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6. Darunavir Nanoformulation Suppresses HIV Pathogenesis in Macrophages and Improves Drug Delivery to the Brain in Mice.

Author

Zhou, Lina, Godse, Sandip, Sinha, Namita, Kodidela, Sunitha, Singh, Udai, and Kumar, Santosh

Subjects
RITONAVIR, ATAZANAVIR, OXIDANT status, HIV, HIV infections, MACROPHAGES, DARUNAVIR
Abstract

Although antiretroviral therapy (ART) can suppress peripheral HIV, patients still suffer from neuroHIV due to insufficient levels of ART drugs in the brain. Hence, this study focuses on developing a poly lactic-co-glycolic acid (PLGA) nanoparticle-based ART drug delivery system for darunavir (DRV) using an intranasal route that can overcome the limitation of drug metabolic stability and blood–brain barrier (BBB) permeability. The physicochemical properties of PLGA-DRV were characterized. The results indicated that PLGA-DRV formulation inhibits HIV replication in U1 macrophages directly and in the presence of the BBB without inducing cytotoxicity. However, the PLGA-DRV did not inhibit HIV replication more than DRV alone. Notably, the total antioxidant capacity remained unchanged upon treatment with both DRV or PLGA-DRV in U1 cells. Compared to DRV alone, PLGA-DRV further decreased reactive oxygen species, suggesting a decrease in oxidative stress by the formulation. Oxidative stress is generally increased by HIV infection, leading to increased inflammation. Although the PLGA-DRV formulation did not further reduce the inflammatory response, the formulation did not provoke an inflammatory response in HIV-infected U1 macrophages. As expected, in vitro experiments showed higher DRV permeability by PLGA-DRV than DRV alone to U1 macrophages. Importantly, in vivo experiments, especially using intranasal administration of PLGA-DRV in wild-type mice, demonstrated a significant increase in the brain-to-plasma ratio of DRV compared to the free DRV. Overall, findings from this study attest to the potential of the PLGA-DRV nanoformulation in reducing HIV pathogenesis in macrophages and enhancing drug delivery to the brain, offering a promising avenue for treating HIV-related neurological disorders. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Resveratrol and its analogs suppress HIV replication, oxidative stress, and inflammation in macrophages.

Author

Kumar, Santosh, Sinha, Namita, Kodidela, Sunitha, Godse, Sandip, Singla, Bhupesh, Singh, Udai P., and Bhat, Hari K.

Subjects
RESVERATROL, HIV infections, MACROPHAGES, ANTIRETROVIRAL agents, OXIDATIVE stress
Abstract

HIV suppression in brain viral reservoirs, especially macrophages, and microglia is critical to suppress HIV neuropathogenesis and subsequently HIV-associated neurocognitive disorders (HAND). Since most antiretroviral therapy (ART) drugs do not achieve optimal therapeutic concentrations in the brain and can cause neurotoxicity, an alternative/adjuvant therapy is needed to suppress HIV neuropathogenesis. In this study, our objectives were to examine the anti-HIV, antioxidant, and anti-inflammatory potential of resveratrol (RES) and its synthetic analogs 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) and 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD) in HIV-infected macrophages. We used HIV replication (viral load), oxidative stress (reactive oxygen species and antioxidant enzymes), and inflammatory response (pro- and anti-inflammatory cytokines/chemokines) assays to achieve the objectives of the study. Our results showed that RES and its analogs HPIMBD and TIMBD at 25 µM concentration significantly decrease HIV replication in both primary monocyte-derived macrophages and U1-differentiated macrophages. Moreover, RES and its analogs do not induce any cytotoxicity for up to 3 days in these cells. Further, treatment with RES and TIMBD (25 µM) also reduced the levels of reactive oxygen species without affecting the expression of antioxidant enzymes, SOD1, and catalase in U1 macrophages. Besides, RES and HPIMBD treatment inhibited the proinflammatory cytokines and chemokines in U1 macrophages, which was associated with decreased levels of anti-inflammatory cytokines. Importantly, our western blot experiments show that RES also decreases cellular proinflammatory cytokine IL-1β, which is usually elevated in both myeloid and neuronal cells upon HIV infection. Taken together, our results suggest that RES and/or its analogs are important adjuvants that may be used not only to suppress HIV but also oxidative stress and inflammation in brain viral reservoirs. [ABSTRACT FROM AUTHOR]

Published
2023
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22. Influence of ABCB‐1, ERCC‐1 and ERCC‐2 gene polymorphisms on response to capecitabine and oxaliplatin (CAPOX) treatment in colorectal cancer (CRC) patients of South India

Author

Ashok Varma, Deepak Gopal Shewade, Kodidela Sunitha, Jayanthi Mathaiyan, and Biswajit Dubashi

Subjects
Male, Oncology, medicine.medical_specialty, ATP Binding Cassette Transporter, Subfamily B, Colorectal cancer, India, Antineoplastic Agents, Single-nucleotide polymorphism, Polymorphism, Single Nucleotide, 030226 pharmacology & pharmacy, Disease-Free Survival, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, Humans, Pharmacology (medical), Prospective Studies, 030212 general & internal medicine, Survival rate, Xeroderma Pigmentosum Group D Protein, Pharmacology, business.industry, CAPOX Regimen, Middle Aged, Endonucleases, medicine.disease, Oxaliplatin, DNA-Binding Proteins, Female, ERCC1, Colorectal Neoplasms, business, medicine.drug
Abstract

What is known and objective High interindividual response variability was reported with capecitabine and oxaliplatin (CAPOX) regimen in colorectal cancer (CRC). The single nucleotide polymorphisms (SNPs) of the genes related to drug efflux transport (ABCB1) and DNA repair (ERCC) could result in altered tumour response. Hence, this study was designed to assess the influence of ABCB1, ERCC-1 and ERCC-2 gene polymorphisms on tumour response to CAPOX treatment in CRC patients of South Indian origin. Patients and methods A total of 145 newly diagnosed CRC patients were included in the final analysis. Response to CAPOX treatment in the adjuvant setting was assessed in terms of disease-free survival rate (DFSR) and overall survival rate (OSR) at 3 years, whereas in the palliative setting, the response was assessed as progression-free survival rate (PFSR) and OSR at 3 years. Five millilitres of the venous blood sample was collected from each patient for genomic DNA extraction by the manual phenol-chloroform method. Genotyping and allelic discrimination analysis were done using real-time PCR (RT-PCR). Results and discussion With ABCB1 gene polymorphism rs1045642 (A > G), patients with AG/GG genotype showed better DFSR [P value = .02, OR = 2 (CI: 1.5-3)] and PFSR [P value = .02, OR = 1.6 (CI: 1.1-2.5)] when compared to AA genotype in the adjuvant and palliative settings, respectively. Similarly with rs1128503 (A > G) polymorphism, patients with AG/GG genotype were found to have better DFSR [P value = .02, OR = 1.9 (CI: 1.3-3)] and PFSR [P value = .01, OR = 2 (CI: 1.1-3.7)] when compared to AA genotype. However, we did not find any association between CAPOX response and ABCB1 gene polymorphisms in a binary logistic regression when non-genetic predictors were considered for analysis. We did not find any association with ERCC1 (rs11615 A > G) and ERCC2 (rs13181 T > G) gene polymorphisms with respect to CAPOX response in either of the treatment settings. What is new and conclusion The response to CAPOX treatment was found to be influenced by the ABCB1 gene variants (rs1128503 and rs1045642), thereby strengthening their predictive role. No association was found between ERCC1 (rs11615 A > G), ERCC2 (rs13181 T > G) gene polymorphisms and tumour response to CAPOX treatment in CRC patients of South Indian origin.

Published
2020

28. Association of NUDT15*3 and FPGS 2572C&gt

Author

Kodidela, Sunitha, Dorababu, Patchava, Thakkar, Dimpal N, Dubashi, Biswajit, Sundaram, Rajan, Muralidharan, Niveditha, Nidanapu, Ravi Prasad, Aribandi, Anil, Pradhan, Suresh Chandra, and Uppugunduri, Chakradhara Rao Satyanarayana

Subjects
relapse, myelosuppression, children, hemic and lymphatic diseases, toxicity, India, 6-mercaptopurine, acute lymphoblastic leukemia, NUDT15, survival, methotrexate, polymorphism
Abstract

Genetic variants influencing the pharmacokinetics and/or pharmacodynamics of the chemotherapeutic drugs used in Acute Lymphoblastic Leukemia (ALL) therapy often contribute to the occurrence of treatment related toxicity (TRT). In this study, we explored the association of candidate genetic variants with early hematological TRT (grade 3&ndash, 4) occurring within the first 100 days of low-dose methotrexate and 6-mercaptopurine based maintenance therapy (n = 73). Fourteen variants in the following candidate genes were genotyped using allele discrimination assay by real-time PCR: ABCB1, DHFR, GGH, FPGS, MTHFR, RFC1, SLCO1B1, TPMT, and NUDT15. Methotrexate polyglutamate (MTXPG3-5) levels in red blood cells were measured by LC-MS/MS. Early hematological TRT (grade 3&ndash, 4) was seen in 54.9% of patients. The NUDT15*3 allele was associated with early TRT occurrence [HR: 3.04 (95% CI: 1.5&ndash, 6.1), p = 0.007]. Sensitivity of early TRT prediction improved (from 30.7% to 89.7%) by considering FPGS variant (rs1544105) carrier status along with NUDT15*3 allele [HR = 2.7 (1.5&ndash, 4.7, p = 0.008)]. None of the considered genetic variants were associated with MTXPG3-5 levels, which in turn were not associated with early TRT. NUDT15*3 allele carrier status could be used as a stratifying marker for Indian ALL patients to distinguish patients at high or low risk of developing early hematological TRT.

Published
2020
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33. Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

Author

Kodidela, Sunitha, primary, Dorababu, Patchava, additional, Thakkar, Dimpal N., additional, Dubashi, Biswajit, additional, Sundaram, Rajan, additional, Muralidharan, Niveditha, additional, Nidanapu, Ravi Prasad, additional, Aribandi, Anil, additional, Pradhan, Suresh Chandra, additional, and Uppugunduri, Chakradhara Rao Satyanarayana, additional

Published
2020
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37. Increased Risk of Early Hematologic Toxicity during Maintenance Therapy in Acute Lymphoblastic Leukemia Patients of South Indian Origin Carrying NUDT15*3 Allele

Author

Kodidela, Sunitha, primary, Patchva, Dorababu, additional, Thakkar:, Dimpal, additional, Dubashi, Biswajit, additional, Sundaram, Rajan, additional, Nidanapu, Ravi Prasad, additional, Nivedita, Muralidharan, additional, Aribandi, Anil, additional, Pradhan, Suresh Chandra, additional, and Uppugunduri, Chakradhara RS, additional

Published
2019
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40. A Polymorphism Located Near PMAIP1/Noxa Gene Influences Susceptibility to Hodgkin Lymphoma Development in South India

Author

Thakkar, Dimpal N, Kodidela, Sunitha, Sandhiya, Selvarajan, Dubashi, Biswajit, and Dkhar, Steven Aibor

Subjects
DNA Repair, TLR4, polymorphisms, PMAIP1/Noxa, Hodgkin lymphoma, Research Article
Abstract

Background: Single nucleotide polymorphisms (SNPs) in DNA repair and Toll-like receptor (TLR) genes have been reported to be associated with Hodgkin Lymphoma (HL) risk. Since such associations may be ethnicity dependent, polymorphisms in TLR4 rs1554973, Xeroderma pigmentosum C (XPC) rs2228000, rs2228001 and a variant near PMAIP1/Noxa gene rs8093763 were here investigated with regard to HL susceptibility in a south Indian population. Normative frequencies of SNPs were established and compared with data for 1000 genome populations. Methods: We conducted a case control study consisting of 200 healthy volunteers and 101 cases with HL. DNA samples were genotyped using real-time PCR. Linkage disequilibrium (LD) analysis between rs2228000 and rs2228001 was performed using HaploView (version 4.2). Results: Among the studied variants, we observed that a variant rs8093763 located near PMAIP1/Noxa gene was associated with HL risk (OR=1.72 and 95% CI=1.004-2.93). The major allele frequencies of XPC (rs2228000 and rs2228001), TLR4 (rs1554973) and PMAIP1/NOXA (rs8093763) variants were 79%, 66%, 67% and 59% respectively. The studied frequencies were significantly different from 1000 genome populations. Conclusion: The results suggest that a variant rs8093763 located near the PMAIP1/Noxa gene may modify risk of HL. We found variation in distribution of polymorphic frequencies between the study population and 1000 genome populations. The results may help identify individual risk of development of HL in our south Indian population.

Published
2017

42. Proteomic Profiling of Exosomes Derived from Plasma of HIV-Infected Alcohol Drinkers and Cigarette Smokers

Author

Kodidela, Sunitha, primary, Wang, Yujie, additional, Patters, Benjamin J., additional, Gong, Yuqing, additional, Sinha, Namita, additional, Ranjit, Sabina, additional, Gerth, Kelli, additional, Haque, Sanjana, additional, Cory, Theodore, additional, McArthur, Carole, additional, Kumar, Anil, additional, Wan, Jim Y., additional, and Kumar, Santosh, additional

Published
2019
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