Analysing potent biomarkers along phytochemicals for breast cancer therapy: an in silico approach.

PURPOSE: This research focused on the identification of herbal compounds as potential anti-cancer drugs, especially for breast cancer, that involved the recognition of Notch downstream targets NOTCH proteins (1-4) specifically expressed in breast tumours as biomarkers for prognosis, along with P53 tumour antigens, that were used as comparisons to check the sensitivity of the herbal bio-compounds. METHODS: After investigating phytochemical candidates, we employed an approach for computer-aided drug design and analysis to find strong breast cancer inhibitors. The present study utilized in silico analyses and protein docking techniques to characterize and rank selected bio-compounds for their efficiency in oncogenic inhibition for use in precise carcinomic cell growth control. RESULTS: Several of the identified phytocompounds found in herbs followed Lipinski's Rule of Five and could be further investigated as potential medicinal molecules. Based on the Vina score obtained after the docking process, the active compound Epigallocatechin gallate in green tea with NOTCH (1-4) and P53 proteins showed promising results for future drug repurposing. The stiffness and binding stability of green tea pharmacological complexes were further elucidated by the molecular dynamic simulations carried out for the highest scoring phytochemical ligand complex. CONCLUSION: The target-ligand complex of green tea active compound Epigallocatechin gallate with NOTCH (1-4) had the potential to become potent anti-breast cancer therapeutic candidates following further research involving wet-lab experiments.

Biochemical Perspectives on Natural Products in Wound Healing: Exploring Phytochemicals in Tissue Repair and Scar Prevention.

Wound healing is a critical process in tissue repair following injury, and traditional herbal therapies have long been utilized to facilitate this process. This review delves into the mechanistic understanding of the significant contribution of pharmacologically demonstrated natural products in wound healing. Natural products, often perceived as complex yet safely consumed compared to synthetic chemicals, play a crucial role in enhancing the wound-healing process. Drawing upon a comprehensive search strategy utilizing databases such as PubMed, Scopus, Web of Science, and Google Scholar, this review synthesizes evidence on the role of natural products in wound healing. While the exact pharmacological mechanisms of secondary metabolites in wound healing remain to be fully elucidated, compounds from alkaloids, phenols, terpenes, and other sources are explored here to delineate their specific roles in wound repair. Each phytochemical group exerts distinct actions in tissue repair, with some displaying multifaceted roles in various pathways, potentially enhancing their therapeutic value, supported by reported safety profiles. Additionally, these compounds exhibit promise in the prevention of keloids and scars. Their potential alongside economic feasibility may propel them towards pharmaceutical product development. Several isolated compounds, from natural sources, are undergoing investigation in clinical trials, with many reaching advanced stages.

Chinese herbal medicine for the treatment of cardiovascular diseases ─ Targeting cardiac ion channels.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality, imposing an increasing global health burden. Cardiac ion channels (voltage-gated NaV, CaV, KVs, and others) synergistically shape the cardiac action potential (AP) and control the heartbeat. Dysfunction of these channels, due to genetic mutations, transcriptional or post-translational modifications, may disturb the AP and lead to arrhythmia, a major risk for CVD patients. Although there are five classes of anti-arrhythmic drugs available, they can have varying levels of efficacies and side effects on patients, possibly due to the complex pathogenesis of arrhythmias. As an alternative treatment option, Chinese herbal remedies have shown promise in regulating cardiac ion channels and providing anti-arrhythmic effects. In this review, we first discuss the role of cardiac ion channels in maintaining normal heart function and the pathogenesis of CVD, then summarize the classification of Chinese herbal compounds, and elaborate detailed mechanisms of their efficacy in regulating cardiac ion channels and in alleviating arrhythmia and CVD. We also address current limitations and opportunities for developing new anti-CVD drugs based on Chinese herbal medicines.

Molecular Aspects and Therapeutic Implications of Herbal Compounds Targeting Different Types of Cancer.

Due to genetic changes in DNA (deoxyribonucleic acid) sequences, cancer continues to be the second most prevalent cause of death. The traditional target-directed approach, which is confronted with the importance of target function in healthy cells, is one of the most significant challenges in anticancer research. Another problem with cancer cells is that they experience various mutations, changes in gene duplication, and chromosomal abnormalities, all of which have a direct influence on the potency of anticancer drugs at different developmental stages. All of these factors combine to make cancer medication development difficult, with low clinical licensure success rates when compared to other therapy categories. The current review focuses on the pathophysiology and molecular aspects of common cancer types. Currently, the available chemotherapeutic drugs, also known as combination chemotherapy, are associated with numerous adverse effects, resulting in the search for herbal-based alternatives that attenuate resistance due to cancer therapy and exert chemo-protective actions. To provide new insights, this review updated the list of key compounds that may enhance the efficacy of cancer treatment.

Protective Application of Chinese Herbal Compounds and Formulae in Intestinal Inflammation in Humans and Animals.

Intestinal inflammation is a chronic gastrointestinal disorder with uncertain pathophysiology and causation that has significantly impacted both the physical and mental health of both people and animals. An increasing body of research has demonstrated the critical role of cellular signaling pathways in initiating and managing intestinal inflammation. This review focuses on the interactions of three cellular signaling pathways (TLR4/NF-κB, PI3K-AKT, MAPKs) with immunity and gut microbiota to explain the possible pathogenesis of intestinal inflammation. Traditional medicinal drugs frequently have drawbacks and negative side effects. This paper also summarizes the pharmacological mechanism and application of Chinese herbal compounds (Berberine, Sanguinarine, Astragalus polysaccharide, Curcumin, and Cannabinoids) and formulae (Wumei Wan, Gegen-Qinlian decoction, Banxia xiexin decoction) against intestinal inflammation. We show that the herbal compounds and formulae may influence the interactions among cell signaling pathways, immune function, and gut microbiota in humans and animals, exerting their immunomodulatory capacity and anti-inflammatory and antimicrobial effects. This demonstrates their strong potential to improve gut inflammation. We aim to promote herbal medicine and apply it to multispecies animals to achieve better health.

Effect of methylmercury on fetal neurobehavioral development: an overview of the possible mechanisms of toxicity and the neuroprotective effect of phytochemicals.

Methylmercury (MeHg) is a global environmental pollutant with neurotoxic effects. Exposure to MeHg via consumption of seafood and fish can severely impact fetal neurobehavioral development even when MeHg levels in maternal blood are as low as about 5 µg/L, which the mother tolerates well. Persistent motor dysfunctions and cognitive deficits may result from trans-placental exposure. The present review summarizes current knowledge on the mechanisms of MeHg toxicity during the period of nervous system development. Although cerebellar Purkinje cells are MeHg targets, the actions of MeHg on thiol components in the neuronal cytoskeleton as well as on mitochondrial enzymes and induction of disturbances of glutamate signaling can impair extra-cerebellar functions, also at levels well tolerated by adult individuals. Numerous herbal substances possess neuroprotective effects, predominantly represented by natural polyphenolic molecules that might be utilized to develop natural drugs to alleviate neurotoxicity symptoms caused by MeHg or other Hg compounds.

Molecular modeling for potential cathepsin L inhibitor identification as new anti-photoaging agents from tropical medicinal plants.

Ultraviolet exposure can cause photoaging toward the human skin which is begun by the inflammation on the exposure area, also resulting in activation of a degradative enzyme cathepsin L. This enzyme is one of the interesting novel therapeutic targets for antiaging agents. Three plants, named Kleinhovia hospita, Aleurites moluccana, and Centella asiatica, are well-known in the tropical region as anti-inflammatory herbs. The aims of this study were to predict the antiaging activity of the 31 compounds from these plants via inhibition of cathepsin L. All compounds were minimized their energies and then used in molecular docking. After that, molecular dynamics (MD) simulation was employed for the 5 candidate ligands and the positive control; schinol. Interaction analysis results of the pre-MD and post-MD simulation structures were obtained. Furthermore, a toxicity test was performed using ADMET Predictor 7.1. Based on the molecular docking and the MD simulation results, kleinhospitine A, ß-amyrin, and castiliferol exhibited lower binding free energy than schinol (-27.0925, -28.6813, -26.0037 kcal/mol) and also had interactions with the S´ region binding site. The toxicity test indicated that ß-amyrin is the most potential candidate since it exhibited the lowest binding energy and the high safety level.

Molecular mechanism of down-regulating adipogenic transcription factors in 3T3-L1 adipocyte cells by bioactive anti-adipogenic compounds.

Obesity is growing at an alarming rate, which is characterized by increased adipose tissue. It increases the probability of many health complications, such as diabetes, arthritis, cardiac disease, and cancer. In modern society, with a growing population of obese patients, several individuals have increased insulin resistance. Herbal medicines are known as the oldest method of health care treatment for obesity-related secondary health issues. Several traditional medicinal plants and their effective phytoconstituents have shown anti-diabetic and anti-adipogenic activity. Adipose tissue is a major site for lipid accumulation as well as the whole-body insulin sensitivity region. 3T3-L1 cell line model can achieve adipogenesis. Adipocyte characteristics features such as expression of adipocyte markers and aggregation of lipids are chemically induced in the 3T3-L1 fibroblast cell line. Differentiation of 3T3-L1 is an efficient and convenient way to obtain adipocyte like cells in experimental studies. Peroxisome proliferation activated receptor γ (PPARγ) and Cytosine-Cytosine-Adenosine-Adenosine-Thymidine/Enhancer-binding protein α (CCAAT/Enhancer-binding protein α or C/EBPα) are considered to be regulating adipogenesis at the early stage, while adiponectin and fatty acid synthase (FAS) is responsible for the mature adipocyte formation. Excess accumulation of these adipose tissues and lipids leads to obesity. Thus, investigating adipose tissue development and the underlying molecular mechanism is important in the therapeutical approach. This review describes the cellular mechanism of 3T3-L1 fibroblast cells on potential anti-adipogenic herbal bioactive compounds.

Recent advances and future directions in anti-tumor activity of cryptotanshinone: A mechanistic review.

In respect to the enhanced incidence rate of cancer worldwide, studies have focused on cancer therapy using novel strategies. Chemotherapy is a common strategy in cancer therapy, but its adverse effects and chemoresistance have limited its efficacy. So, attempts have been directed towards minimally invasive cancer therapy using plant derived-natural compounds. Cryptotanshinone (CT) is a component of salvia miltiorrihiza Bunge, well-known as Danshen and has a variety of therapeutic and biological activities such as antioxidant, anti-inflammatory, anti-diabetic and neuroprotective. Recently, studies have focused on anti-tumor activity of CT against different cancers. Notably, this herbal compound is efficient in cancer therapy by targeting various molecular signaling pathways. In the present review, we mechanistically describe the anti-tumor activity of CT with an emphasis on molecular signaling pathways. Then, we evaluate the potential of CT in cancer immunotherapy and enhancing the efficacy of chemotherapy by sensitizing cancer cells into anti-tumor activity of chemotherapeutic agents, and elevating accumulation of anti-tumor drugs in cancer cells. Finally, we mention strategies to enhance the anti-tumor activity of CT, for instance, using nanoparticles to provide targeted drug delivery.

A computational approach for the screening of potential antiviral compounds against SARS-CoV-2 protease: Ionic liquid vs herbal and natural compounds.

The current scenario across the globe shows unprecedented healthcare and an economic crisis due to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Recently, the World Health Organization (WHO) has declared a pandemic stage worldwide because of the high mortality and morbidity rate caused by novel infection disease. There have been several clinical trials and identification underway to find a treatment of this novel virus. For the treatment of severe infection involves the blocking of the replication of its CoV-2 protein. Hydroxychloroquine and remdesivir has been used on an emergency basis for its treatment. The uncontrolled infection and increasing death rate underline the emergence to develop the antiviral drug. In our study, the blind docking of various classes of compounds including control antiviral drugs (abacavir, acyclovir, quinoline, hydroxyquinoline), antimicrobial drugs (levofloxacin, amoxicillin, cloxacin, ofloxacin), natural compounds (lycorine, saikosaponins, myricetin, amentaflavone), herbal compounds (silymarin, palmatine, curcumin, eugenin) available in Indian Ayurveda was done. Besides, we have also performed the blind docking of various ionic liquids (ILs) such as pyrrolidinium, piperidinium, pyridinium, imidazolium based ILs against CoV-2 protease as they have recently emerged as a potential antimicrobial agent. Further, the pharmacokinetic properties and cytotoxicity of the compounds were determined computationally. The docking results showed successful binding to the active site or near a crucial site. The present computational approach was found helpful to predict the best possible inhibitor of protease and may result in an effective therapeutic agent against COVID-19.

Herbal compounds for rheumatoid arthritis: Literatures review and cheminformatics prediction.

Rheumatoid arthritis (RA) is a systemic disease characterized by autoimmunity, joint inflammation, and cartilage destruction, which affects 0.5-1% of the population. Many compounds from herbal medicines show the potentials to treat RA. On this basis, the compounds with good pharmacokinetic behaviors and drug-likeness properties will be further studied and developed. Therefore, the herbal compounds with anti-RA activities were reviewed in this paper, and the cheminformatics tools were used to predict their drug-likeness properties and pharmacokinetic parameters. A total of 90 herbal compounds were analyzed, which were reported to be effective on RA models through anti-inflammation, chondroprotection, immunoregulation, antiangiogenesis, and antioxidation. Most of the herbal compounds have good drug-likeness properties. Most of the compounds can be an alternative and valuable source for anti-RA drug discovery.

The potential role of miR-29 in health and cancer diagnosis, prognosis, and therapy.

miR-29 family is one of the small noncoding RNAs and has a very important role in many physiologic and pathologic functions through regulating the target genes that play roles in various bioprocesses such as proliferation, survival, apoptosis, and angiogenesis. Thus, we aim to survey the potential of the miR-29 family in normal model and development and progression of malignancy in this study. In addition, the potential role of miR-29 family has been studied as the clinical marker for the diagnosis and prognosis of many cancers as the potential targets to treat cancer. Moreover, it was stated in summary that the herbal compounds can regulate miR-29 family in cancers. Therefore, regulating the expression of the miR-29 family in a variety of cancers can be a new strategy to obtain better results from cancerous patients' treatment in the future.

Natural compounds with DPP-4 inhibitory effects: Implications for the treatment of diabetes.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are antidiabetes agents that decrease blood glucose by preventing the degradation of endogenous glucagon-like peptide-1. The first DPP-4 was sitagliptin followed by several other agents in the class introduced to manage diabetes. Recent studies have suggested that naturally occurring compounds can exert an antidiabetes effect through DPP-4 inhibition. Such compounds may have a place in the treatment of diabetes within the diet; however, while DPP-4 inhibition alone is not associated with hypoglycemia, in combinations with other medication hypoglycemia can result, therefore, it is critical to know what herbal or food-based compounds may have these activities in the management of diabetes patients. In this review, we have outlined the compounds that have DPP-4 inhibition that may have utility in the treatment of diabetes.

Molecular modeling investigation of the potential mechanism for phytochemical-induced skin collagen biosynthesis by inhibition of the protein phosphatase 1 holoenzyme.

The most prominent feature of UV-induced photoaged skin is decreased type 1 procollagen. Increase of the TGF-ß/Smad signaling through inhibition of the TßRI dephosphorylation by the GADD34-PP1c phosphatase complex represents a promising strategy for the increase in type 1 collagen production and prevention of UV-induced skin photoaging. In this study, the molecular docking and dynamics simulations, and pharmacophore modeling method were run to investigate a possible binding site as well as binding modes between apigenin, daidzein, asiaticoside, obovatol, and astragaloside IV and PP1c. Through docking study, the possible binding site for these phytochemicals was predicted as the hydrophobic (PP1-substrate binding) groove. The result indicates that PP1 is the significant target of these compounds. Moreover, the 20,000-ps MD simulations present that the binding locations and modes predicted by the docking have been slightly changed considering that the MD simulations proffer more reliable details upon the protein-ligand recognition. The MM-GBSA binding free energy calculations and pharmacophore modeling rationally identify that the highly hydrophobic surfaces/pockets at close proximity of the catalytic core are the most favorable binding locations of the herbal compounds, and that some experimental facts upon a possible mechanism of increase in collagen biosynthesis can be explained. The present study theoretically offers the reliable binding target of the herbal compounds, and therefore helps to understanding the action mechanism for natural small molecules that enhance collagen production.

Prediction Methods of Herbal Compounds in Chinese Medicinal Herbs.

Chinese herbal medicine has recently gained worldwide attention. The curative mechanism of Chinese herbal medicine is compared with that of western medicine at the molecular level. The treatment mechanism of most Chinese herbal medicines is still not clear. How do we integrate Chinese herbal medicine compounds with modern medicine? Chinese herbal medicine drug-like prediction method is particularly important. A growing number of Chinese herbal source compounds are now widely used as drug-like compound candidates. An important way for pharmaceutical companies to develop drugs is to discover potentially active compounds from related herbs in Chinese herbs. The methods for predicting the drug-like properties of Chinese herbal compounds include the virtual screening method, pharmacophore model method and machine learning method. In this paper, we focus on the prediction methods for the medicinal properties of Chinese herbal medicines. We analyze the advantages and disadvantages of the above three methods, and then introduce the specific steps of the virtual screening method. Finally, we present the prospect of the joint application of various methods.

Targeting Cellular Stress Mechanisms and Metabolic Homeostasis by Chinese Herbal Drugs for Neuroprotection.

Traditional Chinese medicine has been practiced for centuries in East Asia. Herbs are used to maintain health and cure disease. Certain Chinese herbs are known to protect and improve the brain, memory, and nervous system. To apply ancient knowledge to modern science, some major natural therapeutic compounds in herbs were extracted and evaluated in recent decades. Emerging studies have shown that herbal compounds have neuroprotective effects or can ameliorate neurodegenerative diseases. To understand the mechanisms of herbal compounds that protect against neurodegenerative diseases, we summarize studies that discovered neuroprotection by herbal compounds and compound-related mechanisms in neurodegenerative disease models. Those compounds discussed herein show neuroprotection through different mechanisms, such as cytokine regulation, autophagy, endoplasmic reticulum (ER) stress, glucose metabolism, and synaptic function. The interleukin (IL)-1ß and tumor necrosis factor (TNF)-α signaling pathways are inhibited by some compounds, thus attenuating the inflammatory response and protecting neurons from cell death. As to autophagy regulation, herbal compounds show opposite regulatory effects in different neurodegenerative models. Herbal compounds that inhibit ER stress prevent neuronal death in neurodegenerative diseases. Moreover, there are compounds that protect against neuronal death by affecting glucose metabolism and synaptic function. Since the progression of neurodegenerative diseases is complicated, and compound-related mechanisms for neuroprotection differ, therapeutic strategies may need to involve multiple compounds and consider the type and stage of neurodegenerative diseases.

Subchronic toxicity of herbal compound "Jiedu Huayu" granules in rats.

BACKGROUND: "Jiedu Huayu" (JDHY) granules are traditional Chinese herbal compounds that have been used to treat severe liver injury for many years. The purpose of the current study is to evaluate the safety of JDHY granules. METHODS: Subchronic toxicity was tested in male and female rats that were orally administered three different doses (80, 100, and 130 g/kg/d) of JDHY for 13 weeks. Clinical signs, bodyweight, food consumption, hematological and biochemical parameters, organ coefficients, and histological changes were observed during the study. RESULTS: There were no significant changes in toxicity observed in either sex at any dose of JDHY granules treatment. CONCLUSIONS: These results suggest that repeated oral administration of JDHY granules at dosage levels of ≤130 g/kg/d can be considered safe.

Inhibitory Mechanisms of Human CYPs by Three Alkaloids Isolated from Traditional Chinese Herbs.

The three purified herbal compounds tetrahydropalmatine (Tet), neferine and berberine (Ber) were explored in vitro for basic inhibition mechanisms towards recombinant human CYP1A2, CYP2D6 and CYP3A4 metabolic activities. Phenacetin, dextromethorphan and testosterone, respectively, were used as CYP1A2, CYP2D6 and CYP3A4 substrates, and their metabolites were determined by validated HPLC methodologies. Positive inhibition controls were used. Mechanism-based (irreversible) inhibition was assessed by time-dependent and nicotinamide adenine dinucleotide phosphate-dependent and reversible inhibition by Lineweaver-Burk plot assessments. Inhibition mechanisms were also assessed by computerized interaction prediction by using the Discovery Studio CDOCKER software (Accelrys, San Diego, CA, USA). Tetrahydropalmatine showed a mechanism-based inhibition of both CYP1A2 and CYP2D6, and Ber of CYP2D6. Neferine and Ber both showed a nonmechanistic inhibition of CYP1A2. All compounds showed a similar and significant mechanism-based inhibition of CYP3A4. Tetrahydropalmatine and Ber demonstrated both reversible and irreversible inhibition of CYP2D6 and CYP3A4. Tetrahydropalmatine and Ber displayed H-bond and several Pi-bond connections with specific amino acid residues of CYP1A2, CYP2D6 and CYP3A4, giving further knowledge to the identified reversible and irreversible herb-drug interactions. Tetrahydropalmatine and Ber should be considered for herb-drug interactions in clinical therapy until relevant clinical studies are available.

Natural products as the therapeutic strategies for addiction.

World Drug Report 2023 concluded that 296 million people abused drugs, 39.5 million became addiction and 494,000 died as a direct or indirect result of addiction. Addiction has become a growing problem that affects individuals, their families, societies, countries and even the world. However, treatment for addiction is only limited to some developed countries because of the high cost, difficult implementation, and time consuming. Therefore, there is an urgent need to develop a low-cost, effective drug for the development of addiction treatment in more countries, which is essential for the stability and sustainable development of the world. In this review, it provided an overview of the abuse of common addictive drugs, related disorders, and current therapeutic regimen worldwide, and summarized the mechanisms of drug addiction as reward circuits, neuroadaptation and plasticity, cognitive decision-making, genetics, and environment. According to their chemical structure, 43 natural products and 5 herbal combinations with potential to treat addiction were classified, and their sources, pharmacological effects and clinical trials were introduced. It was also found that mitragine, ibogine, L-tetrahydropalmatine and crocin had greater potential for anti-addiction.

Potential therapeutic properties of broccoli extract and soy isoflavones on improvement endometriosis and involved oxidative parameters.

OBJECTIVES: In Endometriosis is a gynecological disorder characterized by the growth of endometrial tissue outside the uterine cavity that is associated with chronic pelvic pain and subfertility. The purpose of the study was to investigate the effect of broccoli extract (BE) alone and in combination with soy isoflavones (SI) on endometrial implants in female rat. METHODS: In this study, endometriosis was induced surgically in 40 mature female rats. The rats were divided into 5 groups that were treated by oral gavage for 6 weeks with 0.5 mL of saline 0.9 %/day (control group), BE (3,000 mg/kg/day), SI (50 mg/kg/day), BE/soy isoflavones (BE 3000 mg/kg/day + soy isoflavones 50 mg/kg/day) and diphereline as a standard medication (3 mg/kg) intramuscularly. At the end of treatments, the volume and histopathology of the endometrial implants were compared among the 5 groups. The serum levels of oxidative parameters including superoxide dismutase (SOD), malondialdehyde (MDA) and tumor necrosis factor alpha (TNF-α) were also compared between the groups. The volume of the implants significantly decreased in diphereline group (p=0.002). RESULTS: The histopathological grade of endometrial implants in BE/SI and diphereline group were significantly decreased compared to the control group (p=0.001). The serum levels of SOD in BE group were enhanced significantly in comparison to the control group (p=0.034). CONCLUSIONS: BE in combination with SI decreased the growth and histopathologic grades of transplanted endometrial implants. These herbal compounds may have the potential therapeutic effect to be used as an alternative medication for the treatment of endometriosis.

Endometriosis happens when tissue similar to the uterus tissue grows outside of the uterus. It can be associated with severe pelvic pain and make several difficulties to get pregnant. Since the use of hormonal drugs is prohibited when planning to get pregnant and due to the common recurrence of lesions after surgery, scientists have been encouraged to study regarding the efficacies of natural products on improvement of endometriosis. In this study, it is represented that the dietary consumption of broccoli extract combined with soy isoflavones may have potential beneficial properties on clinical symptoms of endometriosis.