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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.

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.

Abstract: 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.

PDF file - 491K, Supplementary Figure 3. Effect of trastazumab on stem cell marker expression. Supplementary Figure 2. Trastuzumab inhibits tertiary tumorsphere formation in luminal cell lines. Supplementary Figure 1. Representative FACS analysis demonstrating an overlap between HER2 expression and ALDH activity. Supplementary Figure 4. Trastuzumab treatment or HER2 gene knockdown reduces tumorsphere formation of MCF7 cells. Supplementary Figure 5. Rank mediated upreglation of HER2 expression in MCF7 cells. Supplementary Figure 6. Elevated HER2 expression in bone metastasis compared to matched primary luminal tumors is not due to HER2 gene amplification. Supplemental Figure 7. No significant differences in HER2 protein expression were found in matched primary tumors and bone metastasis in women with HER-positive breast cancer.

Supplementary Figure 1. Molecular structure and cytotoxic profile of secalonic acid D (SAD). Colony morphology, Neighbor-joining rooted tree and sequencing of fungal endophyte (EF-VR2).

Supplementary Material 1. DETAILS OF ANTIBODIES USED IN THE STUDY

Supplementary Figure 2. Schematic presentation of mechanism of action of SAD.

Supplementary Material 2. DETAILS OF PRIMERS USED IN THE STUDY

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).

Cancer metastasis is the leading cause of death in cancer patients and is 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 for secondary tumor formation. Such aggressive cancer cells have fewer treatment options available with poor prognoses. Metastatic cells in circulation known as circulating tumor cells (CTCs) could be an appealing alternative target for cancer therapy with potentially better outcomes. 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 division process and proceed through the various steps of metastasis. Our study showed that a novel CDK inhibitor 4ab besides showing anti-proliferative activity in aggressive cancer cells also induces cell death by activating endoplasmic reticulum stress and strong autophagy induction in both adherent and floating conditions which resulted in cytoplasmic vacuolation (paraptosis) and ultimately resulted in cell death. Further our results showed that 4ab efficiently induced apoptosis in aggressive cancer cells by initiating the ER-mitochondrial membrane potential loss-JNK pathway. Further, our in vivo data showed a promising inhibitory effect of 4ab on aggressive 4T1 cells in tumor formation and metastasis. The above data gave us encouraging results to consider 4ab as a potential inhibitor for anti-metastatic therapeutic intervention.

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.

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.

The emergence of the versatile gene-editing technology using programmable sequence-specific endonuclease system (CRISPR-Cas9) has instigated a major upheaval in biomedical research. In a brief span of time, CRISPR/Cas has been adopted by research labs around the globe because of its potential for significant progress and applicability in terms of efficiency, versatility and simplicity. It is a breakthrough technique for systematic genetic engineering, genome labelling, epigenetic and transcriptional modulation, and multiplexed gene editing, amongst others. This review provides an illustrative overview of the current research trends using CRISPR/Cas technology. We highlight the latest developments in CRISPR/Cas technique including CRISPR imaging, discovery of novel CRISPR systems, and applications in altering the genome, epigenome or RNA in different organisms. Finally, we address the potential challenges of this technique for its future use. Development of new CRISPR/Cas systems.

AKT, a serine threonine kinase, exists in three different isoforms and is known for regulating several biological processes including tumorigenesis. In this study, we investigated the expression and net effect of the individual isoforms in triple negative breast cancers and response to cisplatin treatment using cellular, mice models and clinical samples. Interestingly, analysis of the expressions of AKT isoforms in clinical samples showed relatively higher expression of AKT1 in primary tissues; whereas lung and liver metastatic samples showed elevated expression of AKT2. Similarly, triple-negative breast cancer cell lines, BT-549 and MDA-MB-231, with high proliferative and invasive properties, displayed higher expression levels of AKT1/2. By modulating AKT isoform expression in MCF-10A and BT-549 cell lines, we found that presence of AKT2 was associated with invasiveness, stemness and sensitivity to drug treatment. It was observed that the silencing of AKT2 suppressed the cancer stem cell populations (CD44high CD24low, ALDH1), mammosphere formation, invasive and migratory potential in MCF-10A and BT-549 cells. It was further demonstrated that loss of function of AKT1 isoform is associated with reduced sensitivity towards cisplatin treatment in triple-negative breast cancers cellular and syngeneic mice models. The decrease in cisplatin treatment response in shAKT1 cells was allied with the upregulation in the expression of transporter protein ABCG2, whereas silencing of ABCG2 restored cisplatin sensitivity in these cells through AKT/SNAIL/ABCG2 axis. In conclusion, our study demonstrated the varied expression of AKT isoforms in triple-negative breast cancers and also confirmed differential role of isoforms in stemness, invasiveness and response towards the cisplatin treatment.

Velutibol A (1), a new 14-residue peptaibol was isolated from the Himalayan cold habitat fungus Trichoderma velutinum. The structural characterization was carried out by 1D and 2D NMR studies, and tandem mass studies, and Marfey's method aided in determining the stereochemistry of the amino acids. The CD analysis revealed folding of the peptide in a 310-helical conformation. The intramolecular H-bonding was determined by an NMR-VT experiment. Cytotoxic evaluation was carried out against a panel of cancer cell lines. The cell cycle assay was carried out on human myeloid leukaemia (HL-60) cells and revealed the formation of apoptotic bodies and DNA damage in a dose-dependent manner. Three other peptaibols namely velutibol B (2), velutibol C (3), and velutibol D (4) were also isolated in trace amounts from the psychotropic fungus and characterized through tandem mass spectroscopy and Marfey's analysis.

Data science has been an invaluable part of the COVID-19 pandemic response with multiple applications, ranging from tracking viral evolution to understanding the effectiveness of interventions. Asymptomatic breakthrough infections have been a major problem during the ongoing surge of Delta variant globally. Serological discrimination of vaccine response from infection has so far been limited to Spike protein vaccines used in the higher-income regions. Here, we show for the first time how statistical and machine learning (ML) approaches can discriminate SARS-CoV-2 infection from immune response to an inactivated whole virion vaccine (BBV152, Covaxin, India), thereby permitting real-world vaccine effectiveness assessments from cohort-based serosurveys in Asia and Africa where such vaccines are commonly used. Briefly, we accessed serial data on Anti-S and Anti-NC antibody concentration values, along with age, sex, number of doses, and number of days since the last vaccine dose for 1823 Covaxin recipients. An ensemble ML model, incorporating a consensus clustering approach alongside the support vector machine (SVM) model, was built on 1063 samples where reliable qualifying data existed, and then applied to the entire dataset. Of 1448 self-reported negative subjects, 724 were classified as infected. Since the vaccine contains wild-type virus and the antibodies induced will neutralize wild type much better than Delta variant, we determined the relative ability of a random subset of such samples to neutralize Delta versus wild type strain. In 100 of 156 samples, where ML prediction differed from self-reported uninfected status, Delta variant, was neutralized more effectively than the wild type, which cannot happen without infection. The fraction rose to 71.8% (28 of 39) in subjects predicted to be infected during the surge, which is concordant with the percentage of sequences classified as Delta (75.6%-80.2%) over the same period.

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.

Four known metabolites, macrophin (1), rosellisin (2), 2-(2-hydroxy-5-6-methoxy-3-methylene-1,4-benzodioxin-2(3H)-one (3), and methoxyphenoxyacrylic acid (4) were isolated, for the first time, from an endophytic fungus, Phoma macrostoma inhabiting the inner tissue of medicinal plant Glycyrrhiza glabra Linn. Their structures were characterized by comparison of their NMR data with literature data, and X-ray diffraction data of macrophin (1) as described herein for the first time. The compounds (1–4) were evaluated for their growth-inhibitory activities against a panel of cancer cell lines. Of these substances, macrophin (1) showed prominent cytotoxic activity against the MDA-MB-231, T47D, MCF-7, and MIAPaCa-2 cancer-cell lines with IC50 values of 14.8, 8.12, 13.0, and 0.9 μM, respectively. This biological significance has prompted us to generate a series of five acylated analogs (1a–1e) of 1 to conduct structure–activity relationship (SAR) study. The result illustrates all the analogues (1a–1e) were more potent than 1 against MDMB-231 and MIAPaCa-2 cancer cell lines. The compound 1d, an n-butanoyl substituent, has been proven to be three-fold more potent than 1 with IC50 values of 0.3 and 3.7 µM against MIAPaCa-2 and MDMB-231 cell lines, respectively.

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, β-sitosterol, 2β-(angeloyloxy)furanoeremophilane, gallic acid, 2β-{[(Z)-2-hydroxymethylbut-2-enoyl]oxy}furanoeremophilane, 1-hydroxypentan-2-yl-4-methylbenzoate, sarcinic acid, and sitosterol 3-O-β-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 β-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.

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.

Background: Low therapeutic efficacy and drug-induced systemic toxicity of currently used anti-cancerous chemotherapeutic agents are major compelling factors for finding out clinically efficient molecules with high efficiency and less toxicity. Objective: The current research work was undertaken to evaluate the anticancer potential of Myricanol- 9-acetate (MA), a novel naturally occurring derivative of myricanol. Methods: MCF-7, MiaPaCa-2, and HCT 116 were used for cytotoxicity determination of the MA and ML (Myricanol) by MTT assay. The mechanistic study involved the determination of cell cycle arrest, Δψm loss, ROS generation, western blot assay, flow cytometry by reported methods on MCF-7 cells. Results: MA exhibited anticancer activity against all three cell lines, however, the molecule was found most active against the MCF-7 cell line. We observed IC5020 μM with MA treatment as compared to the IC50 of 42 μM for myricanol treatment. Detailed mechanistic studies revealed that MA induces apoptosis of MCF-7 cell line through ROS generation and dose-dependent drop in mitochondrial membrane potential associated with cell cycle arrest at G0/G1 phase. Our results further demonstrated that down-regulation of Bcl2 and activation of the caspase cascade are the events involved in the MA-induced apoptosis. Flow cytometry results indicated an increase in early and late apoptotic population in a dose-dependent manner with an apoptotic population of about 20% at 30 μM of MA, thus, supporting our results. Conclusion: Present findings suggest that MA might serve as a promising novel drug candidate with high scope for taking it to further evaluation in preclinical and clinical studies.

Neuropsychiatric disorders affect a massive chunk of world population directly or indirectly. The disability caused by neuropsychiatric disorders has a huge burden on one’s personal and family life and on the society, in general. Unfortunately, the affected person faces negative impact of discrimination everywhere, and the families too have to make adjustments and compromises in today’s life events, affecting their quality of life. The neuropsychiatric disorders are complex, which reflects in their inept treatment regimen. The direct connection of neuropsychiatric disorders with one’s behaviour makes them different from the rest of human health complications. The drugs and treatments are usually symptom specific, and the symptoms are usually overlapping between these disorders making the treatment non-specific. The side effects of the medicine and therapies for neuropsychiatric disorders are enormous and often lead to further complications due to off-targets. Plant-based treatments have been a good option of treating these disorders as they come with more advantages than side effects to the human body. So, plant-based therapies stand as a considerable option for treating these disorders.

A strategy for construction of medicinally important 1,4-substituted 1H-1,2,3-triazolo-quinazolin-4(3H)-ones has been devised and presented here. The compounds have been synthesized using one-pot multicomponent strategy under microwave assisted conditions. Triazolyl-quinazolinone based D-ring modified analogs are designed based on IC87114 scaffold, which is first known isoform selective inhibitor of PI3Kδ. Herein, we identified two triazolyl-quinazolinone compounds (5a and 5l) based on same scaffold with PI3Kγ specific inhibitory potential, the selectivity towards this isoform is well supported by in silico results, wherein, these compounds show better interaction and affinity and inhibitory activity for PI3Kγ rather than PI3Kδ. This repositioning of scaffold from PI3Kδ to PI3Kγ isoform can be very useful from medicinal chemistry and drug discovery perspective to unravel molecular interactions of this new scaffold in different cellular pathways.

Arginase is a therapeutic enzyme for arginine-auxotrophic cancers but their low anticancer activity, less proteolytic tolerance and shorter serum half-life are the major shortcomings. In this study, arginase from Pseudomonas aeruginosa IH2 was purified to homogeneity and estimated as 75 kDa on native-PAGE and 37 kDa on SDS-PAGE. Arginase showed optimum activity at pH 8 and temperature 35 °C. Mn 2+ and Mg 2+ ions enhanced arginase activity while, Li + , Cu 2+ , and Al 3+ ions reduced arginase activity. In-vitro serum half-life of arginase was 36 h and proteolytic half-life against trypsin and proteinase-K was 25 and 29 min, respectively. Anticancer activity of arginase was evaluated against colon, breast, leukemia, and prostate cancer cell lines and lowest IC 50 (0.8 IU ml −1 ) was found against leukemia cell line HL-60. Microscopic studies and flow cytometric analysis of Annexin V/PI staining of HL-60 cells revealed that arginase induced apoptosis in dose-dependent manner. Cell cycle analysis suggested that arginase induced cell cycle arrest in G0/G1 phase. The increasing level of MMP loss, ROS generation and decreasing level of SOD, CAT, GPx and GSH suggested that arginase treatment triggered dysfunctioning of mitochondria. The cleavage of caspase-3, PARP-1, activations of caspase-8, 9 and high expression of proapoptotic protein Bax, low expression of anti-apoptotic protein Bcl-2 indicated that arginase treatment activates mitochondrial pathway of apoptosis. Purified arginase did not exert cytotoxic effects on human noncancer cells. Our study strongly supports that arginase could be used as potent anticancer agent but further studies are required which are underway in our lab.

The serine/threonine protein kinase B (PKB), also known as Akt, is one of the multifaceted kinases in the human kinome, existing in three isoforms. PKB plays a vital role in phosphoinositide 3-kinase (PI3K)-mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. Recent studies have shown that the functional significance of an individual isoform of PKB is not redundant in cancer. It has been found that PKB isoforms play distinct roles in the regulation of cellular invasion and migration during tumorigenesis. PKB activation plays a central role during epithelial-mesenchymal transition, a cellular program required for the cancer cell invasion and migration. However, the differential behavior of each PKB isoform has been shown in the regulation of epithelial-mesenchymal transition. Recent studies have suggested that PKBα (Akt1) plays a conflicting role in tumorigenesis by acting either as a pro-oncogenic factor by suppressing the apoptotic machinery or by restricting tumor invasion. PKBβ (Akt2) promotes cell migration and invasion and similarly PKBγ (Akt3) has been reported to promote tumor migration. As PKB is known for its pro-oncogenic properties, it needs to be unraveled how three isoforms of PKB compensate during tumor progression. In this review, we attempted to sum up how different isoforms of PKB play a role in cancer progression, metastasis, and drug resistance.

A new series of bakuchiol 1 Mannich derivatives was synthesized by reaction with various substituted secondary amines. The analogs were evaluated for cytotoxicity against a panel of three different human cancer cell lines breast (MCF-7), colon (HCT-116) and lung (A549). Cytotoxicity screening results showed that many compounds displayed significant in vitro cytotoxic effects against different cancer cell lines. Compounds 9, 12, 14, 16, 17 and 21 showed promising cytotoxic effects compared to parent molecule 1 and among them compound 14 was found to be most potent analog with IC50 5 μM against all the cell lines examined. It was about 8-fold more potent against MCF-7 and A549 and 10-fold more potent against HCT-116 cell line in comparison to the parent molecule 1. Structure activity relationship (SAR) study of all synthesized derivatives was carried out. Further, compound 14 induced apoptosis in lung cancer cells (A549) through caspase activation followed by PARP-1 cleavage.

Different natural aromatic/heterocyclic l-amino acids were biotransformed into aryl/heteroaryl ethanol metabolites via oxidative deamination, decarboxylation and reduction cascades using live baker's yeast cells producing intracellular human CYP2D6 enzyme. Among the three yeast strains expressing 3 different CYP2D6 variants, CYP2D6(2) (i.e. CYP2D6 wild-type) provided the best result under neutral pH conditions at RT. We have successfully converted six natural amino acids into their corresponding alcohols, having one carbon atom less, with moderate yields. Some of the downstream products like tryptophol and tyrosol induced the pTrKB (Tropomyosin receptor kinase B) activation pattern similar to that of BDNF (brain-derived neurotrophic factor), thereby depicting potential antidepressant activity. Control experiments and molecular modelling studies revealed that this tandem bio-transformation probably happens via a pyruvate intermediate. This study establishes that CYP2D6-expressing live yeast cells can be a powerful tool for the enzymatic C-N, C-C bond cleavage of amino-acids.

Withania somnifera exhibits different pharmacological activities which mainly stem from its broad range of bioactive molecules. Majority of these bioactive molecules, fall into the groupings of alkaloids, steroidal lactones, phenolic compounds and glycoproteins. In this study, we evaluated a novel protein fraction, named here as WSPF, isolated from Withania somnifera roots for its cytotoxic properties against various human cancer cell lines. WSPF exhibited apoptotic activity for each cancer cell line tested, demonstrating significant activity against MDA-MB-231 human breast cancer cells with an IC50 value of 92 μg/mL. WSPF induced mitochondrial-mediated apoptosis of MDA-MB-231 cells via extensive reactive oxygen species generation, dysregulation of Bax/Bcl-2, loss of mitochondrial membrane potential and caspase-3 activation. Additionally, we observed G2/M-phase cell cycle arrest, cleavage of nuclear lamin A/C proteins, and nuclear morphological changes. The present results highlight the anti-cancer properties of WSPF, indicating that the proteins in this fraction can be potential therapeutic agents for triple negative breast cancer treatment.

Imbalance in production and clearance of amyloid beta (Aβ) is the primary reason for its deposition in Alzheimer disease. Macroautophagy/autophagy is one of the important mechanisms for clearance of both intracellular and extracellular Aβ. Here, through screening, we identified alborixin, an ionophore, as a potent inducer of autophagy. We found that autophagy induced by alborixin substantially cleared Aβ in microglia and primary neuronal cells. Induction of autophagy was accompanied by up regulation of autophagy proteins BECN1/Beclin 1, ATG5, ATG7 and increased lysosomal activities. Autophagy induced by alborixin was associated with inhibition of the phosphoinositide 3-kinase (PI3K)-AKT pathway. A knock down of PTEN and consistent, constitutive activation of AKT inhibited alborixin-induced autophagy and consequent clearance of Aβ. Furthermore, clearance of Aβ by alborixin led to significant reduction of Aβ-mediated cytotoxicity in primary neurons and differentiated N2a cells. Thus, our findings put forward alborixin as a potential anti-Alzheimer therapeutic lead. Abbreviations: Aβ: amyloid beta; ALB: alborixin; ATG: autophagy-related; BECN1: beclin 1; DAPI: 4, 6-diamidino-2-phenylindole; DCFH-DA: 2,7-dichlorodihydrofluorescein diacetate; fAβ: fibrillary form of amyloid beta; GFAP: glial fibrillary acidic protein; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MAP2: microtubule-associated protein 2; MTOR: mechanistic target of rapamycin kinase; PTEN: phosphatase and tensin homolog; ROS: reactive oxygen species; SQSTM1: sequestosome 1; TMRE: tetramethylrhodamine, ethyl ester

Diapolic acid A–B from an endophytic fungus, Diaporthe terebinthifolii depicting antimicrobial and cytotoxic activity

Diverse 11R,13-dihydroamino and 1,10β-epoxy-11R,13-dihydroamino analogs of ludartin were synthesized using a highly diastereoselective Michael addition and epoxidation reaction. The semisynthetic analogs were characterized using rigorous spectral data analysis. All the compounds were subjected to sulphorhodamine B cytotoxicity screening against a panel of three breast cancer cells, viz., T47D, MCF-7, and MDA-MB 231. Among the synthesized analogs, compounds 11, 19, and 20 proved to be active against the breast cancer cell lines. Compound 11 represents an epoxy analog of arglabin (5), which is a noteworthy and clinically significant antitumor agent and exhibited an IC50s of 0.75 µM and 1.20 µM against MCF-7 and MDA MB-231 cell lines, respectively. Compounds 19 and 20 displayed selectivity among the three breast cancer cell lines and were active against MCF-7 cell lines only displaying IC50s of 1.00 and 1.21 µM, respectively. This study provides initial structure-activity relationship data on ludartin and its analogs against breast cancer cell lines based on the previous literature reports of ludartin as an aromatase inhibitor.

In the present study, a series of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-ones were synthesised and evaluated as antiproliferative agents. The compounds were evaluated against a panel of human cancer cell lines. CH-1 exhibited significant cytoxicity against HCT 116 cell lines with an IC50 value of 1.4 and 4.3 µM against "MiaPaCa-2" cell lines. The compound CH-1 was found to induce apoptosis as evidenced by phase contrast microscopy, Hoechst 33258 staining and mitochondrial membrane potential (MMP) loss. The cell phase distribution studies indicated that the apoptotic population increased from 10.22% in the control sample to 57.19% in a sample treated with 20 µM compound CH-1.

The traditional method of drug discovery process has been surpassed by a rational approach where computer-aided drug designing plays a vital role in the identification of leads from large compound databases. Further, natural products have an important role in drug discovery as these have been the source of most active ingredients of medicines. Herein, in silico structure- and ligand-based approaches have been applied to screen in-house IIIM natural product repository for Akt1 (serine/threonine protein kinases) which is a well-known therapeutic target for cancer due to its overexpression and preventing the cells from undergoing apoptosis. Combined ligand-based and structure-based strategies were applied on to the existing library comprising of about 700 pure natural products, and the compounds identified from screening were biologically evaluated for Akt1 inhibition using Akt1 kinase activity assay. Fourteen promising compounds showed significant inhibition at 500 nM through in vitro screening, and from them, eight were new for Akt1 inhibition. Through the MD studies of Akt1 with the most active compound IN00145, it was inferred that Lys179, Glu191, Glu228, Ala230, Glu234 and Asp292 are the important amino acid residues which provide stability to the Akt1-IN00145 complex. Lead optimization studies were also performed around the actives to design better and selective inhibitors for Akt1. The results emphasized the successful application of virtual screening to identify new Akt1 inhibitor scaffolds that can be developed into a drug candidate in drug discovery programme.

In this study, we for the first time explored the cellular and molecular mechanism of anticancer properties of fascaplysin, a marine sponge-derived alkaloid. Our study demonstrated that fascaplysin induced a cooperative interaction between apoptotic and autophagic pathways to induce cytotoxicity in HL-60 cells. Fascaplysin treatment not only activated pro-apoptotic events like PARP-1 cleavage and caspase activation but also triggered autophagy signaling as shown by the increased expression of LC3-II, ATG7and beclin. Interestingly, it was found that use of pan-caspase inhibitor completely reversed the fascaplysin mediated cell death as analyzed by MTT and cell cycle assays. It was observed that cell death as well as the expression of pro-death proteins was partially reversed, when key autophagy mediators ATG7 was silenced by siRNA in fascaplysin treated cells. Cooperative involvement of autophagy and apoptotic signaling in cytotoxicity was confirmed when combined silencing of pro-apototic (PARP-1) and autophagic (ATG-7) signaling by respective siRNA's lead to substantial rescue of cell death induced by fascaplysin. Although, apoptosis and autophagy are two independent cell death pathways, our findings provide detailed insight by which both the pathways acted cooperatively to elicit fascaplysin induced cell death in HL-60 cells. Our findings provide molecular insight into the anti-cancer potential of fascaplysin by showing that both autophagic and apoptotic signaling can work together in the induction of cell death. J. Cell. Biochem. 116: 985–997, 2015. © 2015 Wiley Periodicals, Inc.

In the present study, a novel series of 3-pyrimidinylazaindoles were designed and synthesized using a bioinformatics strategy as cyclin-dependent kinases CDK2 and CDK9 inhibitors, which play critical roles in the cell cycle control and regulation of cell transcription. The present approach gives new dimensions to the existing SAR and opens a new opportunity for the lead optimizations from comparatively inexpensive starting materials. The study led to the identification of the alternative lead candidate 4ab with a nanomolar potency against CDK2 and CDK9 and potent antiproliferative activities against a panel of tested tumor cell lines along with a better safety ratio of ∼33 in comparison to reported leads. In addition, the identified lead 4ab demonstrated a good solubility and an acceptable in vivo PK profile. The identified lead 4ab showed an in vivo efficacy in mouse triple-negative breast cancer (TNBC) syngeneic models with a TGI (tumor growth inhibition) of 90% without any mortality growth inhibition in comparison to reported leads.

Withania somnifera is wonder shrub used traditionally as a folk medicine for several remedies in the Indian subcontinent. During last few decades numerous scientific studies have shown the potential therapeutic prospects of this herb and of its various constituents in different disease models. Several classes of compounds including withanolides, sitoindosides and other useful alkaloids have been isolated from this plant with promising medicinal value. It has been demonstrated that different parts of plant including roots, leaves and fruits exhibit unique biological activities that actually are manifested to the presence and the abundance of specific constituent/s in the respective parts of the plant. It was also established that same plant grown at different locations under varied environmental conditions influences the synthesis of the individual constituents in different parts of the plant, hence their biological activities. Studies conducted in cellular and murine models have shown that extracts made of roots bear immune activating properties, whereas leaf extracts showed anticancer activities. It has been observed that root and leaf extracts of plant characterised with about a dozen markers displayed that root extracts demonstrated Th1 specific immunomodulatory and anti-inflamatory activities, whereas leaf extracts showed anticancer properties, respectively. It was further explored that anti-cancer potential of leaf extracts was mainly due to Withaferin A, a potent cytotoxic withanoloid, existing in abundance and a major constituent in the leaves of the plant. Similarly, anti-inflammatory and Th1 immune skewing properties of the root extract was conferred to the higher amount of Withanolide A, present in the roots of the plant along with other constituents. Meanwhile several studies have deciphered the role of individual constituents in various biological activities with extensive mechanism of action discussed in this review. This review while summarises the potential medicinal benefits of the W.somnifera, it also emphasizes that marketed product of the plant extracts for human consumption should scientifically validated for bioactive constitutents.

Autophagy is an evolutionary conserved process involving lysosomal degradation of cytoplasmic organelles and proteins required for maintaining the homeostasis in cell. Autophagy control many types of environmental stresses in cell such as nutrient starvation, unfolded protein response, hypoxia and pathogenic infections. Deregulation of autophagy has been associated with many pathological conditions and diseases including inflammation, infection, neurological disorders and cancer. In cancer, several studies have demonstrated that autophagy plays important role in cancer progression, angiogenesis, cell survival, epithelial to mesenchymal transition, metastasis and thereapeutic resistance. However, it has also been observed that prolonged autophagy may cause catabolic catastrophe leading to autophagic cell death. In this chapter, we will try to review the recent advances explaining the role of autophagy in the regulation of genetic and epigenetic events that are critical in carcinogenesis.We will try to explain how autophagy is associated with genetic mutations, miRNAs and various forms of post-translational modifications that play vital role in cancer.

Prenylated flavonoids represent a unique class of naturally occurring compounds and have proved to be an important source of chemically diverse novel metabolites. Nevertheless, they possess wild array of biological activities. 4′-Methoxy licoflavanone is a prenylated flavonoid isolated from stem bark of Erytherina subrossa. Herein, we report the synthesis of O-alkyl analogs (2a–2m) and 1,2,3 triazole conjugate (3–14) of 4′-methoxy licoflavanone by selective modification at C-7 position in the chromane nucleus. In addition, all the derivatives were evaluated for in vitro antiproliferative activity against a panel of cancer cell lines including pancreatic cancer (Mia PaCa-2), prostate cancer (PC-3), and human leukemia (HL-60) cells. The results revealed that some analogs including 2e and 2m exhibited better cytotoxicity effect than parent compound, specifically on Mia PaCa-2 cell lines.

Somatic mutations or deletions of TP53 and PTEN in ductal carcinoma in situ lesions have been implicated in progression to invasive ductal carcinomas. A recent molecular and mutational analysis of breast cancers revealed that inactivation of tumor suppressors, p53 and PTEN, are strongly associated with triple negative breast cancer. In addition, these tumor suppressors have important roles in regulating self-renewal in normal and malignant stem cells. To investigate their role in breast carcinogenesis, we knocked down these genes in human mammary cells and in non-transformed MCF10A cells. p53 and PTEN knockdown synergized to activate pro-inflammatory interleukin-6 (IL6)/Stat3/nuclear factor κB signaling. This resulted in generation of highly metastatic epithelial-to-mesenchymal transition-like cancer stem cells resulting in tumors whose gene expression profile mimicked that found in basal/claudin-low molecular subtype within the triple negative breast tumors. Constitutive activation of this loop in transformed cells was dependent on proteolytic degradation of suppressor of cytokine signaling 3 (SOCS3) resulting in low levels of this protein in basal/claudin-low cell lines and primary tumors. In non-transformed cells, transient activation of the IL6 inflammatory loop induced SOCS3 expression leading to pathway inactivation. In transformed cells, enforced expression of SOCS3 or interfering with IL6 pathway via IL6R blockade inhibited tumor growth and metastasis in mouse xenograft models. Furthermore, circulating tumor cells were significantly reduced in tumor-bearing animals when treated with anti-IL6R antibodies. These studies uncover important connections between inflammation and carcinogenesis and suggest that blocking pro-inflammatory cytokines may be utilized as an attractive strategy to target triple negative breast tumors, which currently lacks molecularly targeted therapies.