In Silico and In vitro Analysis of Phenolic Acids for Identification of Potential DHFR Inhibitors as Antimicrobial and Anticancer Agents.

BACKGROUND: DHFR is an indispensable enzyme required for the survival of almost all prokaryotic and eukaryotic cells, making it an attractive molecular target for drug design. OBJECTIVE: In this study, a combined in silico and in vitro approach was utilized to screen out potential anticancer and antimicrobial agents by using DHFR PDB ID 2W9S (for antimicrobial) and 1U72 (for anticancer). METHODS: Computational work was performed using Maestro Schrodinger Glide software. The DHFR inhibitory activity of the selected compounds was assessed using the DHFR test kit (CS0340-Sigma- Aldrich). RESULTS: Exhaustive analysis of in silico results revealed that some natural phenolic acids have a good docking score when compared to standards, i.e., trimethoprim and methotrexate, and have astonishing interactions with crucial amino acid residues available in the binding pocket of DHFR, such as Phe 92, Asp 27, Ser 49, Asn 18, and Tyr 98. In particular, digallic acid and chlorogenic acid have amazing interactions with docking scores of -9.9 kcal/mol and -9.6 kcal/mol, respectively, for the targeted protein 2W9S. Docking scores of -10.3 kcal/mol and -10.2 kcal/mol, respectively, for targeted protein 1U72. The best hits were then tested in vitro to evaluate the DHFR inhibitory activity of the compounds. DHFR inhibition activity results are in correlation with molecular docking results. CONCLUSION: In silico and in vitro results confirmed the good binding and inhibitory activity of some phenolic acids to the modeled target proteins. Among all the studied natural phenolic acids, chlorogenic acid, digallic acid, and rosmarinic acid appeared to be the most potential leads for future chemical alteration. This study can provide significant speculative guidance for the design and development of potent DHFR inhibitors in the future by using these compounds as leads.

In silico design of novel bioactive molecules to treat breast cancer with chlorogenic acid derivatives: a computational and SAR approach.

Introduction: Cancer is a vast group of diseases comprising abnormal cells that multiply and grow uncontrollably, and it is one of the top causes of death globally. Several types of cancers are diagnosed, but the incidence of breast cancer, especially in postmenopausal women, is increasing daily. Chemotherapeutic agents used to treat cancer are generally associated with severe side effects on host cells, which has led to a search for safe and potential alternatives. Therefore, the present research has been conducted to find novel bioactive molecules to treat breast cancer with chlorogenic acid and its derivatives. Chlorogenic acid was selected because of its known activity in the field. Methods: Several chlorogenic acid derivatives were subjected to computational studies such as molecular docking, determination of absorption, distribution, metabolism, and excretion (ADME), druglikeness, toxicity, and prediction of activity spectra for substances (PASS) to develop a potential inhibitor of breast cancer. The Protein Data Bank (PDB) IDs used for docking purposes were 7KCD, 3ERT, 6CHZ, 3HB5, and 1U72. Result: Exhaustive analysis of results has been conducted by considering various parameters, like docking score, binding energy, types of interaction with important amino acid residues in the binding pocket, ADME, and toxicity data of compounds. Among all the selected derivatives, CgE18, CgE11, CgAm13, CgE16, and CgE9 have astonishing interactions, excellent binding energy, and better stability in the active site of targeted proteins. The docking scores of compound CgE18 were -11.63 kcal/mol, -14.15 kcal/mol, and -12.90 kcal/mol against breast cancer PDB IDs 7KCD, 3HB5, and 1U72, respectively. The docking scores of compound CgE11 were -10.77 kcal/mol and -9.11 kcal/mol against breast cancer PDB IDs 3ERT and 6CHZ, respectively, whereas the docking scores of epirubicin hydrochloride were -3.85 kcal/mol, -6.4 kcal/mol, -8.76 kcal/mol, and -10.5 kcal/mol against PDB IDs 7KCD, 3ERT, 6CHZ, and 3HB5. The docking scores of 5-fluorouracil were found to be -5.25 kcal/mol, -3.43 kcal/mol, -3.73 kcal/mol, and -5.29 kcal/mol against PDB IDs 7KCD, 3ERT, 6CHZ, and 3HB5, which indicates the designed compounds have a better docking score than some standard drugs. Conclusion: Taking into account the results of molecular docking, drug likeness analysis, absorption, distribution, metabolism, excretion, and toxicity (ADMET) evaluation, and PASS, it can be concluded that chlorogenic acid derivatives hold promise as potent inhibitors for the treatment of breast cancer.

Neuroprotection against Aluminum Chloride-Induced Hippocampus Damage in Albino Wistar Rats by Leucophyllum frutescens (Berl.) I.M. Johnst. Leaf Extracts: A Detailed Insight into Phytochemical Analysis and Antioxidant and Enzyme Inhibition Assays.

BACKGROUND: A previously unstudied medicinal plant, Leucophyllum frutescens (Berland.) I.M. Johnst. (Scrophulariaceae) was investigated to evaluate its potential in preventing and treating neurodegenerative diseases, including Alzheimer's disease. METHODS: Methanolic leaf extract (MELE) and its fractions (HELE, CHLE, and BULE) were evaluated for their polyphenolic content and antioxidant activity by five different methods, including in vitro enzyme inhibition assays, which are clinically linked to neurodegenerative diseases. The potentially active n-butanol fraction (BULE) was further evaluated for its neuroprotective effects using an albino rat animal model and phytoconstituents profiling using Liquid chromatography with tandem mass spectrometry (LC-MS/MS), and in silico molecular docking by Maestro® Schrödinger. RESULTS: The n-butanol fraction (BULE) in the hydroalcoholic leaf extract exhibited the highest total phenolic content (230.435 ± 1.575 mg gallic acid equivalent gm-1± SD). The chloroform leaf extract exhibited the highest total flavonoid content (293.343 ± 3.756 mg quercetin equivalent gm-1± SD) as well as the highest antioxidant content, which was equivalent to Trolox, with five assay methods. Similarly, the chloroform and n-butanol fractions from the hydroalcoholic leaf extract significantly inhibited human acetylcholinesterase and butyrylcholinesterase with their IC50 values of 12.14 ± 0.85 and 129.73 ± 1.14 µg∙mL-1, respectively. The in vivo study revealed that BULE exhibited a significant neuroprotective effect at doses of 200 and 400 mg/kg/day in an aluminum chloride-induced neurodegenerative albino rat model. The LC-MS/MS analysis of BULE tentatively confirmed the presence of biologically active secondary metabolites, such as theobromine, propyl gallate, quercetin-3-O-glucoside, myricetin-3-acetylrhamnoside, isoquercitrin-6'-O-malonate, diosmetin-7-O-glucuronide-3'-O-pentose, pinoresinol diglucoside, asarinin, eridictoyl, epigallocatechin, methyl gallate derivative, and eudesmin. The results from the computational molecular docking of the identified secondary metabolites revealed that diosmetin-7-O-glucuronide-3'-O-pentose had the highest binding affinity to human butyrylcholinesterase, while isoquercetin-6'-O-malonate had the highest to human acetylcholinesterase, and pinoresinol diglucoside to human salivary alpha-amylase. CONCLUSIONS: The present study concluded a need for further exploration into this medicinal plant, including the isolation of the bioactive compounds responsible for its neuroprotective effects.

Antioxidant Activity and Chemical Composition of Geranium Oil and Its Synergistic Potential against Pneumococci with Various Antibiotic Combinations.

The essential oil of Pelargonium graveolens L. is valuable for its therapeutic benefits, so this study aimed to determine the synergistic effect of the combination of the essential oil of this plant with antibiotics instead of the extracts prepared with various solvents. In addition, the second goal of this study was to determine whether the essential oil combined with various antibiotics increased the overall killing activity in mouse macrophage cells with the aim of introducing an immunotherapeutic approach to the infection treatments used today. Herein, the volatile profile of Geranium oil (G.O) was analyzed using GC/MS. The current study sought to assess the synergistic characteristics of several antibiotic combinations using G.O against pneumococci, as well as the oil's antioxidant and antimicrobial activities. The major components of the oil were citronellol, geraniol, and isomenthone. In the combinations of G.O and antibiotics, the synergism of the Streptococcus pneumoniae to antibiotics advanced. When the time-kill data were evaluated, G.O + antibiotic combinations quickly diminished the viable cell count of S. pneumoniae from the 6th h. In this study, the combined use of existing antibiotics used in infection treatments with G.O could improve antibiotic effectiveness and thus prevent bacteria from developing antibiotic resistance.

Polyphenols: Natural Preservatives with Promising Applications in Food, Cosmetics and Pharma Industries; Problems and Toxicity Associated with Synthetic Preservatives; Impact of Misleading Advertisements; Recent Trends in Preservation and Legislation.

The global market of food, cosmetics, and pharmaceutical products requires continuous tracking of harmful ingredients and microbial contamination for the sake of the safety of both products and consumers as these products greatly dominate the consumer's health, directly or indirectly. The existence, survival, and growth of microorganisms in the product may lead to physicochemical degradation or spoilage and may infect the consumer at another end. It has become a challenge for industries to produce a product that is safe, self-stable, and has high nutritional value, as many factors such as physical, chemical, enzymatic, or microbial activities are responsible for causing spoilage to the product within the due course of time. Thus, preservatives are added to retain the virtue of the product to ensure its safety for the consumer. Nowadays, the use of synthetic/artificial preservatives has become common and has not been widely accepted by consumers as they are aware of the fact that exposure to preservatives can lead to adverse effects on health, which is a major area of concern for researchers. Naturally occurring phenolic compounds appear to be extensively used as bio-preservatives to prolong the shelf life of the finished product. Based on the convincing shreds of evidence reported in the literature, it is suggested that phenolic compounds and their derivatives have massive potential to be investigated for the development of new moieties and are proven to be promising drug molecules. The objective of this article is to provide an overview of the significant role of phenolic compounds and their derivatives in the preservation of perishable products from microbial attack due to their exclusive antioxidant and free radical scavenging properties and the problems associated with the use of synthetic preservatives in pharmaceutical products. This article also analyzes the recent trends in preservation along with technical norms that regulate the food, cosmetic, and pharmaceutical products in the developing countries.

Phytochemical Profiles, Antioxidant, Cytotoxic, and Anti-Inflammatory Activities of Traditional Medicinal Plants: Centaurea pichleri subsp. pichleri, Conyza canadensis, and Jasminum fruticans.

Centaurea pichleri subsp. pichleri, Conyza canadensis, and Jasminum fruticans are traditionally used plants grown in Turkey. Methanol extracts were obtained from these plants and pharmacological activity studies and phytochemical analyses were carried out. To evaluate the phytochemical composition, spectrophotometric and chromatographic techniques were used. The extracts were evaluated for antioxidant activity by DPPH●, ABTS●+ radical scavenging, and FRAP assays. The cytotoxic effects of the extracts were investigated on DU145 prostate cancer and A549 lung cancer cell lines. The anti-inflammatory effects of extracts were investigated on the NO amount, TNF-α, IFN-γ, and PGE 2 levels in lipopolysaccharide-stimulated Raw 264.7 cells. The richest extract in terms of phenolic compounds (98.19 ± 1.64 mgGAE/gextract) and total flavonoids (21.85 ± 0.64 mgCA/gextract) was identified as C. pichleri subsp. pichleri methanol extract. According to antioxidant activity determinations, the C. pichleri subsp. pichleri extract was found to be the most active extract. Finally, the C. pichleri subsp. pichleri methanol extract was revealed to be the most effective inhibitor of viability in the cytotoxic activity investigation, and the extract with the best anti-inflammatory action. The findings point to C. pichleri subsp. pichleri as a promising source of bioactive compounds in the transition from natural sources to industrial uses, such as new medications, cosmeceuticals, and nutraceuticals.

The Phytochemical Profile and Biological Activity of Malva neglecta Wallr. in Surgically Induced Endometriosis Model in Rats.

Leaves and aerial parts of Malva neglecta Wallr. have been traditionally used in Anatolia for the treatment of pain, inflammation, hemorrhoids, renal stones, constipation, and infertility. This study investigated the effects of M. neglecta leaves in a rat endometriosis model. The dried plant material was extracted with n-hexane, ethyl acetate, and methanol, successively. Experimental endometriosis was surgically induced in six-week-old female, non-pregnant, Wistar albino rats by autotransplant of endometrial tissue to the abdominal wall. After twenty-eight days, rats were evaluated for a second laparotomy. Endometrial foci areas were assessed, and intraabdominal adhesions were scored. Rats were divided into five groups as control, n-hexane, ethyl acetate, methanol, and aqueous extracts, as well as reference. At the end of the treatment, all rats were sacrificed and endometriotic foci areas and intraabdominal adhesions were re-evaluated and compared with the previous findings. Moreover, peritoneal fluid was collected to detect tumor necrosis factor- α (TNF-α), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6) levels, and cDNA synthesis, and a quantitative real-time polymerase chain reaction (PCR) test was done. The phytochemical content of the most active extract was determined using High-Performance Liquid Chromatography (HPLC). Both endometrial volume and adhesion score decreased significantly in the group treated with methanol extract. In addition, significant decreases were observed in TNF-α, VEGF, and IL-6 levels in animals administered methanol extract. HPLC results showed that the activity caused by the methanol extract of M. neglecta was due to the polyphenols. Taken together, these novel findings indicate that M. neglecta may be a promising alternative for the treatment of endometriosis.

Immunomodulatory and anti-inflammatory therapeutic potential of gingerols and their nanoformulations.

Ginger (Zingiber officinale Roscoe), a member of the Zingiberaceae family, is one of the most popular spices worldwide, known since ancient times, and used both as a spice and a medicinal plant. The phenolic compounds found in ginger are predominantly gingerols, shogaols, and paradols. Gingerols are the major phenolic compounds found in fresh ginger and contain mainly 6-gingerol as well as 4-, 5-, 8-, 10-, and 12-gingerols. Gingerols possess a wide array of bioactivities, such as antioxidant and anticancer, among others. Regarding the different array of biological activities and published data on the mechanisms underlying its action, the complex interaction between three key events, including inflammation, oxidative stress, and immunity, appears to contribute to a plethora of pharmacological activities of this compound. Among these, the immunomodulatory properties of these compounds, which attract attention due to their effects on the immune system, have been the focus of many studies. Gingerols can alleviate inflammation given their ability to inhibit the activation of protein kinase B (Akt) and nuclear factor kappa B (NF-κB) signaling pathways, causing a decrease in proinflammatory and an increase in anti-inflammatory cytokines. However, given their low bioavailability, it is necessary to develop new and more effective strategies for treatment with gingerols. In order to overcome this problem, recent studies have addressed new drug delivery systems containing gingerols. In this review, the immunomodulatory activities of gingerol and its underlying mechanisms of action combined with the contributions of developed nanodrug delivery systems to this activity will be examined.

In silico investigation and potential therapeutic approaches of natural products for COVID-19: Computer-aided drug design perspective.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a substantial number of deaths around the world, making it a serious and pressing public health hazard. Phytochemicals could thus provide a rich source of potent and safer anti-SARS-CoV-2 drugs. The absence of approved treatments or vaccinations continues to be an issue, forcing the creation of new medicines. Computer-aided drug design has helped to speed up the drug research and development process by decreasing costs and time. Natural compounds like terpenoids, alkaloids, polyphenols, and flavonoid derivatives have a perfect impact against viral replication and facilitate future studies in novel drug discovery. This would be more effective if collaboration took place between governments, researchers, clinicians, and traditional medicine practitioners' safe and effective therapeutic research. Through a computational approach, this study aims to contribute to the development of effective treatment methods by examining the mechanisms relating to the binding and subsequent inhibition of SARS-CoV-2 ribonucleic acid (RNA)-dependent RNA polymerase (RdRp). The in silico method has also been employed to determine the most effective drug among the mentioned compound and their aquatic, nonaquatic, and pharmacokinetics' data have been analyzed. The highest binding energy has been reported -11.4 kcal/mol against SARS-CoV-2 main protease (7MBG) in L05. Besides, all the ligands are non-carcinogenic, excluding L04, and have good water solubility and no AMES toxicity. The discovery of preclinical drug candidate molecules and the structural elucidation of pharmacological therapeutic targets have expedited both structure-based and ligand-based drug design. This review article will assist physicians and researchers in realizing the enormous potential of computer-aided drug design in the design and discovery of therapeutic molecules, and hence in the treatment of deadly diseases.

Regulation of DAPK1 by Natural Products: An Important Target in Treatment of Stroke.

Stroke is a sudden neurological disorder that occurs due to impaired blood flow to an area of the brain. Stroke can be caused by the blockage or rupture of a blood vessel in the brain, called ischemic stroke and hemorrhagic stroke, respectively. Stroke is more common in men than women. Atrial fibrillation, hypertension, kidney disease, high cholesterol and lipids, genetic predisposition, inactivity, poor nutrition, diabetes mellitus, family history and smoking are factors that increase the risk of stroke. Restoring blood flow by repositioning blocked arteries using thrombolytic agents or endovascular therapy are the most effective treatments for stroke. However, restoring circulation after thrombolysis can cause fatal edema or intracranial hemorrhage, and worsen brain damage in a process known as ischemia-reperfusion injury. Therefore, there is a pressing need to find and develop more effective treatments for stroke. In the past, the first choice of treatment was based on natural compounds. Natural compounds are able to reduce the symptoms and reduce various diseases including stroke that attract the attention of the pharmaceutical industry. Nowadays, as a result of the numerous studies carried out in the field of herbal medicine, many useful and valuable effects of plants have been identified. The death-associated protein kinase (DAPK) family is one of the vital families of serine/threonine kinases involved in the regulation of some biological functions in human cells. DAPK1 is the most studied kinase within the DAPKs family as it is involved in neuronal and recovery processes. Dysregulation of DAPK1 in the brain is involved in the developing neurological diseases such as stroke. Natural products can function in a variety of ways, including reducing cerebral edema, reducing brain endothelial cell death, and inhibiting TNFα and interleukin-1ß (IL-1ß) through regulating the DAPK1 signal against stroke. Due to the role of DAPK1 in neurological disorders, the aim of this article was to investigate the role of DAPK1 in stroke and its modulation by natural compounds.

A comprehensive and current review on the role of flavonoids in lung cancer-Experimental and theoretical approaches.

BACKGROUND: It is well-known that flavonoids, which can be easily obtained from many fruits and vegetables are widely preferred in the treatment of some important diseases. Some researchers noted that these chemical compounds exhibit high inhibition effect against various cancer types. Many experimental studies proving this ability of the flavonoids with high antioxidant activity are available in the literature. PUROPOSE: The main aim of this review is to summarize comprehensively anticancer properties of flavonoids against the lung cancer in the light of experimental studies and well-known theory and electronic structure principles. In this review article, more detailed and current information about the using of flavonoids in the treatment of lung cancer is presented considering theoretical and experimental approaches. STUDY DESIGN: In addition to experimental studies including the anticancer effects of flavonoids, we emphasized the requirement of the well-known electronic structure principle in the development of anticancer drugs. For this aim, Conceptual Density Functional Theory should be considered as a powerful tool. Searching the databases including ScienceDirect, PubMed and Web of Science, the suitable reference papers for this project were selected. METHODS: Theoretical tools like DFT and Molecular Docking provides important clues about anticancer behavior and drug properties of molecular systems. Conceptual Density Functional Theory and CDFT based electronic structure principles and rules like Hard and Soft Acid-Base Principle (HSAB), Maximum Hardness Principle, Minimum Polarizability, Minimum Electrophilicity Principles and Maximum Composite Hardness Rule introduced by one of the authors of this review are so useful to predict the mechanisms and powers of chemical systems. Especially, it cannot be ignored the success of HSAB Principle in the explanations and highlighting of biochemical interactions. RESULTS: Both theoretical analysis and experimental studies confirmed that flavonoids have higher inhibition effect against lung cancer. In addition to many superior properties like anticancer activity, antimicrobial activity, antioxidant activity, antidiabetic effect of flavonoids, their toxicities are also explained with the help of published popular papers. Action modes of the mentioned compounds are given in detail. CONCLUSION: The review includes detailed information about the mentioned electronic structure principles and rules and their applications in the cancer research. In addition, the epidemiology and types of lung cancer anticancer activity of flavonoids in lung cancer are explained in details.

Withdrawal Notice: A New Perspective on the Treatment of Alzheimer's disease and Sleep Deprivation-related Consequences: Curcumin

The article has been withdrawn at the request of the author of the journal Current Pharmaceutical Biotechnology.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused. Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Phytochemical profile, antioxidant, antiproliferative, and enzyme inhibition-docking analyses of Salvia ekimiana Celep & Dogan.

Salvia ekimiana Celep & Dogan is an endemic species of Turkey. To our knowledge, the number of studies on biological activities and phytochemical profiling of this plant is quite limited. Therefore, this study aimed to analyze its activities and phytochemical content in detail. The qualitative-quantitative compositions were determined via spectrophotometric and chromatographic (LC-MS/MS and HPLC) techniques. 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH•) and 2,2'-Azino-bis 3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+) radical scavenging and ascorbate-iron (III)-catalyzed phospholipid peroxidation experiments were performed to measure antioxidant capacity. Hyaluronidase, collagenase, and elastase enzyme inhibition tests were determined in vitro using a spectrophotometer. Antiproliferative activity was evaluated in human lung cancer (A549) and human breast cancer (MCF7) cells. The murine fibroblast (L929) cell line was used as a normal control cell. While the subextract rich in phenolic compounds was n-butanol extract, rosmarinic acid was defined as the main secondary metabolite. The highest antioxidant activity observed for the n-butanol subextract included the following: DPPH• EC50: 0.08±0.00 mg/mL, TEAC/ABTS: 2.19±0.09 mmol/L Trolox, MDA EC50: 0.42±0.03 mg/mL. The methanolic extract, the ethyl acetate, and n-butanol subextracts displayed significant inhibitory activity on collagenase, while the other subextracts did not show any inhibitory activity on hyaluronidase and elastase. Due to strong interactions with their active sites, molecular docking showed luteolin 7-glucuronide, apigenin 7-glucuronide, and luteolin 5-glucoside had the highest binding affinity with target enzymes. The chloroform subextract showed significant cytotoxicity in all cell lines. These novel results revealed that S. ekimiana has strong antioxidant, collagenase enzyme inhibitory, and cytotoxic potential.

A Critical Analysis of Quercetin as the Attractive Target for the Treatment of Parkinson's Disease.

Parkinson's Disease (PD) is a multifaceted disorder with various factors suggested to play a synergistic pathophysiological role, such as oxidative stress, autophagy, pro-inflammatory events, and neurotransmitter abnormalities. While it is crucial to discover new treatments in addition to preventing PD, recent studies have focused on determining whether nutraceuticals will exert neuroprotective actions and pharmacological functions in PD. Quercetin, a flavonol-type flavonoid, is found in many fruits and vegetables and is recognised as a complementary therapy for PD. The neuroprotective effect of quercetin is directly associated with its antioxidant activity, in addition to stimulating cellular defence against oxidative stress. Other related mechanisms are activating Sirtuins (SIRT1) and inducing autophagy, in addition to induction of Nrf2-ARE and Paraoxonase 2 (PON2). Quercetin, whose neuroprotective activity has been demonstrated in many studies, unfortunately, has a disadvantage because of its poor water solubility, chemical instability, and low oral bioavailability. It has been reported that the disadvantages of quercetin have been eliminated with nanocarriers loaded with quercetin. The role of nanotechnology and nanodelivery systems in reducing oxidative stress during PD provides an indisputable advantage. Accordingly, the present review aims to shed light on quercetin's beneficial effects and underlying mechanisms in neuroprotection. In addition, the contribution of nanodelivery systems to the neuroprotective effect of quercetin is also discussed.

Targeting lactate metabolism and glycolytic pathways in the tumor microenvironment by natural products: A promising strategy in combating cancer.

Anticancer drugs are not purely effective because of their toxicity, side effects, high cost, inaccessibility, and associated resistance. On the other hand, cancer is a complex public health problem that could intelligently adopt different signaling pathways and alter the body's metabolism to escape from the immune system. One of the cancer strategies to metastasize is modifying pH in the tumor microenvironment, ranging between 6.5 and 6.9. As a powerful determiner, lactate is responsible for this acidosis. It is involved in immune stimulation, including innate and adaptive immunity, apoptotic-related factors (Bax/Bcl-2, caspase), and glycolysis pathways (e.g., GLUT-1, PKM2, PFK, HK2, MCT-1, and LDH). Lactate metabolism, in turn, is interconnected with several dysregulated signaling mediators, including PI3K/Akt/mTOR, AMPK, NF-κB, Nrf2, JAK/STAT, and HIF-1α. Because of lactate's emerging and critical role, targeting lactate production and its transporters is important for preventing and managing tumorigenesis. Hence, exploring and developing novel promising anticancer agents to minimize human cancers is urgent. Based on numerous studies, natural secondary metabolites as multi-target alternative compounds with health-promoting properties possess more high effectiveness and low side effects than conventional agents. Besides, the mechanism of multi-targeted natural sources is related to lactate production and cancer-associated cross-talked factors. This review focuses on targeting the lactate metabolism/transporters, and lactate-associated mediators, including glycolytic pathways. Besides, interconnected mediators to lactate metabolism are also targeted by natural products. Accordingly, plant-derived secondary metabolites are introduced as alternative therapies in combating cancer through modulating lactate metabolism and glycolytic pathways.

Plant-Derived Natural Compounds for the Treatment of Amyotrophic Lateral Sclerosis: An Update.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a motor neuron disease (MND) that typically causes death within 3-5 years after diagnosis. Regardless of the substantial scientific knowledge accrued more than a century ago, truly effective therapeutic strategies remain distant. Various conventional drugs are being used but are having several adverse effects. OBJECTIVE/AIM: The current study aims to thoroughly review plant-derived compounds with welldefined ALS activities and their structure-activity relationships. Moreover, the review also focuses on complex genetics, clinical trials, and the use of natural products that might decrypt the future and novel therapeutics in ALS. METHODS: The collection of data for the compilation of this review work was searched in PubMed Scopus, Google Scholar, and Science Direct. RESULTS: Results showed that phytochemicals like-Ginkgolides, Protopanaxatriol, Genistein, epigallocatechingallate, resveratrol, cassoside, and others possess Amyotrophic lateral sclerosis (ALS) activity by various mechanisms Conclusion: These plant-derived compounds may be considered as supplements for conventional (ALS). Moreover, further preclinical and clinical studies are required to understand the structureactivity relationships, metabolism, absorption, and mechanisms of plant-derived natural agents.

Assessment of Antioxidant Effect of Beta-Glucan on the Whole Blood Oxidative DNA Damage with the Comet Assay in Colorectal Cancer.

OBJECTIVE: The present study aims to evaluate the antioxidant effect of beta-glucan on oxidative DNA damage by comet assay. METHODS: A total of 19 adult females and males diagnosed with stage 3-4 colorectal cancer and a control group of 20 age-matched healthy subjects were enrolled in the study. Blood samples of the participants were analyzed using Comet Assay for the parameters of DNA damage. RESULTS: Significantly increased DNA damage was observed in patients versus the control group as indicated by greater values of tail moment, tail percent DNA and tail length. Following incubation with ß-glucan, a substantial reduction was found in the aforementioned parameters of DNA damage. Comet assay revealed significant levels of endogenous DNA damage in patients as shown by remarkable increases in the tail moment, the percentage of DNA in the tail and the tail length values, in comparison with the control group. Following treatment of fresh whole blood with ß-glucan incubation, DNA damages were significantly reduced, but lower values were observed after ß-glucan incubation in the patient group versus control group. CONCLUSION: ß-Glucan was found to reduce DNA damage substantially in colorectal cancer patients and show antimutagenic effects. Our results suggested that dietary ß-glucan intake might be important in the genesis of colorectal cancer tumors.

Effects of Natural Products on Neuromuscular Junction.

Neuromuscular junction (NMJ) disorders result from damage, malfunction or absence of one or more key proteins involved in neuromuscular transmission, comprising a wide range of disorders. The most common pathology is antibody-mediated or downregulation of ion channels or receptors, resulting in Lambert-Eaton myasthenic syndrome, myasthenia gravis, and acquired neuromyotonia (Isaac's syndrome), and rarely congenital myasthenic syndromes caused by mutations in NMJ proteins. A wide range of symptomatic treatments, immunomodulating therapies, or immunosuppressive drugs have been used to treat NMJ diseases. Future research must be directed at a better understanding of the pathogenesis of these diseases, and developing novel disease-specific treatments. Numerous secondary metabolites, especially alkaloids isolated from plants, have been used to treat NMJ diseases in traditional and clinical practices. An ethnopharmacological approach has provided leads for identifying new treatments for NMJ diseases. In this review, we performed a literature survey in Pubmed, Science Direct, and Google Scholar to gather information on drug discovery from plant sources for NMJ disease treatments. To date, most research has focused on the effects of herbal remedies on cholinesterase inhibitory and antioxidant activities. This review provides leads for identifying potential new drugs from plant sources for the treatment of NMJ diseases.

Appraisal of the antimicrobial and cytotoxic potentials of nanoparticles biosynthesized from the extracts of Pelargonium quercetorum Agnew.

Aim: The aim of this study is the synthesis of nanosilver particles (AgNPs) from Pelargonium quercetorum Agnew. (Geraniaceae) and evaluation of the antimicrobial and the cytotoxic potential of AgNPs. Methods: The synthesized AgNPs were evaluated for antimicrobial and anticancer efficacy using the minimum inhibition concentration method and MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium bromide) assay. Results: The AgNPs inhibited approximately 90% the growth of gram-positive Staphylococcus aureus and gram-negative Esherichia coli and yeast Candida albicans pathogens at a concentration of 500 µg/mL. The synthesized AgNPs showed excellent toxicity in MCF-7 cells, and specifically, pq70 AgNP inhibited the growth of MCF-7 cells by 52% at a concentration of 3.125 µg/mL. Conclusion: It was determined that the AgNPs, which had been synthesized from extracts that contained a high phenolic composition, were smaller in size, and showed high anticancer and antimicrobial properties.