Role of ONECUT family transcription factors in cancer and other diseases.

Members of ONECUT transcription factor play an essential role in several developmental processes, however, the atypical expression of ONECUT proteins lead to numerous diseases, including cancer. ONECUT family proteins promote cell proliferation, progression, invasion, metastasis, angiogenesis, and stemness. This family of proteins interacts with other proteins such as KLF4, TGF-ß, VEGFA, PRC2, SMAD3 and alters their expression involved in the regulation of various signaling pathways including Jak/Stat3, Akt/Erk, TGF-ß, Smad2/3, and HIF-1α. Furthermore, ONECUT proteins are proposed as predictive biomarkers for pancreatic and gastric cancers. The present review summarizes the involvement of ONECUT family proteins in the development and progression of various human cancers and other diseases.

Kurarinone targets JAK2-STAT3 signaling in colon cancer-stem-like cells.

Natural compounds are known to regulate stemness/self-renewal properties in colon cancer cells at molecular level. In the present study, we first time studied the colon cancer stem-like cells targeting potential of Kurarinone (KU) and explored the underlying mechanism. Cytotoxic potential of KU was checked in colon cancer cells. Colonosphere formation assay was performed to check the spheroid formation reduction potential of KU in HCT-116 cells by using phase-contrast microscopy. Stemness/self-renewal marker expression was studied at mRNA and protein levels in colonosphere. The qRT-PCR, western blot analysis, and flow cytometer techniques were used to assess the effect of KU treatment on cell cycle progression and apoptosis induction in colon cancer cells and colonosphere. Further, effect of KU treatment on pSTAT3 status and its nuclear translocation was also studied. KU treatment significantly decreased HCT-116 cell proliferation and reduced sphere formation potential at IC30 (8.71 µM) and IC50 (20.34 µM) concentrations compared to respective vehicle-treated groups, respectively. KU exposure significantly reduced the expression of CD44, c-Myc, Bmi-1, and Sox2 stemness/self-renewal markers in colonosphere in a dose-dependent manner. KU treatment inhibits JAK2-STAT3 signaling pathway by reducing pSTAT3 levels and its nuclear translocation in HCT-116 cells and colonosphere at IC50 concentration. KU treatment significantly decreased the expression of CCND1 and CDK4 cell cycle-specific markers and arrested the HCT-116 cells and colonosphere in G1-phase. Further, KU treatment increased Bax/Bcl-2 ratio, apoptotic cell population, cleaved caspase 3, and PARP-1 in HCT-116 cells and colonosphere. In conclusion, KU treatment decreases stemness/self-renewal, induces cell cycle arrest and apoptosis in HCT-116 colonosphere by down-regulating CD44-JAK2-STAT3 axis. Thus, targeting stemness/self-renewal and other cancer hallmark(s) by KU through CD44/JAK2/STAT3 signaling pathway might be a novel strategy to target colon cancer stem-like cells.

Induced expression of miR-1250-5p exerts tumor suppressive role in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and it has a prevalence rate of 15%-20% among all breast cancer cases in younger women. Still, the underlying molecular mechanisms of its pathogenesis are not entirely understood. In the previous study, we identified that microRNA (miR)-1250-5p is significantly down-expressed in TNBC cells. Thus, in the present study, we explore the functional anticancer role of miR-1250-5p in the transient mimic transfected TNBC cells. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was used to examine the effect of miR-1250-5p on cell viability of TNBC (MDA-MB-231 and MDA-MB-453) cells. The confocal microscopy, quantitative real-time polymerase chain reaction, and western blot analysis techniques were used to assess the effect of miR-1250-5p on cancer hallmarks in test cells. Induced miR-1250-5p expression in MDA-MB-231 and MDA-MB-453 cells decreased cell viability in a time-dependent manner. Increased miR-1250-5p expression levels significantly decreased cell cycle G1/S phase transition markers (Cyclin D1 and CDK4) at messenger RNA (mRNA) and protein levels in TNBC cells compared to scrambled sequence transfected cells. Transient transfection of TNBC cells with miR-1250-5p mimic increased apoptosis in TNBC cells by increasing the level of active caspase (Caspase 8 and Caspase 3) of the intrinsic pathway. Apoptosis-related morphological changes were also observed in the test cells. Further, the induced expression of miR-1250-5p significantly decreased epithelial-mesenchymal transition (EMT) by altering the mRNA and protein levels of E-cadherin and Vimentin. Moreover, results of confocal microscopy revealed increased reactive oxygen species generation, and decreased mitochondria membrane potential in miR-1250-5p mimic transient transfected TNBC cells. In conclusion, miR-1250-5p acts as tumor suppressor in TNBC cells and its induction by therapeutics might be a novel strategy for the disease treatment.

Loss of miR-6844 alters stemness/self-renewal and cancer hallmark(s) markers through CD44-JAK2-STAT3 signaling axis in breast cancer stem-like cells.

MicroRNAs regulate breast stemness and self-renewal properties in breast cancer cells at the molecular level. Recently we reported the clinical relevance and in vitro expression profile of novel miR-6844 in breast cancer and -derived stem-like cells (mammosphere). In the present study, we first time explore the functional role of loss of miR-6844 in breast cancer cells derived mammosphere. Down expression of miR-6844 significantly decreased cell proliferation in MCF-7 and T47D cells derived mammosphere in a time-dependent manner. MiR-6844 down expression reduced the sphere formation in terms of size and number in test cells. Loss of miR-6844 significantly altered stemness and self-renewal markers (Bmi-1, Nanog, c-Myc, Sox2, and CD44) in mammosphere compared to negative control spheres. Moreover, loss of miR-6844 inhibits the JAK2-STAT3 signaling pathway by decreasing p-JAK2 and p-STAT3 levels in breast cancer cells derived mammosphere. Loss of miR-6844 expression significantly decreased CCND1 and CDK4 mRNA/protein levels and arrested breast cancer stem-like cells in G2/M phase. Reduced expression of miR-6844 increased Bax/Bcl-2 ratio, late apoptotic cell population, and Caspase 9 and 3/7 activity in the mammosphere. Low expression of miR-6844 decreased migratory and invasive cells by altering the expression of Snail, E-cad, and Vimentin at mRNA/protein levels. In conclusion, loss of miR-6844 decreases stemness/self-renewal and other cancer hallmark in breast cancer stem-like cells through CD44-JAK2-STAT3 axis. Thus, downregulation of miR-6844 by therapeutic agents might be a novel strategy to target breast cancer stemness and self-renewal.

Bioinformatics insights into CENP-T and CENP-W protein-protein interaction disruptive amino acid substitution in the CENP-T-W complex.

Kinetochores are multi-protein assemblies present at the centromere of the human chromosome and play a crucial role in cellular mitosis. The CENP-T and CENP-W chains form a heterodimer, which is an integral part of the inner kinetochore, interacting with the linker DNA on one side and the outer kinetochore on the other. Additionally, the CENP-T-W dimer interacts with other regulatory proteins involved in forming inner kinetochores. The specific roles of different amino acids in the CENP-W at the protein-protein interaction (PPI) interface during the CENP-T-W dimer formation remain incompletely understood. Since cell division goes awry in diseases like cancer, this CENP-T-W partnership is a potential target for new drugs that could restore healthy cell division. We employed molecular docking, binding free energy calculations, and molecular dynamics (MD) simulations to investigate the disruptive effects of amino acids substitutions in the CENP-W chain on CENP-T-W dimer formation. By conducting a molecular docking study and analysing hydrogen bonding interactions, we identified key residues in CENP-W (ASN-46, ARG-53, LEU-83, SER-86, ARG-87, and GLY-88) for further investigation. Through site-directed mutagenesis and subsequent binding free energy calculations, we refined the selection of mutant. We chose four mutants (N46K, R53K, L83K, and R87E) of CENP-W to assess their comparative potential in forming CENP-T-W dimer. Our analysis from 250 ns long revealed that the substitution of LEU83 and ARG53 residues in CENP-W with the LYS significantly disrupts the formation of CENP-T-W dimer. In conclusion, LEU83 and ARG53 play a critical role in CENP-T and CENP-W dimerization which is ultimately required for cellular mitosis. Our findings not only deepen our understanding of cell division but also hint at exciting drug-target possibilities.

Discovery of differentially expressed novel miRNAs in breast normal cells and their putative targets.

MicroRNAs (miRNAs) play critical role in normal breast development and their altered expression may lead to breast cancer. Identification of new miRNAs allows us to understand the normal physiological process and associated disease pathophysiology. In the present study we identify the novel miRNAs in withaferin A treated breast normal cells (MCF-10A) using small RNA sequencing. The pathophysiological potential of the identified miRNAs was checked by studying their expression pattern in MDA-MB-231 and MCF-7 breast cancer cells using qRT-PCR technique. The secondary/tertiary structure of the identified miRNAs, target gene enrichment in Gene Ontology terms and KEGG pathway, miRNA-mRNA interaction of the sorted target genes, miRNA-mRNA/miRNA-argonaute protein/miRNA-mRNA-argonaute protein interaction and stability, were studied using bioinformatics tools/software, and molecular dynamics simulations. Hsa-miR-N88585 and hsa-miR-N461089 were identified and validated as novel miRNAs in normal breast cells. Up-expression of identified miRNAs in MDA-MB-231 and MCF-7 cells indicates their oncogenic nature. Identified target genes were enriched in classical signaling pathways (AMPK and Ras) and important GO terms. PLXDC2, BHLHE40, ARMC8, and PECAM1, CDC27, KCNK3 genes were sorted as putative targets for hsa-miR-N88585 and hsa-miR-N461089, respectively. MD simulation revealed stable hsa-miR-N88585/hsa-miR-N461089-AGO protein complex formation which indicates their further processing. In conclusion, the study identifies hsa-miR-N88585 and hsa-miR-N461089 as novel miRNAs in breast normal cells which are significantly inversely expressed in breast cancer cells. Further experiments are required to study the role of identified novel miRNAs in normal breast development and pathophysiology of breast cancer.

Implications of vitamin D deficiency in systemic inflammation and cardiovascular health.

Clinical, epidemiological, and molecular studies have sufficiently highlighted the vitality of vitamin D [25(OH)D and 1,25(OH)2D] in human health and wellbeing. Globally, vitamin D deficiency (VDD) has become a public health concern among all age groups. There is a very high prevalence of VDD per the estimates from several epidemiological studies on different ethnic populations. But, population-specific scales do not support these estimates to define VDD clinically and consistent genetic associations. However, clinical studies have shown the relevance of serum vitamin D screening and oral supplementation in improving health conditions, pointing toward a more prominent role of vitamin D in health and wellness. Routinely, the serum concentration of vitamin D is measured to determine the deficiency and is correlated with physiological conditions and clinical symptoms. Recent research points toward a more inclusive role of vitamin D in different disease pathologies and is not just limited to otherwise bone health and overall growth. VDD contributes to the natural history of systemic ailments, including cardiovascular and systemic immune diseases. Considering its significant impact on premature morbidity and mortality, there is a compelling need to comprehensively review and document the direct and indirect implications of VDD in immune system deregulation, systemic inflammatory conditions, and cardio-metabolism. The recommendations from this review call for furthering our research concerning vitamin D and its direct and indirect implications.

Piper chaba, an Indian spice plant extract, inhibits cell cycle G1/S phase transition and induces intrinsic apoptotic pathway in luminal breast cancer cells.

Piper chaba (Piperaceae) is a medicinal spice plant that possesses several pharmacological activities. In the present study, we for the first time studied the effect of P. chaba extract on breast cancer cells. P. chaba stem methanolic (PCSM) extract produced time and dose dependent cytotoxicity in luminal breast cancer cells (MCF-7 and T47D) with a minimal toxicity in breast normal cells (MCF-10A) at 10-100 µg/mL concentration. PCSM extract exerts 16.79 and 31.21 µg/mL IC50 for T47D and MCF-7 cells, respectively, in 48 h treatment. PCSM significantly arrests the T47D cells at the G0/G1 phase by reducing the CCND1 and CDK4 expression at mRNA and protein levels. PCSM extract treatment significantly altered nuclear morphology, mitochondria membrane potential, and production of reactive oxygen species in T47D cells at IC50 concentration. Extract treatment significantly altered the Bax/Bcl-2 ratio and altered caspase 8 and 3 mRNA/protein levels in T47D cells. Confocal microscopy showed an increase in late apoptosis in PCSM extract-treated breast cancer cells at IC50 . Further, an increased caspase 9 and caspase 3/7 enzymatic activity was observed in test cells compared with nontreated cells. In conclusion, P. chaba phytocompound possesses the potential to induce cell cycle arrest and induce apoptosis in luminal breast cancer cells.

Specific Genetic Polymorphisms Contributing in Differential Binding of Gliadin Peptides to HLA-DQ and TCR to Elicit Immunogenicity in Celiac Disease.

Immunogenicity of gliadin peptides in celiac disease (CD) is majorly determined by the pattern of molecular interactions with HLA-DQ and T-cell receptors (TCR). Investigation of the interactions between immune-dominant gliadin peptides, DQ protein, and TCR are warranted to unravel the basis of immunogenicity and variability contributed by the genetic polymorphisms. Homology modeling of HLA and TCR done using Swiss Model and iTASSER, respectively. Molecular interactions of eight common deamidated immune-dominant gliadin with HLA-DQ allotypes and specific TCR gene pairs were evaluated. Docking of the three structures was performed with ClusPro2.0 and ProDiGY was used to predict binding energies. Effects of known allelic polymorphisms and reported susceptibility SNPs were predicted on protein-protein interactions. CD susceptible allele, HLA-DQ2.5 was shown to have considerable binding affinity to 33-mer gliadin (ΔG = - 13.9; Kd = 1.5E - 10) in the presence of TRAV26/TRBV7. Higher binding affinity was predicted (ΔG = - 14.3, Kd = 8.9E - 11) when TRBV28 was replaced with TRBV20 paired with TRAV4 suggesting its role in CD predisposition. SNP rs12722069 at HLA-DQ8 that codes Arg76α forms three H-bonds with Glu12 and two H-bonds with Asn13 of DQ2 restricted gliadin in the presence of TRAV8-3/TRBV6. None of the HLA-DQ polymorphisms was found to be in linkage disequilibrium with reported CD susceptibility markers. Haplotypic presentations of rs12722069-G, rs1130392-C, rs3188043-C and rs4193-A with CD reported SNPs were observed in sub-ethnic groups. Highly polymorphic sites of HLA alleles and TCR variable regions could be utilized for better risk prediction models in CD. Therapeutic strategies by identifying inhibitors or blockers targeting specific gliadin:HLA-DQ:TCR binding sites could be investigated.

Flavonoids as emerging notch signaling pathway modulators in cancer.

Notch signaling is an evolutionary conserved pathway important for the developmental processes and implicated in the tumor formation. Notch signaling pathway (NSP) inhibitors have been tested in clinical trials alone or in combination with the chemotherapy but none got clinical approval due to severe toxicity in patients. Flavonoids inhibit NSP by inhibiting notch receptor cleavage and/or inhibiting transcriptional regulation by Notch intracellular domain (NICD). Interestingly, some flavonoids are reported to inhibit NSP by mediating the microRNA expression. NSP inhibitory flavonoid(s) in combination with standard therapy is might be an effective strategy in cancer treatment.

Withaferin A mediated changes of miRNA expression in breast cancer-derived mammospheres.

Breast cancer is a heterogeneous disease consisting of atypical cell populations that share stem cell-like characteristics associated with therapeutic resistance, disease relapse, and poor clinical outcome. MicroRNAs (miRNA), and small noncoding RNA, are pivotal in the regulation of self-renewal, stemness, and cellular differentiation. Withaferin A (WA), a steroidal lactone, is a major bioactive constituent of Withania somnifera (Solanaceae) known for its anticancer properties. In this study, the effect of WA on modulation of miRNA expression in breast cancer-derived mammosphere was assessed utilizing small RNA sequencing. Treatment with WA inhibited MCF-7 and T47D cells derived mammosphere formation with a significant decrease in CD44, EpCAM, Nanog, OCT4, and SOX2 as markers of self-renewal and stemness. Small RNA sequencing demonstrated a total of 395 differentially expressed miRNAs (DEMs) including 194 upregulated and 201 downregulated miRNAs in WA-treated MCF-7 mammospheres. Bioinformatics analysis utilizing the KEGG pathway, Gene Ontology enrichment, protein-protein, and miRNA-mRNA interaction network identified altered expression in a few hub genes viz. AKT1, PTEN, MYC, CCND1, VEGFA, NOTCH1, and IGFR1 associated with DEMs in WA-treated mammospheres. Further quantitative RT-PCR analysis validated the expression of DEMs including miR-549a-5p, miR-1247-5p, miR-124-5p, miR-137-5p, miR-34a-5p, miR-146a-5p, miR-99a-5p, miR-181a-5p, let-7c-5p, and let-7a-5p. In particular, let-7c-5p is designated as a tumor suppressor in breast cancer. An increase in miR-let-7c-5p expression was noted after WA treatment, with a simultaneous decrease in CCND1 and c-MYC at mRNA and protein levels. Taken together, our study demonstrated WA-mediated miRNA expression, in particular, upregulation of miR-let-7c-5p, leads to the inhibition of breast cancer cells derived mammospheres.

The Multifaceted Role of Signal Peptide-CUB-EGF Domain-Containing Protein (SCUBE) in Cancer.

Signal peptide, CUB, and EGF-like domain-containing proteins (SCUBE) are secretory cell surface glycoproteins that play key roles in the developmental process. SCUBE proteins participate in the progression of several diseases, including cancer, and are recognized for their oncogenic and tumor suppressor functions depending on the cellular context. SCUBE proteins promote cancer cell proliferation, angiogenesis, invasion, or metastasis, stemness or self-renewal, and drug resistance. The association of SCUBE with other proteins alters the expression of signaling pathways, including Hedgehog, Notch, TGF-ß/Smad2/3, and ß-catenin. Further, SCUBE proteins function as potential prognostic and diagnostic biomarkers for breast cancer, renal cell carcinoma, endometrial carcinoma, and nasopharyngeal carcinoma. This review presents key features of SCUBE family members, and their structure and functions, and highlights their contribution in the development and progression of cancer. A comprehensive understanding of the role of SCUBE family members offers novel strategies for cancer therapy.

Phytochemicals present in Indian ginseng possess potential to inhibit SARS-CoV-2 virulence: A molecular docking and MD simulation study.

Coronaviruses are deadly and contagious pathogens that affects people in different ways. Researchers have increased their efforts in the development of antiviral agents against coronavirus targeting Mpro protein (main protease) as an effective drug target. The present study explores the inhibitory potential of characteristic and non-characteristic Withania somnifera (Indian ginseng) phytochemicals (n ≈ 100) against SARS-Cov-2 Mpro protein. Molecular docking studies revealed that certain W. somnifera compounds exhibit superior binding potential (-6.16 to -12.27 kcal/mol) compared to the standard inhibitors (-2.55 to -6.16 kcal/mol) including nelfinavir and lopinavir. The non-characteristic compounds (quercetin-3-rutinoside-7-glucoside, rutin and isochlorogenic acid B) exhibited higher inhibitory potential in comparison to characteristic W. somnifera compounds withanolide and withanone. Molecular dynamics (MD) simulation studies of the complex for 100 ns confirm favorable and stable binding of the lead molecule. The MMPBSA calculation of the last 10 ns of the protein-ligand complex trajectory exhibited stable binding of quercetin-3-rutinoside-7-glucoside at the active site of SARS-Cov-2 Mpro. Taken together, the study demonstrates that the non-characteristic compounds present in W. somnifera possess enhanced potential to bind SARS-Cov-2 Mpro active site. We further recommend in vitro and in vivo experimentation to validate the anti-SARS-CoV-2 potential of these lead molecules.

Role of ZBTB7A zinc finger in tumorigenesis and metastasis.

The zinc finger and BTB (broad-complex, tramtrack and bric a brac) domain containing protein 7A (ZBTB7A) is a pleiotropic transcription factor that plays an important role in various stages of cell proliferation, differentiation, and other developmental processes. ZBTB7A is a member of the POK family that directly and specifically binds to short DNA recognition sites located near their target genes thereby acting as transcriptional activator or repressor. ZBTB7A overexpression has been associated with tumorigenesis and metastasis in various human cancer types, including breast, prostate, lung, ovarian, and colon cancer. However in some instances downregulation of ZBTB7A results in tumor progression, suggesting its role as a tumor suppressor. ZBTB7A is involved with complicated regulatory networks which include protein-protein and protein-nucleic acid interactions. ZBTB7A involvement in cancer progression and metastasis is perhaps enabled through the regulation of various signaling pathways depending on the type and genetic context of cancer. The association of ZBTB7A with other proteins affects cancer aggressiveness, therapeutic resistance and clinical outcome. This review focuses on the involvement of ZBTB7A in various signaling pathways and its role in cancer progression. We will also review the literature on ZBTB7A and cancer which could be potentially explored for its therapeutic implications.

Induction of apoptosis in breast cancer cells by naphthylisoquinoline alkaloids.

Breast cancer is one of the most common types of cancer in the world and a major cause of mortality. Present therapeutic strategies against breast cancer have severe drawbacks such as allergies, damage to healthy tissues, reoccurrence of cancer, and emergence of drug resistance. Naphthylisoquinoline alkaloids are a group of structurally unique natural products produced by tropical lianas belonging to the plant families Dioncophyllaceae and Ancistrocladaceae indigenous to Asia and Africa. These secondary metabolites have been reported to show anti-infective activity, but they also act against leukemic and pancreatic cancer cells. In the present study we have tested the potential of eleven mono- and dimeric naphthylisoquinoline compounds against two breast cancer cell lines, MCF-7 and MDA-MB-231. Three out of the compounds (agents 1, 4, and 11) showed significant activities against both tested cancer cell lines. Further mechanistic investigations revealed that all of the three substances induce apoptotic cell death via its intrinsic pathway by causing deformation of the nuclear membrane, disruption of the mitochondrial membrane potential (MMP), and elevated reactive oxygen species (ROS) production in both cell lines. Flow cytometric analysis using Annexin V - FITC/PI double staining showed an increased number of apoptotic cells in both, the early and the late phases.

Education for the Anthropocene: Planetary health, sustainable health care, and the health workforce.

Over the past few centuries, human activity has wrought dramatic changes in the natural systems that support human life. Planetary health is a useful concept for health profession education (HPE) teaching and practice because it situates health within a broader understanding of the interdependent socio-ecological drivers of human and planetary health. It facilitates novel ways of protecting both population health and the natural environment on which human health and well-being depends. This paper focuses on the climate crisis as an example of the relationship between environmental change, healthcare, and education. We analyze how HPE can help decarbonize the healthcare sector to address both climate change and inequity in health outcomes. Based on the healthcare practitioner's mandate of beneficence, we propose simple learning objectives to equip HPE graduates with the knowledge, skills, and values to create a sustainable health system, using carbon emission reductions as an example. These learning objectives can be integrated into HPE without adding unduly to the curriculum load.

Leishmania donovani mediated higher expression of CCL4 induces differential accumulation of CD4+CD56+NKT and CD8+CD56+NKT cells at infection site.

Sterile cure from visceralized Leishmania donovani (L. donovani) needs Th1 cell support along with the assistance from innate immune cells, NK cells and NKT cells. NKT cells play as a connecting link between innate and adaptive immune cell and support T helper cell function. Earlier, a categorical function of CD56 positive CD4+ or CD8+ NKT cells was reported in visceral leishmaniasis (VL). It was observed in in vitro that CD4+CD56+NKT cells, but not CD8+CD56+NKT cells, were accumulated at the L. donovani infection site. Therefore, in vitro experiments have been carried out to decipher the mechanism behind preferential accumulation of CD4+CD56+NKT cells at infection site. In this study, 1.89 fold higher expression of CCL4/MIP-1ß was noticed in infected macrophages. The higher expression of CCL4 was correlated with preferential accumulation of CCR5+CD4+CD56+NKT cells and apoptosis of CD8+CD56+NKT cells at in vitro infection site. The CD4+CD56+NKT cells were also observed expressing TGF-ß dominantly. Interaction of CCL4 chemotaxis was interrupted by blocking, which led to drift back the TGF-ß producing CD4+CD56+NKT cells and promoted CD8+CD56+NKT cells recruitment in in vitro infection site. CCR5 blockade also reduced CD25 and FoxP3 positive CD4+CD56+NKT cells in in vitro infection site. Therefore, it was concluded that Leishmania promotes strategic expression of CCL4, which alternately attracts CCR5+ cells, mostly expressing regulatory cytokines, at infection site. This reduces the CD8+CD56+NKT cells at infection site through Smad4 mediated TGF-ß expression and activation of caspases. Data indicates that L. donovani induces higher expression of CCL4 in host cell to attract CCR5+ cells under its strategic plan to downregulate host immune response.

Polydopamine films change their physicochemical and antimicrobial properties with a change in reaction conditions.

The morphology and physicochemical properties of polydopamine are not totally inherent and undergo changes with differing reaction conditions like the choice of solvent used for polymerization. The polymerisation of dopamine to polydopamine carried out in different solvents like sodium hydroxide, sodium bicarbonate, PBS and Tris leads to polydopamine with exceptionally different morphological and physicochemical features with each solvent. Additionally, the different physicochemical characteristics and morphologies bestow the polymer films with different extents of antimicrobial activity. Moreover, the findings supported by chemical evidence from X-ray photoelectron spectroscopy reveal that higher antibacterial activities were obtained against E. coli and S. aureus with polydopamine films prepared by Tris and NaOH solvent induced polymerization. The antibacterial activity observed in saline was found to be higher than that in PBS medium for both E. coli and S. aureus. The higher antibacterial activity of polydopamine films prepared in Tris and NaOH solvents was attributed to the covalent incorporation of -OH groups on the surface provided by nucleophilic Tris and NaOH solvents during the polymerisation process. The distinct physicochemical and morphological changes were supported by the results from contact angle measurements, FE-SEM, EDAX, AFM, and XPS analysis. The present finding provides insight into the different chemistry, morphologies and properties of the designed polydopamine films with controlled antibacterial/antifouling properties. Additionally, new insights into the mechanism of formation, physicochemical changes in morphology and properties of polydopamine coatings were revealed.

Medicinal attributes of Solanum xanthocarpum fruit consumed by several tribal communities as food: an in vitro antioxidant, anticancer and anti HIV perspective.

BACKGROUND: Solanum xanthocarpum (Solanaceae) has been used for treatment of many infectious and degenerative diseases in traditional medicine. Present study reports the medicinal efficacy of S. xanthocarpum fruit as antioxidant, anticancer and anti HIV agents. METHODS: Extracts were prepared using Soxhlet apparatus and partially characterized by thin layer chromatography (TLC). Total flavonoid content was determined spectrophotometrically. Reducing power, DPPH radical scavenging activity and lipid peroxidation inhibition assays were used for measurement of antioxidant potential. Cytotoxic (SRB assay) and anti-HIV RT inhibition (RT assay kit, Roche) activities were determined using ELISA. RESULTS: TLC revealed the diversity of phytoconstituents in various sequential extracts of S. xanthocarpum fruit. Total flavonoid contents in extracts ranged between 10.22-162.49 µg quercetin equivalent/mg. Spectroscopic scanning of water soluble phenolics showed maximum absorbance at 250 and 280 nm. Polar extracts displayed potent radical scavenging activity (>80%). Several sub-fractions (spots) of extracts separated on TLC plates also exhibited powerful radical scavenging activity. Considerable reducing power was observed in extracts. Hexane fraction provided 55% lipoprotection in rat kidney homogenate. Non-polar extracts exhibited appreciable cytotoxic activity (70-91%) against leukemia (THP-1) and lung cancer (HOP-62) cell lines. Lower inhibitory activity was observed in extracts against HIV Reverse Transcriptase enzyme. CONCLUSION: The study demonstrated considerable antioxidant and anticancer activities in S. xanthocarpum fruit.

Cell cycle inhibitory activity of Piper longum against A549 cell line and its protective effect against metal-induced toxicity in rats.

Anticancer potential of Piper longum fruit against human cancer cell lines (DU-145 prostate, A549 lung, THP-1 leukemia, IGR-OVI-1 ovary and MCF-7 breast) as well as its in vitro and in vivo biochemical efficacy in A1Cl3-induced hepatotoxicity were evaluated in the rats. Dried samples were extracted with several solvents using soxhlet apparatus. Flavonoid content in chloroform, benzene, ethyl alcohol and aqueous extracts of fruit was 19, 14, 12 and 11 µg quercetin equivalent/mg of sample, respectively. Hexane extracts exhibited 90-92% cytotoxicity against most of the test cell lines (A549, THP-1, IGR-OVI-1 and MCF-7), while benzene extract displayed 84-87% cytotoxicity against MCF-7, IGR-OV-1 and THP-1 cell lines. Among extracts, hexane, benzene and acetone extracts demonstrated considerable cytotoxicity (91-95%) against A549 (lung cancer) cell line in Sulforhodamine B dye (SRB) assay. Cell cycle analysis revealed that hexane, benzene and acetone extracts produced 41, 63 and 43% sub-G1 DNA fraction, demonstrating cell cycle inhibitory potential of these extracts against A549 cell line. Chloroform, ethyl alcohol and aqueous extracts displayed 71, 64 and 65% membrane protective activity, respectively in lipid peroxidation inhibition assay. P. longum fruit extracts also ameliorated A1Cl3-induced hepatotoxicity, as indicated by alterations observed in serum enzymes ALP, SGOT and SGPT activity, as well as creatinine and bilirubin contents. In conclusion, study established the cytotoxic and hepatoprotective activity in P. longum extracts.