueous mucilage from Asparagus exuvialis and Sesamum capense. The physicochemical properties were determined by biochemical methods. Acid neutralizing and buffering capacities were determined by titration methods. Normal mouse embryonic fibroblast cells were used for cytotoxicity evaluation by MTT assay. The physicochemical characterization confirmed the presence of carbohydrates, alkaloids, saponins, proteins, tannins, flavonoids, and glycosides. Sesamum capense mucilage exhibited the most potent artificial gastric juice neutralizing capacity pH of 4.62±0.01, 8.0±0.00 acid neutralization capacity per gram of acid, and 30 minutes duration of acid neutralization. The aqueous mucilage from S. capense did not cause any significant cytotoxicity to 3T3 cell lines showing an IC50 value of 91.5 ± 0.06 μg mL-1, confirming the safe nature of the mucilage. These findings revealed that S. capense has the potential to neutralize gastric acid responsible for ulceration and can be safely consumed. [ABSTRACT FROM AUTHOR]

Mushrooms have proven to be a valuable source of diverse bioactive compounds that can hold substantial potential for preventing and managing various diseases. This research focused on examining the numerous bioactive compounds found in Pisolithus albus ( P. albus ) (Cooke & Massee) Priest mushrooms, particularly those obtained from ethyl acetate and dichloromethane extracts. Polyphenols, flavonoids, tannins, and alkaloids were also evaluated by chemical analysis. Furthermore, the bioactive compounds of extracts were identified using thin-layer chromatography (TLC), gas chromatography-mass spectrometry (GC-MS), and Liquid Chromatography Mass Spectrometry (LC-MS). Evident diversity in the phytochemical composition was noted between the ethyl acetate (EtOAc) and dichloromethane (DCM) extracts, identifying through spectrometric methods interesting bioactive compounds that exhibit potential utility across medicinal and agricultural domains, including their application as herbicides. This study not only shed light on the bioactive constituents within the two types of extracts but also underscored the advantageous compounds inherent in P. albus mushrooms.

Seaweeds are classified as Chlorophyta, Rhodophyta, and Phaeophyta. They constitute a number of the most significant repositories of new therapeutic compounds for human use. Seaweed has been proven to possess diverse bioactive properties, which include anticancer properties. The present review focuses on colorectal cancer, which is a primary cause of cancer-related mortality in humans. In addition, it discusses various compounds derived from a series of seaweeds that have been shown to eradicate or slow the progression of cancer. Therapeutic compounds extracted from seaweed have shown activity against colorectal cancer. Furthermore, the mechanisms through which these compounds can induce apoptosis in vitro and in vivo were reviewed. This review emphasizes the potential utility of seaweeds as anticancer agents through the consideration of the capability of compounds present in seaweeds to fight against colorectal cancer.

Abstract COVID-19 disease with a high rate of contagious and highly nonspecific symptoms, is an infectious disease caused by a newly discovered coronavirus. Most people who fall sick with COVID-19 will experience mild to moderate symptoms such as respiratory symptoms, cough, dyspnea, fever, and viral pneumonia and recover without any special cure. However, some others need special and emergency treatment to get rid of this widespread disease. Till now, there are numbers of proposed novel compounds as well as standards therapeutics agent existed for other conditions seems to have efficacy against the 2019-nCoV. Some which are being tested for MERS-CoV and SARS-CoV are validated that could be also efficient against this new coronavirus. However, there are currently no effective specific antivirals or drug combinations introduced for 2019-nCoV specifically that be supported by high-level evidence. The main purpose of this paper is to review typical and ongoing treatments for coronavirus disease including home remedies, herbal medicine, chemical drugs, plasma therapy, and also vaccinies. In this regards, famous herbal medicines and common chemical drugs which are routinely to be prescribed for patients are introduced. Moreover, a section is assigned to the drug interactions and some outdated drugs which have been proved to be inefficient. We hope that this work could pave the way for researchers to develop faster and more reliable methods for earlier treatment of patients and rescue more people. Graphical abstract

Rice (Oryza sativa L.) is the staple food of the majority of the population, particularly in Asia and Africa. Enriching rice with nutritional and therapeutic contents can improve its benefits for patients with lifestyle disorders. This study aimed to profile the phytochemical contents of the therapeutically known traditional rice Mappillai Samba against white rice CBMAS 14065 using non-targeted gas chromatography–mass spectrometry (GC-MS/MS). An analysis of the data using a mass spectrometry–data independent analysis (MS-DIAL) and MetaboAnalyst identified 113 metabolites belonging to 21 different classes of metabolites. A partial least square-discriminant analysis (PLS-DA) revealed 43 variable importance in projection (VIP) metabolites. This study identified therapeutically important metabolites, including phenylpropanoids, phytosterols, flavonoids, and polyamines, in the grains of Mappillai Samba. Three significant metabolic pathways, viz., phenylpropanoid biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis, and steroid biosynthesis, were responsible for the grain metabolome variation between CBMAS 14065 and Mappillai Samba. Overall, the results of this study unravelled the biochemical complexity of Mappillai Samba, paving the way for the genetic mapping of the therapeutic compound accumulation in rice and the development of similar therapeutic rice varieties through molecular breeding. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common cancer and deadly disease worldwide. Despite substantial advances made in the treatment of gastric cancer, existing therapies still encounter bottlenecks. Chemotherapy, for instance, could lead to serious side effects, high drug resistance and treatment failure. Phytochemical-derived compounds from plants offer novel strategies as potent drug molecules in cancer therapy. Given the low toxicity and higher tolerance rate of naturally occurring compounds, the present study evaluated the effects of syringic acid on cytotoxicity, oxidative stress, mitochondrial membrane potential, apoptosis, and inflammatory responses in gastric cancer cell line (AGS). AGS cells were treated with various concentrations (5–40 μg/mL) of syringic acid for 24 h, after which cytotoxicity was analyzed. Reactive Oxygen Species (ROS), antioxidant enzyme activities, mitochondrial membrane potential (MMP, Δψm), cell morphologies, the expression of apoptotic markers and protein expression patterns were also investigated. Results indicated that syringic acid-treated cells developed anti-cancer activities by losing MMP, cell viability, and enhancing intracellular ROS. Syringic acid selectively developed apoptosis in a dose-dependent manner via enhanced regulation of caspase-3, caspase-9 and Poly ADP-ribose Polymerase (PARP) whereas decreasing the expression levels of p53 and BCL-2. Syringic acid also lowered activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) whereas Thio Barbituric Acid Reactive Substances (TBARS) increased. Syringic acid suppressed gastric cancer cell proliferation, inflammation, and induced apoptosis by upregulating mTOR via AKT signaling pathway. The study suggests syringic acid may constitute a promising chemotherapeutic candidate for gastric cancer treatment. Our study is the first report on the anti-cancer effects of syringic acid against gastric cancer cells via apoptosis, inhibition of inflammation, and the suppression of the mTOR/AKT signaling pathway.

The world is severely facing the pandemic COVID-19 Corona viral disease. Many people died and more than five millions are fighting for their life in the world. The viral candidate has become to play villain role for the real life due to non-availability of medication. In this background attempt is made to present a review report on the probable and effective compounds to inhibit the viral activity of SARS-CoV-2. The works on the use of plant-based and synthetic compounds to suppress the viral functioning is summarized. Wherever possible, the mechanism of action with the results and effect of dose are described. Compounds showing exemplary abilities to inhibit viral functioning including those associated to SARS, Ebola, MERS, etc., were highlighted. The mechanism of action and inhibitory ability of the candidate compounds have been highlighted so that the choice to undertake further research to identify effective anti-viral drugs to treat COVID-19 decease. This review will definitely make researchers to raise the hope for use or modification of existing medications to treat this epidemic COVID-19 disease. [ABSTRACT FROM AUTHOR]

Encapsulation technologies can be used to preserve therapeutic and bioactive compounds from harsh conditions (e.g., light, moisture, and oxygen) and biological destruction (enzymes, metabolism, and phagocytosis). Encapsulation involves the incorporation of the active moieties into a shell structure (e.g., protein, polysaccharide or lipid-based material). These techniques can improve the physicochemical properties of the encapsulated compounds, provide sustained release to specific organs, "cover up" undesirable properties, and improve their solubility, dispersion, and bioavailability. Different techniques have been applied to encapsulate drug compounds, including emulsification, inclusion complexation, nanoparticulate systems (solid lipid nanoparticles and nanostructured lipid carriers), liposome entrapment, nanoprecipitation, freeze drying, spray drying, etc. However, high temperatures or toxic solvents are used in some of these techniques such as spray drying, and liposome entrapment can degrade the bioactive compounds or reduce their functionality. Electrohydrodynamic spraying (electrospraying) is a versatile tool for liquid atomization by means of electrical forces. This technique is simple and easily controllable without any harsh conditions and could be a promising alternative method to encapsulate sensitive compounds. By optimizing the process variables e.g., properties of polymer solutions (type, viscosity, conductivity), solvent type, process parameters (applied voltage between the needle tip and the collector surface, applied flow rate, distance between the needle tip and the collector, ambient temperature, and relative humidity) this technique can be effectively used for micro- and nanoencapsulation of drug compounds. This article reviews the effects of electrospraying parameters in production of monodisperse particles with well-controlled shapes and high encapsulation efficiency. It also, summarizes the latest reports of encapsulation of therapeutic compounds, and critically discusses the limitations and future perspectives of this technique. Unlabelled Image [ABSTRACT FROM AUTHOR]

COVID-19 disease with a high rate of contagious and highly nonspecific symptoms, is an infectious disease caused by a newly discovered coronavirus. Most people who fall sick with COVID-19 will experience mild to moderate symptoms such as respiratory symptoms, cough, dyspnea, fever, and viral pneumonia and recover without any special cure. However, some others need special and emergency treatment to get rid of this widespread disease. Till now, there are numbers of proposed novel compounds as well as standards therapeutics agent existed for other conditions seems to have efficacy against the 2019-nCoV. Some which are being tested for MERS-CoV and SARS-CoV are validated that could be also efficient against this new coronavirus. However, there are currently no effective specific antivirals or drug combinations introduced for 2019-nCoV specifically that be supported by high-level evidence. The main purpose of this paper is to review typical and ongoing treatments for coronavirus disease including home remedies, herbal medicine, chemical drugs, plasma therapy, and also vaccinies. In this regards, famous herbal medicines and common chemical drugs which are routinely to be prescribed for patients are introduced. Moreover, a section is assigned to the drug interactions and some outdated drugs which have been proved to be inefficient. We hope that this work could pave the way for researchers to develop faster and more reliable methods for earlier treatment of patients and rescue more people. [ABSTRACT FROM AUTHOR]

Rice (Oryza sativa L.) is the staple food of the majority of the population, particularly in Asia and Africa. Enriching rice with nutritional and therapeutic contents can improve its benefits for patients with lifestyle disorders. This study aimed to profile the phytochemical contents of the therapeutically known traditional rice Mappillai Samba against white rice CBMAS 14065 using non-targeted gas chromatography–mass spectrometry (GC-MS/MS). An analysis of the data using a mass spectrometry–data independent analysis (MS-DIAL) and MetaboAnalyst identified 113 metabolites belonging to 21 different classes of metabolites. A partial least square-discriminant analysis (PLS-DA) revealed 43 variable importance in projection (VIP) metabolites. This study identified therapeutically important metabolites, including phenylpropanoids, phytosterols, flavonoids, and polyamines, in the grains of Mappillai Samba. Three significant metabolic pathways, viz., phenylpropanoid biosynthesis, ubiquinone and other terpenoid-quinone biosynthesis, and steroid biosynthesis, were responsible for the grain metabolome variation between CBMAS 14065 and Mappillai Samba. Overall, the results of this study unravelled the biochemical complexity of Mappillai Samba, paving the way for the genetic mapping of the therapeutic compound accumulation in rice and the development of similar therapeutic rice varieties through molecular breeding.

Abstract Background Natural products of animals, plants and microbes are potential source of important chemical compounds, with diverse applications including therapeutics. Endophytic bacteria that are especially associated with medicinal plants presents a reservoir of therapeutic compounds. Fagonia indica has been recently investigated by numerous researchers because of its striking therapeutic potential especially in cancer. It is also reported that endophytes play a vital role in the biosynthesis of various metabolites; therefore we believe that endophytes associated with F. indica are of crucial importance in this regard. The present study aims successful isolation, molecular identification of endophytic bacteria and their screening for bioactive metabolites quantification and in vitro pharmacological activities. Methods 16S rRNA gene sequencing was used for the identification of isolated endophytic bacteria. Methanolic extracts were evaluated for total phenolic contents (TPC), total flavonoids contents (TFC), DPPH free radical scavenging activity, reducing power and total anti-oxidant assays were performed. And also screened for antibacterial and antifungal activities by disc diffusion method and their MIC were calculated by broth dilution method using microplate reader. Further, standard protocols were followed for antileishmanial activity and protein kinase inhibition. Analysis and statistics were performed using SPSS, Table curve and Origin 8.5 for graphs. Results Bacterial strains belonging to various genera (Bacillus, Enterobacter, Pantoea, Erwinia and Stenotrophomonas) were isolated and identified. Total phenolic contents and total flavonoids contents varies among all the bacterial extracts respectively in which Bacillus subtilis showed high phenolic contents 243 µg/mg of gallic acid equivalents (GAE) and Stenotrophomonas maltophilia showed high flavonoids contents 15.9 µg/mg quercitin equivalents (QA), total antioxidant capacity (TAC) 37.6 µg/mg of extract, reducing power (RP) 206 µg/mg of extract and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity with 98.7 μg/mL IC50 value. Although all the extracts tested were active to inhibit growth of selected pathogenic microbes (bacteria and fungi), but significant antibacterial activity was observed against Klebsiella pneumonia and B. subtilis. An Enterobacter cloaca was active against Leishmania tropica with IC50 value of 1.4 µg/mg extracts. B. subtilis and Bacillus tequilensis correspondingly exhibit significant protein kinase inhibition of 47 ± 0.72 and 42 ± 1.21 mm bald zones, indicating anti-infective and antitumor potential. Conclusions Our findings revealed that crude extracts of selected endophytic bacteria from F. indica possess excellent biological activities indicating their potential as an important source of antibiotics (antifungal, antibacterial) compounds.

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are autosomal dominant neuromuscular diseases caused by microsatellite expansions and belong to the family of RNA-dominant disorders. Availability of cellular models in which the DM mutation is expressed within its natural context is essential to facilitate efforts to identify new therapeutic compounds. Here, we generated immortalized DM1 and DM2 human muscle cell lines that display nuclear RNA aggregates of expanded repeats, a hallmark of myotonic dystrophy. Selected clones of DM1 and DM2 immortalized myoblasts behave as parental primary myoblasts with a reduced fusion capacity of immortalized DM1 myoblasts when compared with control and DM2 cells. Alternative splicing defects were observed in differentiated DM1 muscle cell lines, but not in DM2 lines. Splicing alterations did not result from differentiation delay because similar changes were found in immortalized DM1 transdifferentiated fibroblasts in which myogenic differentiation has been forced by overexpression of MYOD1. As a proof-of-concept, we show that antisense approaches alleviate disease-associated defects, and an RNA-seq analysis confirmed that the vast majority of mis-spliced events in immortalized DM1 muscle cells were affected by antisense treatment, with half of them significantly rescued in treated DM1 cells. Immortalized DM1 muscle cell lines displaying characteristic disease-associated molecular features such as nuclear RNA aggregates and splicing defects can be used as robust readouts for the screening of therapeutic compounds. Therefore, immortalized DM1 and DM2 muscle cell lines represent new models and tools to investigate molecular pathophysiological mechanisms and evaluate the in vitro effects of compounds on RNA toxicity associated with myotonic dystrophy mutations.

The conversion of the normal cellular prion protein (PrPC) to the misfolded pathogenic scrapie prion protein (PrPSc) is the biochemical hallmark of prion replication. So far, various chemical compounds that inhibit this conformational conversion have been identified. Here, we report the novel anti-prion activity of SGI-1027 and its meta/meta analogue (M/M), previously known only as potent inhibitors of DNA methyltransferases (DNMTs). These compounds effectively decreased the level of PrPSc in cultured cells with permanent prion infection, without affecting PrPC at the transcriptional or translational levels. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a PrP aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded PrP aggregates, implying that binding of these compounds hinders the PrP conversion process. A series of binding and docking analyses demonstrated that both SGI-1027 and M/M directly interacted with the C-terminal globular domain of PrPC, but only SGI-1027 bound to a specific region of PrPC with high affinity, which correlates with its potent anti-prion efficacy. Therefore, we report SGI-1027 and related compounds as a novel class of potential anti-prion agents that preferentially function through direct interaction with PrPC. A novel activity of DNMT inhibitor SGI-1027 was discovered to suppress the pathogenic process of prion. The direct binding of SGI-1027 to prion protein with a normal conformation was discovered to suppress the formation of misfolded prion proteins. Image 1 [ABSTRACT FROM AUTHOR]

The title compound, C20H16N2O, (I), has been unwittingly obtained from the slow evaporation of a saturated solution of commercial benserazide hydrochloride [benserazide, (II), being one of the principal therapeutic compounds used for the management of Parkinson's disease, mostly used in combination with levodopa]. The molecule of (I) is composed of two planar 4-methylquinoline aromatic moieties [maximum deviations of 0.0104 (18) and 0.016 (2) Å], almost perpendicular to each other [dihedral angle = 89.5 (2)°], bridged by an O atom. The supramolecular organization consists of a π-bonded chain, resulting from the stacking of molecules related by inversion centres located along direction [111].

Seafoods and seaweeds represent some of the most important reservoirs of new therapeutic compounds for humans. Seaweed has been shown to have several biological activities, including anticancer activity. This review focuses on colorectal and breast cancers, which are major causes of cancer-related mortality in men and women. It also describes various compounds extracted from a range of seaweeds that have been shown to eradicate or slow the progression of cancer. Fucoidan extracted from the brown algae Fucus spp. has shown activity against both colorectal and breast cancers. Furthermore, we review the mechanisms through which these compounds can induce apoptosis in vitro and in vivo. By considering the ability of compounds present in seaweeds to act against colorectal and breast cancers, this review highlights the potential use of seaweeds as anticancer agents.

Background: Natural products of animals, plants and microbes are potential source of important chemical com- pounds, with diverse applications including therapeutics. Endophytic bacteria that are especially associated with medicinal plants presents a reservoir of therapeutic compounds. Fagonia indica has been recently investigated by numerous researchers because of its striking therapeutic potential especially in cancer. It is also reported that endophytes play a vital role in the biosynthesis of various metabolites; therefore we believe that endophytes associated with F. indica are of crucial importance in this regard. The present study aims successful isolation, molecular identification of endophytic bacteria and their screening for bioactive metabolites quantification and in vitro pharmacological activities. Methods: 16S rRNA gene sequencing was used for the identification of isolated endophytic bacteria. Methanolic extracts were evaluated for total phenolic contents (TPC), total flavonoids contents (TFC), DPPH free radical scavenging activity, reducing power and total anti-oxidant assays were performed. And also screened for antibacterial and antifungal activities by disc diffusion method and their MIC were calculated by broth dilution method using microplate reader. Further, standard protocols were followed for antileishmanial activity and protein kinase inhibition. Analysis and statistics were performed using SPSS, Table curve and Origin 8.5 for graphs. Results: Bacterial strains belonging to various genera (Bacillus, Enterobacter, Pantoea, Erwinia and Stenotrophomonas) were isolated and identified. Total phenolic contents and total flavonoids contents varies among all the bacterial extracts respectively in which Bacillus subtilis showed high phenolic contents 243 µg/mg of gallic acid equivalents (GAE) and Stenotrophomonas maltophilia showed high flavonoids contents 15.9 µg/mg quercitin equivalents (QA), total antioxidant capacity (TAC) 37.6 µg/mg of extract, reducing power (RP) 206 µg/mg of extract and 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity with 98.7 μg/mL IC50 value. Although all the extracts tested were active to inhibit growth of selected pathogenic microbes (bacteria and fungi), but significant antibacterial activity was observed against Klebsiella pneumonia and B. subtilis. An Enterobacter cloaca was active against Leishmania tropica with IC50 value of 1.4 µg/mg extracts. B. subtilis and Bacillus tequilensis correspondingly exhibit significant protein kinase inhibition of 47 ± 0.72 and 42 ± 1.21 mm bald zones, indicating anti-infective and antitumor potential. Conclusions: Our findings revealed that crude extracts of selected endophytic bacteria from F. indica possess excellent biological activities indicating their potential as an important source of antibiotics (antifungal, antibacterial) compounds. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. It is caused by a loss of dopaminergic neurons in the substantia nigra pars compacta, leading to a decrease in dopamine levels in the striatum and thus producing movement impairment. Major physiological causes of neurodegeneration in PD are oxidative stress (OS) and mitochondrial dysfunction; these pathophysiological changes can be caused by both genetic and environmental factors. Although most PD cases are sporadic, it has been shown that 5–10% of them are familial forms caused by mutations in certain genes. One of these genes is the DJ-1 oncogene, which is involved in an early-onset recessive PD form. Currently, PD is an incurable disease for which existing therapies are not sufficiently effective to counteract or delay the progression of the disease. Therefore, the discovery of alternative drugs for the treatment of PD is essential. In this study we used a Drosophila PD model to identify candidate compounds with therapeutic potential for this disease. These flies carry a loss-of-function mutation in the DJ-1β gene, the Drosophila ortholog of human DJ-1, and show locomotor defects reflected by a reduced climbing ability. A pilot modifier chemical screen was performed, and several candidate compounds were identified based on their ability to improve locomotor activity of PD model flies. We demonstrated that some of them were also able to reduce OS levels in these flies. To validate the compounds identified in the Drosophila screen, a human cell PD model was generated by knocking down DJ-1 function in SH-SY5Y neuroblastoma cells. Our results showed that some of the compounds were also able to increase the viability of the DJ-1- deficient cells subjected to OS, thus supporting the use of Drosophila for PD drug discovery. Interestingly, some of them have been previously proposed as alternative therapies for PD or tested in clinical trials and others are first suggested in this study as potential drugs for the treatment of this disease. [ABSTRACT FROM AUTHOR]

Fish protein hydrolysate was prepared from muscle of small red scorpionfish ( Scorpaena notata) by treatment with a protease from the fungus Penicillium digitatum. Protein hydrolysate was found to strongly inhibit the angiotensin I converting enzyme and exhibited high antioxidative activity through 1,1-diphenyl-2-picrylhydrazyl free radical scavenging assay. After ultrafiltration, peptides were isolated by a two-step procedure: size exclusion chromatography on a Toyopearl HW-40 followed by reversed-phase high-performance liquid chromatography with a high purification yield of 2.5 mg of peptide per gram of initial protein. Two major peptides were then identified by nanoscale liquid chromatography coupled to tandem mass spectrometry (nano-LC-MS/MS), corresponding to the following sequences: Leu-Val-Thr-Gly-Asp-Asp-Lys-Thr-Asn-Leu-Lys (1,204.665 Da) and Asp-Thr-Gly-Ser-Asp-Lys-Lys-Gln-Leu (992.511 Da). These peptides, mainly composed of hydrophilic amino acids, showed high antioxidative and angiotensin I converting enzyme inhibitory activities. These data suggest that the two novel peptides isolated from the muscle hydrolysate of small red scorpionfish can be a beneficial ingredient for functional foods or pharmaceuticals against hypertension and oxidative stress. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in the substantia nigra pars compacta . Current therapies are only symptomatic and are not able to stop or delay its progression. In order to search for new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds that are able to improve locomotor ability in DJ-1β mutant flies (a Drosophila model of familial PD) and reduce oxidative stress (OS)-induced lethality in DJ-1 -deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor . Our results showed that VIN is able to suppress PD-related phenotypes in both Drosophila and human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OS-induced lethality by decreasing apoptosis, increased mitochondrial viability, and reduced OS levels in DJ-1 -deficient human cells. In addition, our results show that VIN might be exerting its beneficial role, at least partially, by the inhibition of voltage-gated sodium channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD and that VIN represents a potential therapeutic treatment for the disease.

Seafoods and seaweeds represent some of the most important reservoirs of new therapeutic compounds for humans. Seaweed has been shown to have several biological activities, including anticancer activity. This review focuses on colorectal and breast cancers, which are major causes of cancer-related mortality in men and women. It also describes various compounds extracted from a range of seaweeds that have been shown to eradicate or slow the progression of cancer. Fucoidan extracted from the brown algae Fucus spp. has shown activity against both colorectal and breast cancers. Furthermore, we review the mechanisms through which these compounds can induce apoptosis in vitro and in vivo. By considering the ability of compounds present in seaweeds to act against colorectal and breast cancers, this review highlights the potential use of seaweeds as anticancer agents. [ABSTRACT FROM AUTHOR]

Abstract: Prevention of obesity and therapeutic weight loss interventions have provided only limited long term success. Therefore there is an urgent need to develop novel pharmacological treatment strategies, which target mechanisms underlying positive energy balance, excessive fat accumulation and adverse fat distribution. Adipokines may have potential for future pharmacological treatment strategies of obesity and metabolic diseases, because they are involved in the regulation of appetite and satiety, energy expenditure, endothelial function, blood pressure, insulin sensitivity, adipogenesis, fat distribution and insulin secretion and others. There are important road blocks on the way from an adipokine candidate to the clinical use a therapeutic compound. Such road blocks include an incomplete understanding of the mechanism of action, resistance to a specific adipokine, side effects of the adipokine and others. This review focuses on the potential of selected adipokines as therapeutic tools or targets and discusses important road blocks, which currently prevent their clinical use. [Copyright &y& Elsevier]

Abstract: Aims: This study was conducted to suggest the role of WNT/β-catenin pathway in the anti-adipogenic effect of platycodin D, a natural compound found in Platycodon grandiflorum. Main methods: Gene knockdown experiments using small interfering RNA (siRNA) transfection were conducted to elucidate crucial role of β-catenin in the anti-adipogenic effects of platycodin D. Real-Time PCR and Western blot were used to analyze the expression levels of mRNAs and proteins in the WNT/β-catenin pathway. Key findings: During the adipocyte differentiation of 3 T3-L1 cells, members of the WNT/β-catenin pathway were normally down-regulated, whereas platycodin D significantly reinstated the WNT/β-catenin pathway. The mRNA and protein expressions of disheveled (DVL) 2, which stabilize β-catenin, were increased by platycodin D treatment, but the protein level of AXIN, which induces the degradation of β-catenin, was decreased in platycodin D-treated cells. The nuclear level of β-catenin was normally down-regulated during adipogenesis, but platycodin D treatment led to the accumulation of β-catenin in the nucleus which resulted in the up-regulation of its target genes, cyclin D (CCND) 1 and peroxisome proliferator-activated receptor gamma (PPAR)γ. The anti-adipogenic effects of platycodin D were significantly attenuated in β-catenin siRNA-transfected cells compared with those of control siRNA-transfected cells. β-catenin siRNA transfection significantly recovered the levels of PPARγ, CCAAT/enhancer binding protein (C/EBP)α and fatty acid binding protein (FABP)4 as well as intracellular lipid droplet formation, all of which were reduced by platycodin D treatment. Significance: WNT/β-catenin pathway can be used as a therapeutic target of natural compounds for the regulation of adipogenesis. [Copyright &y& Elsevier]

Abstract: Studies with neutralizing anti-interleukin (IL)-12 antibodies and IL-12-deficient mice have suggested that endogenous IL-12 plays an important role in the normal host defense against infection by a variety of intracellular microorganisms. However, IL-12 also appears to play a central role in the pathogenesis of autoimmune diseases such as multiple sclerosis or rheumatic arthritis. Therefore, it is crucial to understand how IL-12 is produced and its production is regulated at the molecular level. IL-12 production is differentially regulated through multiple pathways, which can be classified as follows: nuclear factor-kappaB (NF-κB) and other transcription factors, p38 mitogen-activated protein (MAP) kinase, cyclic adenosine monophosphate (cyclic AMP)-modulating molecules, cell membrane ion channels and pumps, nitric oxide (NO), and receptors. In this review we describe the regulatory mechanisms of IL-12 production in immune cells and also some agents to control IL-12 production for the treatment of immune-related diseases. [Copyright &y& Elsevier]

Campylobacter enteritis is the most common cause of foodborne bacterial diarrhea in humans. Although various studies have been performed to clarify the pathomechanism in Campylobacter infection, the mechanism itself and bacterial virulence factors are yet not completely understood. The purpose of this chapter is to (i) give an overview on Campylobacter-induced diarrheal mechanisms, (ii) illustrate underlying barrier defects, (iii) explain the role of the mucosal immune response and (iv) weigh preventive and therapeutic approaches. Our present knowledge of pathogenetic and diarrheal mechanisms of Campylobacter jejuni is explained in the first part of this chapter. In the second part, the molecular basis for the Campylobacter-induced barrier dysfunction is compared with that of other species in the Campylobacter genus. The bacteria are capable of overcoming the intestinal epithelial barrier. The invasion into the intestinal mucosa is the initial step of the infection, followed by a second step, the epithelial barrier impairment. The extent of the impairment depends on various factors, including tight junction dysregulation and epithelial apoptosis. The disturbed intestinal epithelium leads to a loss of water and solutes, the leak flux type of diarrhea, and facilitates the uptake of harmful antigens, the leaky gut phenomenon. The barrier dysfunction is accompanied by increased pro-inflammatory cytokine secretion, which is partially responsible for the dysfunction. Moreover, cytokines also mediate ion channel dysregulation (e.g., epithelial sodium channel, ENaC), leading to another diarrheal mechanism, which is sodium malabsorption. Future perspectives of Campylobacter research are the clarification of molecular pathomechanisms and the characterization of therapeutic and preventive compounds to combat and prevent Campylobacter infections.

The conversion of the normal cellular prion protein (PrP C ) to the misfolded pathogenic scrapie prion protein (PrP Sc ) is the biochemical hallmark of prion replication. So far, various chemical compounds that inhibit this conformational conversion have been identified. Here, we report the novel anti-prion activity of SGI-1027 and its meta/meta analogue (M/M), previously known only as potent inhibitors of DNA methyltransferases (DNMTs). These compounds effectively decreased the level of PrP Sc in cultured cells with permanent prion infection, without affecting PrP C at the transcriptional or translational levels. Furthermore, SGI-1027 prevented effective prion infection of the cells. In a PrP aggregation assay, both SGI-1027 and M/M blocked the formation of misfolded PrP aggregates, implying that binding of these compounds hinders the PrP conversion process. A series of binding and docking analyses demonstrated that both SGI-1027 and M/M directly interacted with the C-terminal globular domain of PrP C , but only SGI-1027 bound to a specific region of PrP C with high affinity, which correlates with its potent anti-prion efficacy. Therefore, we report SGI-1027 and related compounds as a novel class of potential anti-prion agents that preferentially function through direct interaction with PrP C ., (© 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.)