Synthesis and Evaluation of Natural and Unnatural Tetrahydrocannabiorcol for Its Potential Use in Neuropathologies.

(-)-trans-Δ9-Tetrahydrocannabinol (trans-(-)-Δ9-THC) has shown neuroprotective potential, but its medicinal benefits are not fully exploited due to the limitations of psychoactive properties. The lower homologues are non-psychoactive in nature but lack comprehensive scientific validation regarding neuroprotective potential. The present study describes the synthesis of non-psychoactive lower homologues of THC-type compounds and their neuroprotective potential. Both natural tetrahydro-cannabiorcol (trans-(-)-Δ9-THCO) and unnatural Δ9-tetrahydrocannabiorcol (trans-(+)-Δ9-THCO) were successfully synthesized starting from R-limonene and S-limonene, respectively, and investigated for neuroprotective potential in cellular models. The structures of both enantiomers were confirmed by NMR, HMBC, HQSC, NOESY, and COSY experiments. Results indicated that both enantiomers were nontoxic to the cells treated up to 50 µM. Neuroprotective properties of the enantiomers showed that treatments could significantly reverse the corticosterone-induced toxicity in SH-SY5Y cells and simultaneously cause elevated expression of brain-derived neurotrophic factor (BDNF). It was also observed that unnatural trans-(+)-Δ9-THCO displayed better activity than the natural enantiomer and can be further explored for its potential use in neuropathological ailments.

Unveiling the mechanisms and challenges of cancer drug resistance.

Cancer treatment faces many hurdles and resistance is one among them. Anti-cancer treatment strategies are evolving due to innate and acquired resistance capacity, governed by genetic, epigenetic, proteomic, metabolic, or microenvironmental cues that ultimately enable selected cancer cells to survive and progress under unfavorable conditions. Although the mechanism of drug resistance is being widely studied to generate new target-based drugs with better potency than existing ones. However, due to the broader flexibility in acquired drug resistance, advanced therapeutic options with better efficacy need to be explored. Combination therapy is an alternative with a better success rate though the risk of amplified side effects is commonplace. Moreover, recent groundbreaking precision immune therapy is one of the ways to overcome drug resistance and has revolutionized anticancer therapy to a greater extent with the only limitation of being individual-specific and needs further attention. This review will focus on the challenges and strategies opted by cancer cells to withstand the current therapies at the molecular level and also highlights the emerging therapeutic options -like immunological, and stem cell-based options that may prove to have better potential to challenge the existing problem of therapy resistance. Video Abstract.

Design, synthesis and neuroprotective evaluation of nitrogen heterocyclic and triazole derivatives of sarracinic acid.

Novel sarracinic acid derivatives bearing triazole or N-heterocyclic moiety were prepared via two separate reaction schemes. The triazoles and the N-heterocyclic derivatives were synthesised using standard click chemistry approach and amination of 2-bromoethyl ester of sarracinic acid respectively. All the synthesised derivatives were screened for in vitro neuroprotective activity against corticosterone induced impairment in neuroblastoma cell line SH-SY5Y. Two analogs SA-2 and SA-12 exhibited strong neuroprotective activity. The cell viability, after high dose corticosterone induced cell death, increased remarkably with the pre treatment of SA-2 and SA-12. The in vitro biological activity of SA-2 and SA-12 was verified through docking studies. The docking studies were in good agreement with the biological results. SA-2 and SA-12 showed strong binding affinities with the target protein having ΔGb = -8.88 and -7.52; inhibition constant (ki) = 3.08 nM and 30.9 nM respectively.

Cancer metastasis: Molecular mechanisms and clinical perspectives.

Metastatic progression combined with non-responsiveness towards systemic therapy often shapes the course of disease for cancer patients and commonly determines its lethal outcome. The complex molecular events that promote metastasis are a combination of both, the acquired pro-metastatic properties of cancer cells and a metastasis-permissive or -supportive tumor micro-environment (TME). Yet, dissemination is a challenging process for cancer cells that requires a series of events to enable cancer cell survival and growth. Metastatic cancer cells have to initially detach themselves from primary tumors, overcome the challenges of their intravasal journey and colonize distant sites that are suited for their metastases. The implicated obstacles including anoikis and immune surveillance, can be overcome by intricate intra- and extracellular signaling pathways, which we will summarize and discuss in this review. Further, emerging modulators of metastasis, like the immune-microenvironment, microbiome, sublethal cell death engagement, or the nervous system will be integrated into the existing working model of metastasis.

Lavender plant: Farming and Health benefits.

Natural remedies from a range of sources, including plants, animals, microorganisms, and marine life, have made a significant contribution to the treatment of many ailments. Lavender is a Mediterranean shrub from the Lamiaceae family. Lavender flowers (Lavandula flores) include active ingredients (3%), anthocyanins, sugars, phytosterols, minerals, and tannins and are majorly used for herbal applications. Lavender essential oil's descriptive and analytical composition varies depending on genotype, growing region, climatic circumstances, propagation, and morphological characteristics. There are around 300 chemical components in essential oil. Linalool, terpinen-4-ol, linalyl acetate, ocimene, acetate lavandulol, and cineole are the most prominent constituents. Lavender oil has antibacterial and antioxidant properties. The lavender extract helps to prevent dementia and may slow cancer cell growth, while lavender oil is used to treat skin problems. This review will cover the recent medical, economic and regional advancements in levander propagation and how the Council of Scientific & Industrial Research Indian Institute of Integrative (CSIR IIIM) aroma mission is actively acting as a bridge between farmers and their economic improvement by attracting them to the field of medicinal plant cultivation.

Small molecule '4ab' induced autophagy and endoplasmic reticulum stress-mediated death of aggressive cancer cells grown under adherent and floating conditions.

Metastasis is the leading cause of death in cancer patients and a major challenging aspect of cancer biology. Various adaptive molecular signaling pathways play a crucial role in cancer metastasis and later in the formation of secondary tumors. Aggressive cancer cells like triple negative breast cancer (TNBCs) are more inclined to undergo metastasis hence having a high recurrence rate and potential of micro-metastasis. Tumor cells in circulation known as circulating tumor cells (CTCs) offer an attractive drug target to treat metastatic disease. Cell cycle regulation and stress response of CTCs in blood has a crucial role in their survival and progression and thus may be considered therapeutically active hotspots. The cyclin D/cyclin-dependent kinase (CDK) pathway regulates cell cycle checkpoints, a process that is frequently dysregulated in cancer cells. Selective CDK inhibitors can limit the phosphorylation of cell cycle regulatory proteins by inducing cell cycle phase arrest, and thus may be an effective therapeutic strategy for aggressive cancer cells in their dividing phase at the primary or secondary site. However, during the floating condition, cancer cells halt their multiplication process and proceed through the various steps of metastasis. Current study showed that a novel CDK inhibitor 4ab induced autophagy and endoplasmic reticulum (ER) stress in agressive cancer cells grown under adherent and floating conditions resulting in paraptosis. Further, our results showed that 4ab efficiently induced cell death in aggressive cancer cells through ER stress-mediated activation of JNK signaling. Additionally, was observed that treatment of 4ab in tumor-bearing mice displayed a significant reduction in tumor burden and micro-metastasis. The outcome of these studies showed that 4ab can be a potential anti-tumor and anti-metastatic agent. Graphical representation of 4ab: image representing the effect of 4ab on death-inducing pathways in aggressive cancer cells. 4ab induces ER stress and activates autophagy leading to vacuolation of there by causing apoptosis in aggressive cancer cells.

TFA-mediated stereoselective aza-Michael addition for the synthesis of 3ß-arylamine derivatives of withaferin A and evaluation of their anticancer potential.

A simple and efficient protocol for the aza-Michael addition of various aromatic anilines to ring A of withaferin A has been developed. Stereoselectivity, functional group tolerance, broad substrate scope, short reaction time and moderate to high yield are the merits of the protocol. One of the synthesized compounds 11 shows an IC 50 value of 3.8 µM against aggressive, highly metastatic triple-negative breast cancer cell line MDA-MB-231.

Targeting redox regulation and autophagy systems in cancer stem cells.

Cancer is a dysregulated cellular level pathological condition that results in tumor formation followed by metastasis. In the heterogeneous tumor architecture, cancer stem cells (CSCs) are essential to push forward the progression of tumors due to their strong pro-tumor properties such as stemness, self-renewal, plasticity, metastasis, and being poorly responsive to radiotherapy and chemotherapeutic agents. Cancer stem cells have the ability to withstand various stress pressures by modulating transcriptional and translational mechanisms, and adaptable metabolic changes. Owing to CSCs heterogeneity and plasticity, these cells display varied metabolic and redox profiles across different types of cancers. It has been established that there is a disparity in the levels of Reactive Oxygen Species (ROS) generated in CSCs vs Non-CSC and these differential levels are detected across different tumors. CSCs have unique metabolic demands and are known to change plasticity during metastasis by passing through the interchangeable epithelial and mesenchymal-like phenotypes. During the metastatic process, tumor cells undergo epithelial to mesenchymal transition (EMT) thus attaining invasive properties while leaving the primary tumor site, similarly during the course of circulation and extravasation at a distant organ, these cells regain their epithelial characteristics through Mesenchymal to Epithelial Transition (MET) to initiate micrometastasis. It has been evidenced that levels of Reactive Oxygen Species (ROS) and associated metabolic activities vary between the epithelial and mesenchymal states of CSCs. Similarly, the levels of oxidative and metabolic states were observed to get altered in CSCs post-drug treatments. As oxidative and metabolic changes guide the onset of autophagy in cells, its role in self-renewal, quiescence, proliferation and response to drug treatment is well established. This review will highlight the molecular mechanisms useful for expanding therapeutic strategies based on modulating redox regulation and autophagy activation to targets. Specifically, we will account for the mounting data that focus on the role of ROS generated by different metabolic pathways and autophagy regulation in eradicating stem-like cells hereafter referred to as cancer stem cells (CSCs).

Isolation and characterisation of pharmaceutically versatile molecules from Rumex dentatus and evaluation of their cytotoxic activity against human cancer cell lines.

The disclosed study reveals isolation, characterization and anticancer evaluation of Rumex dentatus. The extracts and isolated compounds were used for cytotoxic activity against (lung (A549), pancreatic (MIAPaCa), colon (HCT-116), breast (MDA-MB-231) and breast (MDA-MB-468) cell lines. The extracts were screened for cytotoxicity using MTT colorimetric assay. Out of all extracts, methanolic (30) %: chloroform fraction (TAW6) with 75.01% inhibition at a concentration 100 µg/mL was observed. The selected extracts were further processed for column chromatography and led to isolation of seven compounds (A to G). The structural determination of isolated compounds was carried out using 1HNMR, 13CNMR, IR and HRMS. All the isolates were tested for cytotoxic activity and compound B was found most active with IC50 values 11.29 µg against HCT-116 (Colon). The compound B was then used for detailed study via transwell invasion assay and wound healing assay. Thus the significant anticancer activity particularly against colon cancerous cell lines recommends that the (Rumex dentatus) could act as a potential drug candidate for cancer, more particularly for colon cancer.

Redox balance and autophagy regulation in cancer progression and their therapeutic perspective.

Cellular ROS production participates in various cellular functions but its accumulation decides the cell fate. Malignant cells have higher levels of ROS and active antioxidant machinery, a characteristic hallmark of cancer with an outcome of activation of stress-induced pathways like autophagy. Autophagy is an intracellular catabolic process that produces alternative raw materials to meet the energy demand of cells and is influenced by the cellular redox state thus playing a definite role in cancer cell fate. Since damaged mitochondria are the main source of ROS in the cell, however, cancer cells remove them by upregulating the process of mitophagy which is known to play a decisive role in tumorigenesis and tumor progression. Chemotherapy exploits cell machinery which results in the accumulation of toxic levels of ROS in cells resulting in cell death by activating either of the pathways like apoptosis, necrosis, ferroptosis or autophagy in them. So understanding these redox and autophagy regulations offers a promising method to design and develop new cancer therapies that can be very effective and durable for years. This review will give a summary of the current therapeutic molecules targeting redox regulation and autophagy for the treatment of cancer. Further, it will highlight various challenges in developing anticancer agents due to autophagy and ROS regulation in the cell and insights into the development of future therapies.

Myrica esculenta Buch.-Ham. (ex D. Don): A Review on its Phytochemistry, Pharmacology and Nutritional Potential.

Myrica esculenta is an important ethnomedicinal plant used in the traditional system of medicine and as an important nutraceutical. Several studies on the plant justify its use in alternative systems of medicine and establish a scientific rationale for its possible therapeutic application. The plant contains a range of biologically active classes of compounds, particularly diarylheptanoids, flavonoids, terpenes, tannins, and glycosides. The nutraceutical potential of the plant can be particularly attributed to its fruit, and several studies have demonstrated the presence of carbohydrates, proteins, fats, fiber content, and minerals like sodium, potassium, calcium, manganese, iron, copper, and zinc, in it. The current review aims to provide complete insight into the phytochemistry, pharmacological potential, and nutritional potential of the plant, which would not only serve as a comprehensive source of information but also will highlight the scope of isolation and evaluation of these molecules for various disease conditions.

Understanding the cell survival mechanism of anoikis-resistant cancer cells during different steps of metastasis.

Anchorage-independent survival of cancer cells is associated with metastasis as it enables cells to travel to secondary target sites. Tissue integrity is generally maintained by detachment-induced cell death called 'anoikis', but cancer cells undergoing the multistep metastatic process show resistance to anoikis. Anoikis resistance enables these cells to survive through the extracellular matrix (ECM) deprived phase, which starts when cancer cells detach and move into the circulation till cells reach to the secondary target site. Comprehensive analysis of the molecular and functional biology of anoikis resistance in cancer cells will provide crucial details about cancer metastasis, enabling us to identify novel therapeutic targets against cancer cell dissemination and ultimately secondary tumor formation. This review broadly summarizes recent advances in the understanding of cellular and molecular events leading to anoikis and anoikis resistance. It further elaborates more about the signaling cross-talk in anoikis resistance and its regulation during metastasis.

Activation of lysosomal mediated cell death in the course of autophagy by mTORC1 inhibitor.

Lysosomal biogenesis plays a vital role in cell fate. Under certain conditions, excessive lysosomal biogenesis leads to susceptibility for lysosomal membrane permeabilization resulting in various pathological conditions including cell death. In cancer cells apoptosis machinery becomes dysregulated during the course of treatment, thus allows cancer cells to escape apoptosis. So it is therefore imperative to identify cytotoxic agents that exploit non-apoptotic mechanisms of cell death. Our study showed that pancreatic cancer cells treated with SDS-203 triggered an incomplete autophagic response and a nuclear translocation of transcriptional factor TFEB. This resulted in abundant biosynthesis and accumulation of autophagosomes and lysosomes into the cells leading to their death. It was observed that the silencing of autophagy genes didn't alter the cell fate, whereas siRNA-mediated silencing of TFEB subdued SDS-203 mediated lysosomal biogenesis and associated cell death. Further mouse tumors treated with SDS-203 showed a significant reduction in tumor burden and increased expression of lysosomal markers. Taken together this study demonstrates that SDS-203 treatment triggers non-apoptotic cell death in pancreatic cancer cells through a mechanism of lysosome over accumulation.

Neuroprotective activity of natural products isolated from Senecio graciliflorus DC against corticosterone-induced impairment in SH-SY5Y cells.

Senecio graciliflorus DC root extract was studied for secondary metabolite composition following the bioactivity-guided isolation technique. The ethyl acetate extract of Senecio graciliflorus root yielded nine chemical constituents: 3,4-di-tert-butyl toluene, stigmasterol, ß-sitosterol, 2ß-(angeloyloxy)furanoeremophilane, gallic acid, 2ß-{[(Z)-2-hydroxymethylbut-2-enoyl]oxy}furanoeremophilane, 1-hydroxypentan-2-yl-4-methylbenzoate, sarcinic acid, and sitosterol 3-O-ß-D-glucopyranoside. The structures of the chemical constituents were elucidated on the basis of spectral data analysis in the light of literature. All the compounds are being reported for the first time from this plant. The isolated constituents were screened for neuroprotective effects against corticosterone-induced impairment in neuroblastoma cell lines (SH-SY5S cells). The viability of SH-SY5S cells was determined using MTT assay. Among various isolated compounds, three natural products (sarcinic acid, gallic acid, and ß-sitosterol) displayed robust neurotropic activity. The compounds increased neuronal cell survival in differentiated neuroblastoma cells (SH-SY5Y) from high-dose corticosterone (400 µM)-induced cell death. All the three constituents showed maximum AKT/ERK pathway activation at 20 µM concentration. The studies are aimed to explore small molecules for treating neurodegeneration underlying various neurological disorders to restore neuronal cell plasticity.

Platanic Acid-Aryl Enones as Potential Anticancer Compounds: Synthesis and Biological Profiling against Breast, Prostate and Lung Cancer Cell Lines.

A series of rationally designed platanic acid-based compounds derived from naturally occurring betulinic acid were synthesized through a sequence of Lemieux-Johnson oxidation and Aldol condensation reaction. All the compounds were screened for cytotoxicity against a panel of human cancer and normal cell lines using MTT assay. From the biological data, it was observed that some of these semi-synthetic congeners exhibited potent biological profiles compared to platanic acid. One of the compounds with the p-tolyl substitution was found to be most active in this study, and its cytotoxicity against two of the cell lines, MDA-MB 231 and A-549 were in tune with the standard compound, 5-fluorouracil.

A rohitukine derivative IIIM-290 induces p53 dependent mitochondrial apoptosis in acute lymphoblastic leukemia cells.

Rohitukine, a chromone alkaloid extracted from Dysoxylum binectariferum, has a propitious anticancer activity. Our previous study shows that a new Rohitukine derivative IIIM-290 restricts the growth of pancreatic cancer in vivo and in vitro. In the present findings, we report the mechanism of cell death induced by IIIM-290 in MOLT-4 cells (acute lymphoblastic leukemia) and its anticancer potential against various murine leukemic tumor models in vivo. We found that IIIM-290 induced apoptosis through upregulation of different apoptotic proteins like PUMA, BAX, cytochrome c, cleaved (active) caspase-3, and cleaved PARP in MOLT-4 cells. Moreover, IIIM-290 abated mitochondrial membrane potential, elevated calcium levels, reactive oxygen species, and arrested growth of MOLT-4 cells in the synthesis (S) phase of the cell cycle. Interestingly, the elevation in proapoptotic markers was p53 dependent-the silencing of p53 abrogated apoptosis (programmed cell death) triggered by IIIM-290 in MOLT-4 cells. Furthermore, IIIM-290 significantly enhanced the survival of animals with P388 and L1210 leukemia. Thus, our results put IIIM-290 as a potential candidate for the anticancer lead.