An Update on Pharmacological and Phytochemical Aspects of Costus pictus D. Don - A Promising Anti-diabetic Plant.

BACKGROUND: The genus Costus is the largest genus in the family Costaceae and encompasses about 150 known species. Among these, Costus pictus D. Don (Synonym: Costus mexicanus) is a traditional medicinal herb used to treat diabetes and other ailments. Currently, available treatment options in modern medicine have several adverse effects. Herbal medicines are gaining importance as they are cost-effective and display improved therapeutic effects with fewer side effects. Scientists have been seeking therapeutic compounds in plants, and various in vitro and in vivo studies report Costus pictus D. Don as a potential source in treating various diseases. Phytochemicals with various pharmacological properties of Costus pictus D. Don, viz. anticancer, anti-oxidant, diuretic, analgesic, and anti-microbial have been worked out and reported in the literature. OBJECTIVE: The aim of the review is to categorize and summarize the available information on phytochemicals and pharmacological properties of Costus pictus D. Don and suggest outlooks for future research. METHODS: This review combined scientific data regarding the use of Costus pictus D. Don plant for the management of diabetes and other ailments. A systematic search was performed on Costus pictus plant with anti-diabetic, anti-cancer, anti-microbial, anti-oxidant, and other pharmacological properties using several search engines such as Google Scholar, PubMed, Science Direct, SciFinder, other online journals and books for detailed analysis. RESULTS: Research data compilation and critical review of the information would be beneficial for further exploration of its pharmacological and phytochemical aspects and, consequently, new drug development. Bioactivity-guided fractionation, isolation, and purification of new chemical entities from the plant as well as pharmacological evaluation of the same will lead to the search for safe and effective novel drugs for better healthcare. CONCLUSION: This review critically summarizes the reports on natural compounds, and different extract of Costus pictus D. Don with their potent anti-diabetic activity along with other pharmacological activity. Since this review has been presented in a very interactive manner showing the geographical region of availability, parts of plant used, mechanism of action and phytoconstituents in different extracts of Costus pictus responsible for particular action, it will be of great importance to the interested readers to focus on the development of the new drug leads for the treatment of diseases.

Regulating pri/pre-microRNA up/down expressed in cancer proliferation, angiogenesis and metastasis using selected potent triterpenoids.

MicroRNAs (miRNAs) play a crucial role in cancer progression by selectively inducing translational degradation of messenger RNA (mRNA) via sequence-specific interactions with the 3'-untranslated region (3'-UTR). The potential targeting of miRNA has been recognized as a significant avenue for investigating the biological progression of diverse cancer types. Consequently, targeting of pri-miRNA and pre-miRNA by phytochemicals emerges as a viable strategy in the realm of anticancer therapies. Among phytochemicals, triterpenoids have garnered significant recognition for their chemotherapeutic and chemopreventive capabilities in combating multiple cancers. To date, there is a dearth of literature about the molecular interactions between triterpenoids and miRNAs. The primary objective of this investigation is to discern the potential triterpenoids that can function as modulators for specific miRNAs, namely pri-miRNA-19b-2, pre-miR21, microRNA 20b, pri-miRNA-208a, pri-miRNA-378a, pri-miRNA-320b-2, and pri-miRNA-300, achieved through the use of in silico investigations. The study primarily focused on performing drug-likeness, computer-aided toxicity, and pharmacokinetic prediction studies for triterpenoids. Furthermore, molecular docking and simulation techniques were employed to investigate these compounds. The triterpenoids studied were shown to have drug-likeness characteristics, although asiatic acid, lupeol, and pristimerin were able to pass all toxicity tests. Among the triterpenoids that underwent docking, pristimerin had a significant binding energy of -10.9 kcal/mol during its interaction with pri-miR-378a. The stable interaction between the pristimerin and miRNA complex was demonstrated by molecular dynamics simulation. As a result, pristimerin has the potential to act as a modulator of carcinogenic miRNAs, making it a promising candidate for cancer prevention and treatment due to its tailored modulation of miRNA activity.

Escin-sorafenib synergy up-regulates LC3-II and p62 to induce apoptosis in hepatocellular carcinoma cells.

INTRODUCTION: Hepatocellular carcinoma (HCC) is a common solid cancer and the leading cause of cancer deaths worldwide. Sorafenib is the first drug used to treat HCC but its effectiveness needs to be improved, and it is important to find ways to treat cancer that combine sorafenib with other drugs. Synergistic therapies lower effective drug doses and side effects while enhancing the anticancer effect. PURPOSE: In the present study, the therapeutic potential of sorafenib in combination with escin and its underlying mechanism in targeting liver cancer has been established. STUDY DESIGN/METHODS: The IC50 of sorafenib and escin against HepG2, PLC/PRF5 and Huh7 cell lines were determined using MTT assay. The combination index, dose reduction index, isobologram and concentrations producing synergy were evaluated using the Chou-Talaly algorithm. The sub-effective concentration of sorafenib and escin was selected to analyze cytotoxic synergistic potential. Cellular ROS, mitochondrial membrane potential, annexin V and cell cycle were evaluated using a flow-cytometer, and autophagy biomarkers were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role. A DEN-induced liver cancer rat model was developed to check the synergy of sorafenib and escin. RESULTS: Different concentrations of escin reduced the IC50 of sorafenib in HepG2, PLC/PRF5 and Huh7 cell lines. Chou-Talaly algorithm determined cytotoxic synergistic concentrations of sorafenib and escin in these cell lines. Mechanistically, this combination over-expressed p62 and LC-II, reflecting autophagy block and induced late apoptosis, further reconfirmed by ATG5 knockdown. Sorafenib and escin combination  reduced HCC serum biomarker α-feto protein (α-FP) by 1.5 folds. This combination restricted liver weight, tumor number and size, also, conserved morphological features of liver cells. The combination selectively targeted the G0 /G1 phase of cancer cells. CONCLUSION: Escin and sorafenib combination potentially up-regulates p62 to block autophagy to induce late apoptosis in liver cancer cells.

Monoterpenoids: An upcoming class of therapeutic agents for modulating cancer metastasis.

Monoterpenoids, a sub-class of terpenoids, are secondary metabolites frequently extracted from the essential oils of aromatic plants. Their antitumor properties including antiproliferative, apoptotic, antiangiogenic, and antimetastatic effects along with other biological activities have been the subject of extensive study due to their diverse characteristics. In recent years, numerous investigations have been conducted to understand its potential anticancer impacts, specifically focusing on antiproliferative and apoptotic mechanisms. Metastasis, a malignancy hallmark, can exert either protective or destructive influences on tumor cells. Despite this, the potential antimetastatic and antiangiogenic attributes of monoterpenoids need further exploration. This review focuses on specific monoterpenoids, examining their effects on metastasis and relevant signaling pathways. The monoterpenoids exhibit a high level of complexity as natural products that regulate metastatic proteins through various signaling pathways, including phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin, mitogen-activated protein kinase/extracellular signal-regulated kinase/jun N-terminal kinase, nuclear factor kappa B, vascular endothelial growth factor, and epithelial mesenchymal transition process. Additionally, this review delves into the biosynthesis and classification of monoterpenoids, their potential antitumor impacts on cell lines, the plant sources of monoterpenoids, and the current status of limited clinical trials investigating their efficacy against cancer. Moreover, monoterpenoids depict promising potential in preventing cancer metastasis, however, inadequate clinical trials limit their drug usage. State-of-the-art techniques and technologies are being employed to overcome the challenges of utilizing monoterpenoids as an anticancer agent.

Cinchonine: A Versatile Pharmacological Agent Derived from Natural Cinchona Alkaloids.

BACKGROUND: Cinchonine is one of the Cinchona alkaloids that is commercially extracted from the Peruvian bark of Cinchona officinalis L. (Family: Rubiaceae). It is also obtained in much lower quantities from other species of Cinchona, such as Cinchona calisaya, Cinchona succirubra, and Cinchona pubescens, and in some other plants, such as Remijia peruviana. Cinchonine has been historically used as an anti-malarial agent. It also has a wide range of other biological properties, including anti-cancer, anti-obesity, anti-inflammatory, anti-parasitic, antimicrobial, anti-platelet aggregation, and anti-osteoclast differentiation. AIM AND OBJECTIVE: This review discusses the pharmacological activity of cinchonine under different experimental conditions, including in silico, in vitro, and in vivo. It also covers the compound's physicochemical properties, toxicological aspects, and pharmacokinetics. METHODOLOGY: A comprehensive literature search was conducted on multiple online databases, such as PubMed, Scopus, and Google Scholar. The aim was to retrieve a wide range of review/research papers and bibliographic sources. The process involved applying exclusion and inclusion criteria to ensure the selection of relevant and high-quality papers. RESULTS: Cinchonine has numerous pharmacological properties, making it a promising compound for various therapeutic applications. It induces anticancer activity by activating caspase-3 and PARP-1, and triggers the endoplasmic reticulum stress response. It up-regulates GRP78 and promotes the phosphorylation of PERK and ETIF-2α. Cinchonine also inhibits osteoclastogenesis, inhibiting TAK1 activation and suppressing NFATc1 expression by regulating AP-1 and NF-κB. Its potential anti-inflammatory effects reduce the impact of high-fat diets, making it suitable for targeting obesity-related diseases. However, research on cinchonine is limited, and further studies are needed to fully understand its therapeutic potential. Further investigation is needed to ensure its safety and efficacy in clinical applications. CONCLUSION: Overall, this review article explains the pharmacological activity of cinchonine, its synthesis, and physicochemical properties, toxicological aspects, and pharmacokinetics.

Myricetin 3-rhamnoside retards the proliferation of hormone-independent breast cancer cells by targeting hyaluronidase.

Breast cancer is the second-leading cause of cancer-related death in women and the most often diagnosed malignancy. As the majority of chemotherapeutic medications are associated with recurrence, drug resistance, and side effects, scientists are shifting to beneficial agents for prevention and treatment, such as natural molecules. Myricetin 3-rhamnoside, a natural flavonol glycoside is known for diverse pharmacological activities but fewer reports describe the antiproliferative ability. The study aims to investigate the antiproliferative efficacy and target [hyaluronidase (HYAL) and ornithine decarboxylase (ODC), two poor breast cancer prognostic markers] modulatory potential of myricetin 3-rhamnoside on breast cancer cell lines using cytotoxicity assays and in silico docking, molecular dynamics analysis, cell-free and cell-based test methods. Myricetin 3-rhamnoside significantly retard the growth of MDA-MB-231 cells in SRB (IC50 88.64 ± 7.14 µM) and MTT (56.26 ± 8.50 µM) assay. It suppressed the transition of cells to the S-phase by inducing arrest in the G0/G1 phase with a fold change of 1.10. It shows robust binding interaction with ODC (-7.90 kcal/mol) and HYAL (-9.46 kcal/mol) and inhibits ODC (15.22 ± 2.61 µM) and HYAL (11.92 ± 2.89 µM) activity, but in a cell-based assay, the prominent response was observed against HYAL (21.46 ± 4.03 µM). Besides, it shows a 1.38 fold-down regulation of HYAL and forms a stable complex with HYAL. The binding pocket for myricetin 3-rhamnoside and the simulation pocket during the simulation are identical, indicating that myricetin 3-rhamnoside is actively blocking hyaluronidase. The computational prediction suggests it is a safe molecule. These observations imply that myricetin 3-rhamnoside could be used as a pharmacophore to design and synthesize a novel and safe agent for managing hormone-independent breast cancer.Communicated by Ramaswamy H. Sarma.

New frontiers in the design and discovery of therapeutics that target calcium ion signaling: a novel approach in the fight against cancer.

INTRODUCTION: The Ca2+ signaling toolkit is currently under investigation as a potential target for addressing the threat of cancer. A growing body of evidence suggests that calcium signaling plays a crucial role in promoting various aspects of cancer, including cell proliferation, progression, drug resistance, and migration-related activities. Consequently, focusing on these altered Ca2+ transporting proteins has emerged as a promising area of research for cancer treatment. AREAS COVERED: This review highlights the existing research on the role of Ca2+-transporting proteins in cancer progression. It discusses the current studies evaluating Ca2+ channel/transporter/pump blockers, inhibitors, or regulators as potential anticancer drugs. Additionally, the review addresses specific gaps in our understanding of the field that may require further investigation. EXPERT OPINION: Targeting specific Ca2+ signaling cascades could disrupt normal cellular activities, making cancer therapy complex and elusive. Therefore, there is a need for improvements in current Ca2+ signaling pathway focused medicines. While synthetic molecules and plant compounds show promise, they also come with certain limitations. Hence, exploring the framework of targeted drug delivery, structure-rationale-based designing, and repurposing potential drugs to target Ca2+ transporting proteins could potentially lead to a significant breakthrough in cancer treatment.

Exploration of selected monoterpenes as potential TRPC channel family modulator in lung cancer, an in-silico upshot.

Lung cancer is still the most frequent cause of cancer-related death, accounting for nearly two million cases yearly. As cancer is a multifactorial disease, developing novel molecular therapeutics that can simultaneously target multiple associated cellular processes has become necessary. Ion channels are diverse regulators of cancer-related processes such as abnormal proliferation, invasion, migration, tumor progression, inhibition of apoptosis, and chemoresistance. Among the various families of ion channels, the transient receptor potential canonical channel family steps out in the context of lung cancer, as several members have been postulated as prognostic markers for lung cancer. Phytochemicals have been found to have health benefits in the treatment of a variety of diseases and disorders. Among phytochemicals, monoterpenes are effective in treating both the early and late stages of cancer. The molecular docking interaction analysis was conducted to evaluate the binding potential of selected monoterpenes with TRPC3, TRPC4, TRPC5, and TRPC6 involved in different phases of carcinogenesis. Amongst the selected monoterpenes, thymoquinone exhibited the highest binding energy of -6.7 kcal/mol against the TRPC4 channel, and all amino acid binding residues were similar to those of the known inhibitor for TRPC4. In addition, molecular-dynamic simulation results parameters, such as RMSD, RMSF, and Rg, indicated that thymoquinone did not impact the protein compactness and exhibited stability during the interaction. The average interaction energy between thymoquinone and TRPC4 protein was -26.85 kJ/mol. In-silico Drug-likeness and ADMET profiling indicated that thymoquinone is a druggable candidate with minimal toxicity. We propose further investigation and evaluation of thymoquinone for lead optimization and drug development.Communicated by Ramaswamy H. Sarma.

Thymoquinone exhibited the highest BE −6.7 kcal/mol against the TRPC4 channel.Thymoquinone passed all drug-likeness parameters.Thymoquinone showed 99.38% of intestinal absorption in ADMET analysis.MD confirms thymoquinone forms stable molecular interaction with TRPC4.

Myricitrin from bayberry as a potential inhibitor of cathepsin-D: Prospects for squamous lung carcinoma prevention.

Cathepsin-D (CATD) inhibitors' design and development drawn interest due to their potential therapeutic applications in managing different cancer types, including lung cancer. This study investigated myricitrin, a flavonol-3-O-rhamnoside, for its binding affinity to CATD. Molecular docking experiments revealed a strong binding affinity (-7.8 kcal/mol). Molecular dynamics (MD) simulation confirmed the complex's stability, while enzyme activity studies showed inhibitory concentration (IC50) of 35.14 ± 6.08 µM (in cell-free) and 16.00 ± 3.48 µM (in cell-based) test systems. Expression analysis indicated downregulation of CATD with a fold change of 1.35. Myricitrin demonstrated antiproliferative effects on NCIH-520 cells [IC50: 64.11 µM in Sulphorhodamine B (SRB), 24.44 µM in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)], but did not affect healthy CHANG cells. It also prolonged the G2/M phase (at 10 µM: 1.19-fold; at 100 µM: 1.13-fold) and increased sub-diploid population by 1.35-fold. Based on the analysis done using SwissADME program, it is predicted that myricitrin is not a cytochrome p450s (CYPs) inhibitor, followed the rule of Ghose and found not permeable to the blood-brain barrier (BBB) which suggests it as a safe molecule. In summary, the experimental findings may establish the foundation for myricitrin and its analogues to be used therapeutically in CATD-mediated lung cancer prevention.

Molecular regulation of autophagy and suppression of protein kinases by aescin, a triterpenoid saponin impedes lung cancer progression.

Lung cancer is the most common and lethal cancer worldwide, yet there are no adequate and novel medications to control this illness. Previous reports suggested the potential of protein kinases to target lung cancer by regulating autophagy. This study establishes the role of aescin, a triterpenoid saponin, in targeting protein kinases responsible for lung cancer proliferation and mobility. The experimental data revealed that aescin significantly impedes lung cancer cell proliferation by downregulating protein kinases such as AKT, mTOR, MEK, and ERK. Downregulation of AKT-mTOR may promote a string of events inducing cytotoxic autophagy-mediated apoptosis in the presence of aescin. Besides, aescin decreases mobility and invasion by downregulating HIF-1α and VEGF gene expressions. Moreover, it successfully monitors EGFR gene expression, improves lung histology, and regulates biochemical parameters in a pre-clinical DEN-induced lung cancer model. Aescin was observed to be safe and non-toxic in both in silico toxicity predictions and ex vivo erythrocyte fragility assays. Hence, this study elucidates the molecular mechanism of aescin in targeting protein kinases and suggests that it could be a safer and more viable therapeutic agent for lung cancer treatment.

3,5,7-trihydroxyflavone restricts proliferation of androgen-independent human prostate adenocarcinoma cells by inducing ROS-mediated apoptosis and reduces tumour growth.

Flavonoids are among the largest groups of secondary metabolites. Studies suggest that dietary intake of flavonoids reduces the risk of cancer. 3,5,7-trihydroxyflavone (THF) belongs to the flavone class of flavonoids and potentially inhibits the growth of many cancers; however, it is unexplored in prostate cancer. This study reports the antiproliferative potential of THF in prostate cancer cell line via reactive oxygen species (ROS)-mediated cascades and examines the tumour reduction potential in swiss albino mice. The potency of THF was evaluated by employing cytotoxicity assays and wound healing assays. Cell cycle, ROS, mitochondrial membrane potential (MMP), and Annexin-V-FITC assay were performed using a flow cytometer. In vivo, anticancer potential was achieved using the mice Ehrlich Ascites Carcinoma (EAC) model. THF inhibits cell growth with IC50 of 64.30 µM (MTT), 81.22 µM (NRU) and 25.81 µM (SRB), substantiated by cell migration assay. Cell-cycle analysis revealed that THF increases the subdiploid population. Furthermore, the Annexin-V-FITC assay evoked a significant induction of late apoptosis at a higher concentration of THF. THF also disrupts MMP, caused by an increased generation of ROS. In the EAC model, THF significantly inhibits tumour growth and increases the percent survival of mice and ROS levels in EAC cells. Hence, it may be concluded that THF might execute its antiproliferative effect via inducing ROS generation and could be a promising lead for preclinical and clinical validations.

Escin enhanced the efficacy of sorafenib by autophagy-mediated apoptosis in lung cancer cells.

Combining anti-cancer drugs has been exploited as promising treatment strategy to target lung cancer. Synergistic chemotherapies increase anti-cancer effect and reduce effective drug doses and side effects. In this study, therapeutic potential of escin in combination with sorafenib has been explored. 3-(4,5-Dimethylthiazol-2-yl)-2 5-diphenyltetrazolium bromide assay was used to calculate IC50 values. The synergy was evaluated using Chou-Talaly algorithm. Cellular reactive oxygen species, mitochondrial membrane potential, annexin V, and cell-cycle studies were done by flow-cytometer, and autophagy biomarkers expression were determined using western blotting. Moreover, autophagy was knocked down using ATG5 siRNA to confirm its role, diethylnitrosamine-induced lung cancer model was used to check the synergy of sorafenib/escin. Escin significantly reduced the IC50 of sorafenib in A549 and NCIH460 cells. The combination of sorafenib/escin produced a 2.95 and 5.45 dose reduction index for sorafenib in A549 and NCI-H460 cells. The combination of over-expressed p62 and LC3-II reflects autophagy block-mediated late apoptosis. This phenomenon was reconfirmed by ATG5 knockdown. This combination also selectively targeted G0/G1 phase of cancer cells. In in vivo study, the combination reduced tumour load and lower elevated serum biochemical parameters. The combination of sorafenib/escin synergistically inhibits autophagy to induce late apoptosis in lung cancer cells' G0/G1 phase.

Narirutin downregulates lipoxygenase-5 expression and induces G0/G1 arrest in triple-negative breast carcinoma cells.

BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 20% of breast cancer that does not express HER2, progesterone and estrogen receptors. It is associated with a high mortality rate, morbidity, metastasis, recurrence, poor prognosis and resistance to chemotherapy. Lipoxygenase-5 (LOX-5), cyclooxygenase-2 (COX-2), cathepsin-D (CATD), ornithine decarboxylase (ODC) and dihydrofolate reductase (DHFR) are involved in breast cancer carcinogenesis; hence, there is a pressing need to identify novel chemicals that targets these enzymes. Narirutin, a flavanone glycoside abundantly present in citrus fruits, is reported to have immune-modulatory, anti-allergic and antioxidant potential. Still, the cancer chemopreventive mechanism against TNBC has not been explored. METHODS: In vitro experiments, enzyme activity, expression analysis, molecular docking and MD simulation were carried out. RESULTS: Narirutin suppressed the growth of MDA-MB-231 and MCF-7 in a dose-proportional manner. The pronounced effect with >50% inhibition was observed in SRB and MTT assays for MDAMB-231 cells. Unexpectedly, narirutin suppressed the proliferation of normal cells (24.51%) at 100 µM. Further, narirutin inhibits the activity of LOX-5 in cell-free (18.18 ± 3.93 µM) and cell-based (48.13 ± 7.04 µM) test systems while moderately affecting COX-2, CATD, ODC and DHFR activity. Moreover, narirutin revealed a down-regulation of LOX-5 expression with a fold change of 1.23. Besides, MD simulation experiments confirm that narirutin binding forms a stable complex with LOX-5 and improves the stability and compactness of LOX-5. In addition, the prediction analysis demonstrates that narirutin could not cross the blood-brain barrier and did not act as an inhibitor of different CYPs. CONCLUSIONS AND SIGNIFICANCE: Narirutin could be a potent cancer chemopreventive lead for TNBC, further paving the way for synthesizing novel analogues.

Narirutin. A flavonoid found in citrus fruits modulates cell cycle phases and inhibits the proliferation of hormone-refractory prostate cancer cells by targeting hyaluronidase.

Narirutin is a dietary flavanone found in lemons, oranges, passion fruit, bergamot and grapefruit. It possesses anti-allergic, cardioprotective, neuroprotective, hepatoprotective potential, and its enriched fraction suppresses the growth of prostate cancer cells; however, there is currently no information on the chemopreventive potential of narirutin alone against hormone-refractory prostate cancer cells (PC-3) and its mode of action. Thus, the chemopreventive possibility of narirutin was investigated in PC-3 cells by utilising cytotoxicity assays. Further, a mechanism was deduced targeting hyaluronidase, an early-stage diagnosis marker, by cell-free, cell-based and in silico studies. The results indicate that narirutin reduced the viability of PC-3 cells with the inhibitory concentration range of 66.87-59.80 µM. It induced G0/G1 phase arrest with a fold change of 1.12. Besides, it increased the generation of reactive oxygen species (ROS) with a fold change of 1.34 at 100 µM. Narirutin inhibited hyaluronidase's activity in cell-free (11.17 µM) and cell-based assays (67.23 µM) and showed a strong binding interaction with hyaluronidase. Finally, the MD simulation analysis supported the idea that narirutin binding enhanced compactness and stability and created a stable complex with hyaluronidase. In addition, ADMET prediction indicates that it is a non-toxic, non-CYPs inhibitor and thus didn't alter the metabolism. The results reveal that narirutin may be a potential chemopreventive agent for hormone-resistant prostate cancer cells in addition to offering data for supporting diet-based nutraceutical agents to prevent prostate cancer.

Carvacrol as a Prospective Regulator of Cancer Targets/Signalling Pathways.

BACKGROUND: Carvacrol is a naturally occurring phenolic isopropyl monoterpene isolated from oregano, thyme, pepperwort, ajwain, marjoram, and wild bergamot. It possesses pharmacological activities, including anticancer, anti-genotoxic, and anti-inflammation associated with antioxidant properties. The antioxidant property of carvacrol is found to be accountable for its anticancer property. Thus, the present review summarizes and discusses the anticancer potential of carvacrol, revealing its target, signalling pathways, efficacy, pharmacokinetics, and toxicity. OBJECTIVE: Carvacrol showed promising activity to be considered in more detail for cancer treatment. This review aims to summarize the evidence concerning the understanding of anticancer potential of carvacrol. However, the mode of action of carvacrol is not yet fully explored and hence requires detailed exploratory studies. This review consists of carvacol's in vitro, in vivo, preclinical and clinical studies. METHODS: A literature search was done by searching various online databases like Pubmed, Scopus, and Google Scholar with the specific keyword "Carvacrol," along with other keywords, such as "antioxidant properties," "oncology research," "genotoxicity," and "anti-inflammatory property". RESULTS: Carvacrol possesses weak mutagenic and genotoxic potential at non-toxic doses. Carvacrol alone shows the potential to target cancerous cells and significantly deter the growth of cancer cells; this is a targeted method. It offers anti-inflammatory effects by decreasing oxidative stress, primarily targeting ER and mitochondria. Carvacrol depicts targeted explicitly ROSdependent and mitochondrial-mediated apoptosis in different cancer cells. Moreover, carvacrol significantly regulates the cell cycle and prevents tumor progression. Few reports also suggest its significant role in inhibiting cell migration, invasion, and angiogenesis in tumor cells. Hence, carvacrol affects cell survival and cell-killing activity by targeting key biomarkers and major signalling pathways, including PI3K/AKT/mTOR, MAPK, STAT3, and Notch. CONCLUSION: Until now, its anticancer mechanism is not yet fully explored. A limited number of research studies have been conducted on carvacrol. It possesses both cancer prevention and cancer therapeutic properties. This molecule needs more validatory research so that it can be analyzed precisely.

Purpurin ameliorates alcohol-induced hepatotoxicity by reducing ROS generation and promoting Nrf2 expression.

INTRODUCTION AND AIM: Purpurin, a naturally occurring anthraquinone isolated from the roots of Rubia cordifolia, exhibits anti-cancer, anti-genotoxic, anti-microbial, neuromodulatory and photodynamic activity. However, purpurin's in vivo and in vitro antioxidant mechanism remains unexplored. The present study explores the anti-oxidative mechanism of purpurin under the influence of alcohol using in vivo and in vitro test systems. METHODS: Mice hepatocytes and alcohol-induced liver toxicity model were used to evaluate the effect of purpurin. The non-enzymatic and enzymatic oxidative stress markers were estimated by the colorimetric method. The reactive oxygen species (ROS) were quantified in mitochondria and cells using flow cytometer. Real-time PCR and western blotting were used to quantify cytochrome 450 subtype 2E1 (CYP2E1) and Nrf2 expression in the liver tissue of mice. In silico studies were performed through receptor-ligand binding interaction. KEY FINDINGS: Purpurin effectively reduced total cellular and mitochondrial ROS in primary hepatocytes and WRL-68 cells. It prevented alcohol-induced ROS-dependent biochemical and cellular insults observed by analysing the serum glutamic pyruvic transaminase (SGPT), glutamic-oxaloacetic transaminase (SGOT) levels and CYP2E1 expression in liver tissue of alcohol-administered mice. Moreover, it also restored the activity of antioxidant enzymes. Its antioxidant effect was established by glutathione and ROS-dependent mechanisms using buthionine sulfoximine and N-acetyl cysteine. Along with alcohol, purpurin up-regulated Nrf2 expression in hepatocytes. SIGNIFICANCE: This work confirmed the ameliorative effect of purpurin for alcohol-induced hepatotoxicity by drabbing free radicals and curbing oxidative stress via activation of antioxidant signalling pathways.

Anti-inflammatory, anti-oxidant and cardio-protective properties of novel fluorophenyl benzimidazole in L-NAME-induced hypertensive rats.

BACKGROUND: Chronic inflammation and oxidative stress play important role in development of hypertension. Recently, we have reported novel fluorophenyl benzimidazole (FPD) for vasorelaxation and antihypertensive activity in SHRs. The present study envisaged the anti-inflammatory, anti-oxidant and cardio-protective properties of FPD in L-NAME model of hypertension with special emphasis on reversal of vascular remodeling, gene expression and restoration of hemodynamic. METHODS: Antihypertensive activity of FPD was evaluated in L-NAME treated Wistar rats, and the parameters studied were anti-inflammatory activity, histomorphological changes, gene expression profile and anti-oxidant properties. RESULTS: FPD at 50 and 100 mg kg-1 once daily for 15 days significantly reduced SBP, DBP and MAP in L-NAME treated rats and the values were well comparable to vehicle control group. Further, FPD treatment showed a significant increase in hepatic GSH content, SOD, catalase activity, decreased MDA level and restoration of pro and anti-inflammatory cytokine levels. The mRNA expression profile of genes associated with regulation of vascular tone, remodeling and inflammation showed a significant level of alteration by chronic L-NAME treatment and was dose-dependently restored upon treatment with FPD. Further, FPD treatment restored serum lipid profile, CK, CK-MB and LDH level and also reversed the histomorphological changes like intimal wall thickening, hyperplasia of cardiomyocytes and ventricular wall thickening. CONCLUSIONS: Taken together, FPD produced potent antihypertensive activity in L-NAME model through vasorelaxation, anti-oxidative and anti-inflammatory properties leading to restoration of serum lipid profile, cardiac biomarker, expression profile of target genes and reversal of histomorphological changes.

Promising Essential Oils/Plant Extracts in the Prevention and Treatment of Dandruff Pathogenesis.

BACKGROUND: Dandruff is a scalp disorder affecting the male populace predominantly. Topical agents and synthetic drugs used for dandruff treatment have specific side effects including burning at the application site, depression, dizziness, headache, itching or skin rash, nausea, stomach pain, vision change, vomiting, discoloration of hair, dryness or oiliness of the scalp and increased loss of hair. Thus, essential oils and extracts from plants could be valuable in the treatment and prevention of dandruff. AIMS & OBJECTIVES: This review aims to highlight current findings in dandruff occurrence, its etiology, promising plant essential oils/extracts, and novel treatment strategies. The main emphasis has been given on the anti-dandruff effect of essential oils and plant extracts to disrupt microbial growth. The proposed mechanism(s) of action, novel approaches used to perk up its biopharmaceutical properties, and topical application have been discussed. RESULTS: The literature survey was done, and bibliographic sources and research papers were retrieved from different search engines and databases, including SciFinder, PubMed, NCBI, Scopus, and Google Scholar. The selection of papers was accomplished based on exclusion and inclusion criteria. The scalp of diverse populations revealed an association of dandruff with microbial symbiosis, including Staphylococcus, Propionibacterium, Malassezia, and Candida as the pathogens responsible for the cause of dandruff. Topical antifungals are considered the first line of treatment for dandruff including azoles, with clotrimazole (1%), ketoconazole (2%), and miconazole (2%). Other commonly used therapies integrate benzoyl peroxide, coal tar, glycerin, zinc pyrithione, lithium succinate/gluconate, salicylic acid, selenium disulfide/sulfide, sodium sulfacetamide, etc. However, these medicaments and chemicals are known to cause specific side effects. Alternative therapies, including tea tree oil, thyme, Aloe vera, Mentha have been reported to demonstrate anti-dandruff activity by disrupting the microbial growth associated with dandruff formation. CONCLUSION: Overall, this review explains the occurrence of dandruff, its pathogenesis, and the potential applicability of promising plant essential oils/extracts and their novel treatment strategies. Further studies based on pre-clinical and clinical research are essential before making any conclusion about its efficacy in humans.

Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release.

Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death.

Carvacrol Arrests the Proliferation of Hypopharyngeal Carcinoma Cells by Suppressing Ornithine Decarboxylase and Hyaluronidase Activities.

Carvacrol, a monoterpene known for its pharmacological activities, is present in the essential oil of Origanum majorana, Origanum vulgare, Thymus vulgaris, and Lippia graveolens. It is used in food as a flavoring and preservative agent in cosmetics and medicines because of its useful bioactivities in clinical practice. However, carvacrol was not much explored for its anticancer potential. Targeting enzymes involved in carcinogenesis, such as ornithine decarboxylase (ODC), cyclooxygenase-2 (COX-2), lipoxygenase-5 (LOX-5), and hyaluronidase (HYAL) by monoterpenes are amongst the efficient approaches for cancer prevention and treatment. In this study, the efficacy of carvacrol was investigated against deregulated cancer biomarkers/targets in organ-specific human cancer cell lines (FaDu, K562, and A549) utilizing in vitro, in silico, and in vivo approaches. The efficacy of carvacrol was evaluated on human cancer cell lines using neutral red uptake (NRU), sulpho rhodamine B (SRB), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assays. The mechanistic study was carried out in cell-based test systems. Further, the potency of carvacrol was confirmed by the quantitative real-time PCR analysis and molecular docking studies. The in vivo anti-tumor potential of carvacrol was performed on mice S-180 model, and the toxicity examination was accomplished through in silico approach. Carvacrol significantly impeded the growth of FaDu, K562, and A549 cell lines with IC50 values ranging from 9.61 ± 0.05 to 81.32 ± 11.83 µM. Further, the efficacy of carvacrol was explored against different cancer targets in FaDu, K562, and A549 cell lines. Carvacrol inhibits the ODC, COX-2, LOX-5, and HYAL activities in FaDu cell line and ODC, COX-2, and HYAL activities in K562 cell line. The results were validated by expression analysis revealing the downregulation of the targeted gene with a significant change in the transcript level of ODC and HYAL in FaDu cell line with a fold change of 1.56 and 1.61, respectively. A non-significant effect of carvacrol was observed on the downstream signaling pathway of PI3K and HIF-1α/vascular endothelial growth factor (VEGF) in FaDu cells. The cell cycle, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and Annexin V-fluorescein isothiocyanate (FITC) experiments demonstrate that carvacrol induces apoptosis of FaDu cells. Further, the potency of carvacrol was also evaluated in vivo on mice S-180 tumor model, wherein it inhibits tumor growth (72%) at 75 mg/kg body weight (bw). ADMET studies predicted carvacrol as a safe molecule. Overall, carvacrol delayed the growth of FaDu, K562, and A549 cell lines by targeting enzymes involved in the carcinogenesis process. The existence of one hydroxyl group at the para position of carvacrol could be responsible for the anti-proliferative activity. Thus, carvacrol could be used as a pharmacophore to develop a safe and effective multi-targeted anti-cancer medicament.