Human Genetics And Molecular Medicine - Research Publications

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    Betaine Intervention as a Novel Approach to Preventing Doxorubicin-Induced Cardiotoxicity
    (Elsevier Inc., 2023-09-24T00:00:00) Jaiswal, Aiswarya; Rawat, Pushkar Singh; Singh, Sumeet Kumar; Bhatti, Jasvinder Singh; Khurana, Amit; Navik, Umashanker
    The anthracycline anticancer drug doxorubicin (Dox) is widely prescribed for treating lung, ovary, breast, lymphoma, sarcoma, and pediatric cancer. Mechanistically, Dox intercalates the DNA and inhibits the topoisomerase II enzyme in fast-proliferating cancer. The clinical application of Dox is limited due to its cardiotoxicity, including congestive heart failure, alterations in myocardial structure, arrhythmia, and left ventricular dysfunction. Dox causes cardiotoxicity via various mechanisms, including oxidative stress, mitochondrial dysfunctioning, deranged Ca2+ homeostasis, inflammation, fibrosis, downregulating AMPK, etc. Betaine is a zwitterion-based drug known as N, N, N trimethylglycine that regulates the methionine cycle and homocysteine (a risk factor for cardiovascular disease) detoxification through betaine-homocysteine methyltransferases. Betaine is nontoxic and has several beneficial effects in different disease models. Betaine treatment decreases the amyloid ? generation, reduces obesity, improves steatosis and fibrosis, and activates AMP-activated protein kinase (AMPK). Further, betaine downregulates 8?hydroxy-2-deoxyguanosine, malondialdehyde, and upregulates catalases, glutathione peroxidase, and superoxide dismutase activity. Therefore, we hypothesized that betaine might be a rational drug candidate to effectively combat Dox-associated oxidative stress, inflammation, and mitochondrial dysfunction. � 2023 The Author(s)
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    Natural Compound-Based Nanoparticles to Target Free Radicals in Cancer
    (Springer Singapore, 2022-09-28T00:00:00) Yadav, Umesh Prasad; Rhuthuparna, M.; Vasudeva, Kanika; Suman, Prabhat; Munshi, Anjana; Kumar, Santosh; Singh, Sandeep
    Cell proliferation and malignant transformation are enabled by genetic and epigenetic changes. During the malignancy process, malignant cells acquire distinguishing characteristics. Cancer cells have acquired the ability to generate more reactive oxygen species (ROS), resulting in high oxidative stress. ROS-mediated signaling is needed for cancer cell physiology, and high levels of ROS cause oxidative stress-induced cytotoxicity in cancer cells. To avoid ROS-mediated cytotoxicity, cancer cells modulate their redox state through various antioxidant mechanisms and keep their ROS levels below the threshold. Cancer treatment that targets oxidative stress is an appealing option. Many natural oxidative stress modulators and bioactive compounds have been used in the treatment of cancer. Conventional uptake of bioactive molecule is associated with lower bioavailability, solubility, unlikely biodistribution, and side effects. Traditional drug uptake is improved by nanoformulation, making it easier to overcome side effects, improve biodistribution, and extend drug duration time. Natural prooxidant-loaded nanoparticles efficiently carry prooxidant to the tumor site and selectively and efficiently induce oxidative stress-mediated cell death in cancer cells. � Springer Nature Singapore Pte Ltd. 2022.
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    Oxidative stress in the pathophysiology of type 2 diabetes and related complications: Current therapeutics strategies and future perspectives
    (Elsevier Inc., 2022-04-07T00:00:00) Bhatti, Jasvinder Singh; Sehrawat, Abhishek; Mishra, Jayapriya; Sidhu, Inderpal Singh; Navik, Umashanker; Khullar, Naina; Kumar, Shashank; Bhatti, Gurjit Kaur; Reddy, P. Hemachandra
    Type 2 diabetes (T2DM) is a persistent metabolic disorder rising rapidly worldwide. It is characterized by pancreatic insulin resistance and ?-cell dysfunction. Hyperglycemia induced reactive oxygen species (ROS) production and oxidative stress are correlated with the pathogenesis and progression of this metabolic disease. To counteract the harmful effects of ROS, endogenous antioxidants of the body or exogenous antioxidants neutralise it and maintain bodily homeostasis. Under hyperglycemic conditions, the imbalance between the cellular antioxidant system and ROS production results in oxidative stress, which subsequently results in the development of diabetes. These ROS are produced in the endoplasmic reticulum, phagocytic cells and peroxisomes, with the mitochondrial electron transport chain (ETC) playing a pivotal role. The exacerbated ROS production can directly cause structural and functional modifications in proteins, lipids and nucleic acids. It also modulates several intracellular signaling pathways that lead to insulin resistance and impairment of ?-cell function. In addition, the hyperglycemia-induced ROS production contributes to micro- and macro-vascular diabetic complications. Various in-vivo and in-vitro studies have demonstrated the anti-oxidative effects of natural products and their derived bioactive compounds. However, there is conflicting clinical evidence on the beneficial effects of these antioxidant therapies in diabetes prevention. This review article focused on the multifaceted role of oxidative stress caused by ROS overproduction in diabetes and related complications and possible antioxidative therapeutic strategies targeting ROS in this disease. � 2022 Elsevier Inc.
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    Epigenetic Instability Caused by Oxidative Stress Triggers Tumorigenesis
    (Springer Nature, 2022-01-31T00:00:00) Preet Kaur, Raman; Kaur, Prabhsimran; Munshi, Anjana
    Cancer is a multifactorial disease that is caused by various modifiable as well as non-modifiable factors. Among non-modifiable factors, genetic and epigenetic factors have been reported to play a critical role in the progression of cancer. Epigenetics refers to the change in gene expression without any change in the genome. The major epigenome targets include modification of histones by either methylation or acetylation and methylation of DNA at CpG islands. Change in acetylation and methylation pattern leads to not only inhibition of tumor suppressor genes but also the activation of oncogenes. Oxidative stress is a significant phenomenon observed in human body as a result of various intracellular as well as extracellular factors. This stress interferes with the function of histone methyltransferases and histone deacetylases, resulting in modifications of the epigenome. Further, these oxidative stress-induced epigenetic modifications may occur at various regions, including the promoters of tumor suppressor genes. These result in silencing of genes, leading to increased cell proliferation. In addition, reactive oxygen species have also been found to be involved in regulating the various steps of tumor development, including transformation, survival, proliferation, invasion, metastasis, and angiogenesis. Therefore, oxidative stress can be used as a target for developing cancer-related treatment modalities that reduce oxidative stress levels and thereby help in the resumption of the normal activity of epigenetic enzymes preserving epigenetic integrity. � Springer Nature Singapore Pte Ltd. 2022.
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    Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management
    (Elsevier Masson s.r.l., 2021-05-13T00:00:00) Rawat, Pushkar Singh; Jaiswal, Aiswarya; Khurana, Amit; Bhatti, Jasvinder Singh; Navik, Umashanker
    Doxorubicin (Dox) is a secondary metabolite of the mutated strain of Streptomyces peucetius var. Caesius and belongs to the anthracyclines family. The anti-cancer activity of Dox is mainly exerted through the DNA intercalation and inhibiting topoisomerase II enzyme in fast-proliferating tumors. However, Dox causes cumulative and dose-dependent cardiotoxicity, which results in increased risks of mortality among cancer patients and thus limiting its wide clinical applications. There are several mechanisms has been proposed for doxorubicin-induced cardiotoxicity and oxidative stress, free radical generation and apoptosis are most widely reported. Apart from this, other mechanisms are also involved in Dox-induced cardiotoxicity such as impaired mitochondrial function, a perturbation in iron regulatory protein, disruption of Ca2+ homeostasis, autophagy, the release of nitric oxide and inflammatory mediators and altered gene and protein expression that involved apoptosis. Dox also causes downregulation of DNA methyltransferase 1 (DNMT1) enzyme activity which leads to a reduction in the DNA methylation process. This hypomethylation causes dysregulation in the mitochondrial genes like peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1-alpha (PGC-1?), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) unit in the heart. Apart from DNA methylation, Dox treatment also alters the micro RNAs levels and histone deacetylase (HDAC) activity. Therefore, in the current review, we have provided a detailed update on the current understanding of the pathological mechanisms behind the well-known Dox-induced cardiotoxicity. Further, we have provided some of the most plausible pharmacological strategies which have been tested against Dox-induced cardiotoxicity. � 2021 The Authors
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    Protective effects of a mitochondria-targeted small peptide SS31 against hyperglycemia-induced mitochondrial abnormalities in the liver tissues of diabetic mice, Tallyho/JngJ mice
    (Elsevier B.V., 2021-02-25T00:00:00) Bhatti, Jasvinder Singh; Tamarai, Kavya; Kandimalla, Ramesh; Manczak, Maria; Yin, Xiangling; Ramasubramanian, Bhagavathi; Sawant, Neha; Pradeepkiran, Jangampalli Adi; Vijayan, Murali; Kumar, Subodh; Reddy, P. Hemachandra
    Type 2 Diabetes mellitus (T2DM) has become a major public health issue associated with a high risk of late-onset Alzheimer's disease (LOAD). Mitochondrial dysfunction is one of the molecular events that occur in the LOAD pathophysiology. The present study was planned to investigate the molecular alterations induced by hyperglycemia in the mitochondria of diabetic mice and further explore the possible ameliorative role of the mitochondria-targeted small peptide, SS31 in diabetic mice. For this purpose, we used a polygenic mouse model of type 2 diabetes, TALLYHO/JngJ (TH), and nondiabetic, SWR/J mice strains. The diabetic status in TH mice was confirmed at 8 weeks of age. The 24 weeks old experimental animals were segregated into three groups: Non-diabetic controls (SWR/J mice), diabetic (TH mice) and, SS31 treated diabetic TH mice. The mRNA and protein expression levels of mitochondrial proteins were investigated in all the study groups in the liver tissues using qPCR and immunoblot analysis. Also, the mitochondrial functions including H2O2 production, ATP generation, and lipid peroxidation were assessed in all the groups. Mitochondrial dysfunction was observed in TH mice as evident by significantly elevated H2O2 production, lipid peroxidation, and reduced ATP production. The mRNA expression and Western blot analysis of mitochondrial dynamics (Drp1 and Fis1 � fission; Mfn1, Mfn2, and Opa1 -fusion), and biogenesis (PGC-1?, Nrf1, Nrf2, and TFAM) genes were significantly altered in diabetic TH mice. Furthermore, SS31 treatment significantly reduced the mitochondrial abnormalities and restore mitochondrial functions in diabetic TH mice. � 2019 Elsevier B.V. and Mitochondria Research Society. All rights reserved.
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    Mitochondria-Targeted Small Peptide, SS31 Ameliorates Diabetes Induced Mitochondrial Dynamics in Male TallyHO/JngJ Mice
    (Springer, 2020-10-07T00:00:00) Bhatti, Jasvinder Singh; Thamarai, Kavya; Kandimalla, Ramesh; Manczak, Maria; Yin, Xiangling; Kumar, Subodh; Vijayan, Murali; Reddy, P. Hemachandra
    The escalating burden of type 2 diabetes (T2D) and its related complications has become a major public health challenge worldwide. Substantial evidence indicates that T2D is one of the culprits for the high prevalence of Alzheimer�s disease (AD) in diabetic subjects. This study aimed to investigate the possible mitochondrial alterations in the pancreas induced by hyperglycemia in diabetes. We used a diabetic TallyHO/JngJ (TH) and non-diabetic, SWR/J mice strains. The diabetic and non-diabetic status in animals was assessed by performing intraperitoneal glucose tolerance test at four time points, i.e., 4, 8, 16, and 24�weeks of age. We divided 24-week-old TH and SWR/J mice into 3 groups: controls, diabetic TH mice, and diabetic TH mice treated with SS31 peptide. After the treatment of male TH mice with SS31, intraperitoneally, for 4�weeks, we studied mitochondrial dynamics, biogenesis, and function. The mRNA and protein expression levels of mitochondrial proteins were evaluated using qPCR and immunoblot analysis. The diabetic mice after 24�weeks of age showed overt pancreatic injury as demonstrated by disintegration and atrophy of ? cells with vacuolization and reduced islet size. Mitochondrial dysfunction was observed in TH mice, as evidenced by significantly elevated H2O2 production, lipid peroxidation, and reduced ATP production. Furthermore, mRNA expression and immunoblot analysis of mitochondrial dynamics genes were significantly affected in diabetic mice, compared with controls. However, treatment of animals with SS31 reduced mitochondrial dysfunction and restored most of the mitochondrial functions and mitochondrial dynamics processes to near normal in TH mice. In conclusion, mitochondrial dysfunction is established as one of the molecular events that occur in the pathophysiology of T2D. Further, SS31 treatment may confer protection against the mitochondrial alterations induced by hyperglycemia in diabetic TallyHO/JngJ mice. � 2020, Springer Science+Business Media, LLC, part of Springer Nature.