Showing papers by "Kalpana Joshi published in 2022"

Prostate Apoptosis Response-4 (Par-4): A Novel Target in Pyronaridine-Induced Apoptosis in Glioblastoma (GBM) Cells

Abstract: Simple Summary GBM treatment is an area of high unmet need due to the heterogeneous and anaplastic character of this cancer in turn leading to an extremely poor prognosis. Finding new molecular entities by traditional or de novo approaches to drug discovery is lengthy and expensive. Repurposing existing drugs can be attractive as the process is often less risky, more cost, and time-effective. Amongst potential drug-repurposing candidates, Pyronaridine (PYR), an antimalarial drug has shown anti-cancer effects against several cancers, however, its potential for the treatment of GBM has not been explored. In this study, we have identified a unique mechanism of action of PYR against GBM by upregulating a tumor suppressor protein, Par-4 along with the elucidation of the complex network of pathways mediated through Par-4 leading to GBM cell death. Abstract Glioblastoma (GBM) is an aggressive form of brain tumor with a median survival of approximately 12 months. With no new drugs in the last few decades and limited success in clinics for known therapies, drug repurposing is an attractive choice for its treatment. Here, we examined the efficacy of pyronaridine (PYR), an anti-malarial drug in GBM cells. PYR induced anti-proliferative activity in GBM cells with IC50 ranging from 1.16 to 6.82 µM. Synergistic activity was observed when PYR was combined with Doxorubicin and Ritonavir. Mechanistically, PYR triggered mitochondrial membrane depolarization and enhanced the ROS levels causing caspase-3 mediated apoptosis. PYR significantly decreased markers associated with proliferation, EMT, hypoxia, and stemness and upregulated the expression of E-cadherin. Interestingly, PYR induced the expression of intracellular as well as secretory Par-4, a tumor suppressor in GBM cells, which was confirmed using siRNA. Notably, Par-4 levels in plasma samples of GBM patients were significantly lower than normal healthy volunteers. Thus, our study demonstrates for the first time that PYR can be repurposed against GBM with a novel mechanism of action involving Par-4. Herewith, we discuss the role of upregulated Par-4 in a highly interconnected signaling network thereby advocating its importance as a therapeutic target.

Promising Anticancer Activity of Multitarget Cyclin Dependent Kinase Inhibitors against Human Colorectal Carcinoma Cells.

Abstract: BACKGROUND Colorectal cancer (CRC) is the third leading cause of cancer death worldwide, and its incidence is steadily rising in developing nations. Cell cycle aberrations due to deregulation of cyclin dependent kinases (CDKs) and cyclins are common events during colorectal carcinogenesis. Yet, efficacy of multitarget CDK inhibitors as therapeutic agents has not been much explored against CRC. OBJECTIVE The anticancer potential of multitarget CDK inhibitor riviciclib (also known as P276-00), was investigated against CRC cell lines of varied genetic background. METHOD Cytotoxicity of riviciclib - potent CDK1, CDK4 and CDK9-specific inhibitor was evaluated in vitro. Further, its effect on clonogenic potential, cell cycle, apoptosis and transcription was tested using colony forming assay, flow cytometry and western blot analysis respectively. Also, efficacy of riviciclib in combination with standard chemotherapeutic agents was assessed. Dependency of CRC cells on specific CDKs for their survival was confirmed using siRNA studies. RESULTS Riviciclib exerted significant cytotoxicity against CRC cells and inhibited their colony forming potential. It induced apoptosis along with inhibition of cell cycle CDKs and cyclins as well as transcriptional CDKs and cyclins. Moreover, dual combination of riviciclib with standard chemotherapeutic drugs exhibited synergism in CRC cells. siRNA studies indicated that CRC cells are dependent on specific CDKs for their survival which are targets of riviciclib. CONCLUSION This study provides evidence that multitarget CDK inhibitors can serve as promising therapeutic agents against CRC alone or in combination.

Ayurveda-based Botanicals as Therapeutic Adjuvants in Paclitaxel-induced Myelosuppression

Abstract: Chemotherapy-induced myelosuppression is one of the major challenges in cancer treatment. Ayurveda-based immunomodulatory botanicals Asparagus racemosus Willd (AR/Shatavari) and Withania somnifera (L.). Dunal (WS/Ashwagandha) have potential role to manage myelosuppression. We have developed a method to study the effects of AR and WS as therapeutic adjuvants to counter paclitaxel (PTX)-induced myelosuppression. Sixty female BALB/c mice were divided into six groups—vehicle control (VC), PTX alone, PTX with aqueous and hydroalcoholic extracts of AR (ARA, ARH) and WS (WSA, WSH). The myelosuppression was induced in mice by intraperitoneal administration of PTX at 25 mg/kg dose for three consecutive days. The extracts were orally administered with a dose of 100 mg/kg for 15 days prior to the induction with PTX administration. The mice were observed daily for morbidity parameters and were bled from retro-orbital plexus after 2 days of PTX dosing. The morbidity parameters simulate clinical adverse effects of PTX that include activity (extreme tiredness due to fatigue), behavior (numbness and weakness due to peripheral neuropathy), body posture (pain in muscles and joints), fur aspect and huddling (hair loss). The collected samples were used for blood cell count analysis and cytokine profiling using Bio-Plex assay. The PTX alone group showed a reduction in total leukocyte and neutrophil counts (4,800 ± 606; 893 ± 82) when compared with a VC group (9,183 ± 1,043; 1,612 ± 100) respectively. Pre-administration of ARA, ARH, WSA, and WSH extracts normalized leukocyte counts (10,000 ± 707; 9,166 ± 1,076; 10,333 ± 1,189; 9,066 ± 697) and neutrophil counts (1,482 ± 61; 1,251 ± 71; 1,467 ± 121; 1,219 ± 134) respectively. Additionally, higher morbidity score in PTX group (7.4 ± 0.7) was significantly restricted by ARA (4.8 ± 1.1), ARH (5.1 ± 0.6), WSA (4.5 ± 0.7), and WSH (5 ± 0.8). (Data represented in mean ± SD). The extracts also significantly modulated 20 cytokines to evade PTX-induced leukopenia, neutropenia, and morbidity. The AR and WS extracts significantly prevented PTX-induced myelosuppression (p < 0.0001) and morbidity signs (p < 0.05) by modulating associated cytokines. The results indicate AR and WS as therapeutic adjuvants in cancer management.

Folate Mediated One Carbon Metabolism in Head and Neck Squamous Cell Carcinoma: A Systematic Review

Abstract: Introduction: Head and neck cancer (HNC) is one of the most prevalent cancers of upper aerodigestive tract, with squamous cell carcinomas accounting for the majority of cases. Vitamin B such as folate has been associated with carcinogenesis. Folate is essential for one carbon metabolism, which involves the transfer of one carbon units for Deoxyribonucleic Acid (DNA) and Ribonucleic Acid (RNA) production, amino acid metabolism and methylation. Aim: To evaluate the association of folate mediated One carbon metabolism with Head and Neck Squamous Cell Carcinoma (HNSCC). Materials and Methods: For this systematic review, Electronic bibliographic databases search of PubMed, Google Scholar and Scopus was done. The electronic search was performed between November 15th to November 30th, 2020 by two researchers independently. All original research, observational studies, full text articles, in which blood samples or questionnaires or both, focused on the assessment of folate mediated one carbon metabolism in HNSCC, published upto November 2020 were reviewed. Four studies published from 2005 to 2019 were included in which three studies were case-control and one study was a comparative cross-sectional study. This systematic review was carried out by two reviewers, using Preferred Reporting Items for Systematic reviews and Meta Analyses (PRISMA) checklist and the New Castle Ottawa Scale (NOS) for quality assessment. Results: In this systematic review, total of four studies included, had 1504 HNSCC patients and 2970 Controls. One study was reported from Nigeria, one from the European countries, one from Japan, and one from the United States of America (USA). One study had a quality score of 8 whereas 3 studies had 7, considering all the four studies included are of good quality. Conclusion: Significant low levels of serum folate was present in HNSCC when compared to controls. Serum folate levels can differ due to tumor growth and subsequent metabolic changes, or they may precede and accelerate tumor progression.

Utility of serum homocysteine in oral squamous cell carcinoma patients as a potential biomarker

Abstract: Background: In India, Oral cancer is one of the most common cancers. Despite advances in treatments, prognosis for oral cancer has remained poor with a five-year survival rate of 40–50%. Therefore, it is necessary to develop effective diagnostic methods for early diagnosis and better prognosis. Homocysteine (Hcy) has been reported as a 'tumour marker' in various cancers such as breast cancer, colorectal cancer, lung cancer, cervical cancer. Aim: To study the levels of serum Hcy in oral squamous cell carcinoma (OSCC) patients. Objectives: To assess the clinical utility of serum Hcy as a potential tumour marker for OSCC cases. Methodology: Serum Hcy levels were studied and compared between patients with OSCC and healthy individuals. Results: Serum Hcy levels were higher in patients having OSCC. Conclusion: Serum Hcy levels could be utilized as a biological marker in the diagnosis and the prognosis of OSCC patients.

Comparison of hydrodynamic characteristics of Tulsion and Siran immobilised beads in a fluidised bed bioreactor

Abstract: The fluidised bed reactors are successfully utilised in various bioprocesses to produce high value products using immobilised cells and enzymes. The present work aims at evaluating hydrodynamic characteristics of a three phase fluidised bed bioreactor using Tulsion® A-1X MP, Tulsion® ADS-400 and Tulsion® ADS-800, polystyrene and polyacrylic based three types of free and immobilised cells solid carriers viz. and comparing their performance with Siran® SIKUG41 glass beads. The hydrodynamic parameters such as particle density (cells and beads), drag coefficient, minimum and maximum fluidisation velocity, particle settling velocity were estimated and compared in water and biological media (E2 and MSM) having varying rheological properties. The relationships between drag coefficient (CD)–Reynolds numbers (NRe), superficial liquid velocity (Uf)–void fraction(ε), expansion index(n)–NRe were obtained. The scanning electron microscopy studies revealed that the pore sizes of Tulsion beads (20–300 nm) were significantly smaller compared to Siran carriers (7–120 μm) leading to cells growth only on the surface of the beads. The biomass grown was estimated to be 0.75–1.2 mgCDW/g for Tulsion beads and 1.27–1.3 mgCDW/g for Siran beads with immobilised cells of P. putida and R. erythropolis, respectively. As per the results obtained, the reactor could be operated as a fluidised bed reactor with Tulsion and Siran beads at ε>0.4 and ε>0.6. The cell immobilised Tulsion and Siran beads have shown higher drag co-efficient in E2 and MSM media compared to water. The empirical correlations describing beads properties in falling (NRe) and fluidisation conditions in the form of Archimedes Number (NAr) were developed for ε in the range of 0.3–0.8 at 0.3

Hla-drb1 allele distribution in healthy individuals classified based on mizaj (temperament) of unani system of medicine

Abstract: Objective: Assessment of Mizaj of 500 healthy individuals between the age group of 25and 40 years of the age group of either gender was carried out by validated Unani questionnaire and Sheldon’s somatotype. The present study was designed to investigate if the frequency of HLA-DRB1 alleles in the healthy adult population has any association with four Mizaj. Methods: Mizaj of the healthy individuals (n=500) was assessed by a validated Unani questionnaire based on 10 parameters related to phenotypic and psychological entities known as Ajnas-e-Ashra. Mizaj of the same subjects was further assessed by Sheldon’s somatoplot. Polymerase chain reaction-sequence-specific typing method was used for human leukocyte antigen (HLA) genotyping of 180 healthy volunteers. Conclusion: An expected correlation between HLA-DRB1 alleles and Mizaj types is observed. Five single-nucleotide polymorphisms (p<0.05) were significantly associated with different Mizaj. The study suggests that the Mizaj classification of the Unani system of medicine has a genetic basis. This study would be one step toward a personalized approach as per the Mizaj of an individual to disease proneness, lifestyle modification, and medicine.

Hydrophobins: A revolutionary protein with potential uses in the food industry

Abstract: Hydrophobins are low molecular weight proteins produced by filamentous fungi. These proteins have characteristics of four pairs of cysteine and have surface-active properties due to the presence of hydrophilic-hydrophobic spatial arrangements. This property of hydrophobin makes it capable of stabilizing emulsions and foams which attracts industrial applications. Hydrophobins isolated from GRAS-cleared strains like mushrooms can be used in the food industry as biosurfactants, foaming agents, and stabilizers of air-filled emulsions in food. Due to the requirement for product texture improvements, food industries find hydrophobin as a suitable candidate as it produces foam that is stable for 4 months. Hydrophobins gain more importance when it comes to fat replacement in emulsion-based foods. Air-filled emulsions created using hydrophobins are stable for 45 days and can be used for partial replacement of fat in foods resulting in low-fat products. Hydrophobins play a crucial role in the formation of yeast bio-capsules which are used to complete alcoholic fermentation. These bio-capsules are used in wine production. Hydrophobins are also used to inhibit ice crystal formation in frozen products. Despite being industrially useful molecules, hydrophobins have limitations due to poor yields. This review summarizes the properties of hydrophobins and their existing possibilities in food industry applications.