Department Of Human Genetics And Molecular Medicine
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Item Nanotheranostics revolutionizing neurodegenerative diseases: From precision diagnosis to targeted therapies(Editions de Sante, 2023-10-16T00:00:00) Joshi, Riya; Missong, Hemi; Mishra, Jayapriya; Kaur, Satinder; Saini, Sumant; Kandimalla, Ramesh; Reddy, P. Hemachandra; Babu, Arockia; Bhatti, Gurjit Kaur; Bhatti, Jasvinder SinghNeurodegenerative disorders pose a significant burden on global healthcare systems, and the development of effective therapeutics and diagnostics remains a critical challenge. Nanotheranostics, the integration of nanotechnology-based diagnostic and therapeutic modalities, has emerged as a promising strategy to address these challenges. This review article provides a comprehensive analysis of the latest advancements in nanotheranostics for the treatment and monitoring of neurological disorders, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The application of targeted drug delivery systems, gene therapy, and non-invasive imaging techniques are explored in-depth, highlighting the potential of nanotheranostics to revolutionize the management of neurological disorders. The article delves into the design and synthesis of various nanocarriers, such as liposomes, dendrimers, and polymeric nanoparticles, which enable the targeted delivery of therapeutic agents across the blood-brain barrier. Gene therapy approaches, including CRISPR/Cas9 and RNA interference demonstrating the potential of nanotheranostics to enable precise genetic modifications in the treatment of neurological disorders. Additionally, non-invasive imaging techniques, such as magnetic resonance imaging (MRI) and positron emission tomography (PET), are examined in the context of their integration with nanotheranostics for real-time monitoring of treatment efficacy and disease progression. The review also identifies current challenges and limitations in the field of nanotheranostics, such as toxicity, immunogenicity, and issues with large-scale production. Furthermore, it outlines future research directions and potential strategies to overcome these limitations, paving the way for the clinical translation of nanotheranostics as next-generation therapeutics in neurological disorders. � 2023Item Targeting dynamin-related protein-1 as a potential therapeutic approach for mitochondrial dysfunction in Alzheimer's disease(Elsevier B.V., 2023-06-29T00:00:00) Bhatti, Jasvinder Singh; Kaur, Satinder; Mishra, Jayapriya; Dibbanti, Harikrishnareddy; Singh, Arti; Reddy, Arubala P.; Bhatti, Gurjit Kaur; Reddy, P. HemachandraAlzheimer's disease (AD) is a neurodegenerative disease that manifests its pathology through synaptic damage, mitochondrial abnormalities, microRNA deregulation, hormonal imbalance, increased astrocytes & microglia, accumulation of amyloid ? (A?) and phosphorylated Tau in the brains of AD patients. Despite extensive research, the effective treatment of AD is still unknown. Tau hyperphosphorylation and mitochondrial abnormalities are involved in the loss of synapses, defective axonal transport and cognitive decline in patients with AD. Mitochondrial dysfunction is evidenced by enhanced mitochondrial fragmentation, impaired mitochondrial dynamics, mitochondrial biogenesis and defective mitophagy in AD. Hence, targeting mitochondrial proteins might be a promising therapeutic strategy in treating AD. Recently, dynamin-related protein 1 (Drp1), a mitochondrial fission protein, has gained attention due to its interactions with A? and hyperphosphorylated Tau, altering mitochondrial morphology, dynamics, and bioenergetics. These interactions affect ATP production in mitochondria. A reduction in Drp1 GTPase activity protects against neurodegeneration in AD models. This article provides a comprehensive overview of Drp1's involvement in oxidative damage, apoptosis, mitophagy, and axonal transport of mitochondria. We also highlighted the interaction of Drp1 with A? and Tau, which may contribute to AD progression. In conclusion, targeting Drp1 could be a potential therapeutic approach for preventing AD pathology. � 2023Item Stem cells in the treatment of Alzheimer's disease � Promises and pitfalls(Elsevier B.V., 2023-04-06T00:00:00) Bhatti, Jasvinder Singh; Khullar, Naina; Mishra, Jayapriya; Kaur, Satinder; Sehrawat, Abhishek; Sharma, Eva; Bhatti, Gurjit Kaur; Selman, Ashley; Reddy, P. HemachandraAlzheimer's disease (AD) is the most widespread form of neurodegenerative disorder that causes memory loss and multiple cognitive issues. The underlying mechanisms of AD include the build-up of amyloid-? and phosphorylated tau, synaptic damage, elevated levels of microglia and astrocytes, abnormal microRNAs, mitochondrial dysfunction, hormonal imbalance, and age-related neuronal loss. However, the etiology of AD is complex and involves a multitude of environmental and genetic factors. Currently, available AD medications only alleviate symptoms and do not provide a permanent cure. Therefore, there is a need for therapies that can prevent or reverse cognitive decline, brain tissue loss, and neural instability. Stem cell therapy is a promising treatment for AD because stem cells possess the unique ability to differentiate into any type of cell and maintain their self-renewal. This article provides an overview of the pathophysiology of AD and existing pharmacological treatments. This review article focuses on the role of various types of stem cells in neuroregeneration, the potential challenges, and the future of stem cell-based therapies for AD, including nano delivery and gaps in stem cell technology. � 2023 Elsevier B.V.Item Progression of pre-rheumatoid arthritis to clinical disease of joints: Potential role of mesenchymal stem cells(Elsevier Inc., 2023-03-28T00:00:00) Sardana, Yogesh; Bhatti, Gurjit Kaur; Singh, Charan; Sharma, Pushpender Kumar; Reddy, P. Hemachandra; Bhatti, Jasvinder SinghRheumatoid arthritis (RA) related autoimmunity is developed at mucosal sites due to the interplay between genetic risk factors and environmental triggers. The pre-RA phase that leads to anti-citrullinated protein antibodies, rheumatoid factor, and other autoantibodies spread in the systemic circulation may not affect articular tissue for years until a mysterious second hit triggers the localization of RA-related autoimmunity in joints. Several players in the joint microenvironment mediate the synovial innate and adaptive immunological processes, eventually leading to clinical synovitis. There still exists a gap in the early phase of RA pathogenesis, i.e., the progression of diseases from the systemic circulation to joints. The lack of better understanding of these events results in the inability to answer questions about why only after a certain point of time the disease appears in joints and why in some cases, it simply remains latent and doesn't affect joints at all. In the current review, we focused on the immunomodulatory and regenerative role of mesenchymal stem cells and associated exosomes in RA pathology. We also highlighted the age-related dysregulations in activities of mesenchymal stem cells and how that might trigger homing of systemic autoimmunity to joints. � 2023 Elsevier Inc.Item Mitochondrial miRNA as epigenomic signatures: Visualizing aging-associated heart diseases through a new lens(Elsevier Ireland Ltd, 2023-02-11T00:00:00) Bhatti, Jasvinder Singh; Khullar, Naina; Vijayvergiya, Rajesh; Navik, Umashanker; Bhatti, Gurjit Kaur; Reddy, P. HemachandraAging bears many hard knocks, but heart disorders earn a particular allusion, being the most widespread. Cardiovascular diseases (CVDs) are becoming the biggest concern to mankind due to sundry health conditions directly or indirectly related to heart-linked abnormalities. Scientists know that mitochondria play a critical role in the pathophysiology of cardiac diseases. Both environment and genetics play an essential role in modulating and controlling mitochondrial functions. Even a minor abnormality may prove detrimental to heart function. Advanced age combined with an unhealthy lifestyle can cause most cardiomyocytes to be replaced by fibrotic tissue which upsets the conducting system and leads to arrhythmias. An aging heart encounters far more heart-associated comorbidities than a young heart. Many state-of-the-art technologies and procedures are already being used to prevent and treat heart attacks worldwide. However, it remains a mystery when this heart bomb would explode because it lacks an alarm. This calls for a novel and effective strategy for timely diagnosis and a sure-fire treatment. This review article provides a comprehensive overture of prospective potentials of mitochondrial miRNAs that predict complicated and interconnected pathways concerning heart ailments and signature compilations of relevant miRNAs as biomarkers to plot the role of miRNAs in epigenomics. This article suggests that analysis of DNA methylation patterns in age-associated heart diseases may determine age-impelled biomarkers of heart disease. � 2023 Elsevier B.V.Item Modulating autophagy and mitophagy as a promising therapeutic approach in neurodegenerative disorders(Elsevier Inc., 2022-11-04T00:00:00) Mishra, Jayapriya; Bhatti, Gurjit Kaur; Sehrawat, Abhishek; Singh, Charan; Singh, Arti; Reddy, Arubala P.; Reddy, P. Hemachandra; Bhatti, Jasvinder SinghThe high prevalence of neurodegenerative diseases has become a major public health challenge and is associated with a tremendous burden on individuals, society and federal governments worldwide. Protein misfolding and aggregation are the major pathological hallmarks of several neurodegenerative disorders. The cells have evolved several regulatory mechanisms to deal with aberrant protein folding, namely the classical ubiquitin pathway, where ubiquitination of protein aggregates marks their degradation via lysosome and the novel autophagy or mitophagy pathways. Autophagy is a catabolic process in eukaryotic cells that allows the lysosome to recycle the cell's own contents, such as organelles and proteins, known as autophagic cargo. Their most significant role is to keep cells alive in distressed situations. Mitophagy is also crucial for reducing abnormal protein aggregation and increasing organelle clearance and partly accounts for maintaining cellular homeostasis. Furthermore, substantial data indicate that any disruption in these homeostatic mechanisms leads to the emergence of several age-associated metabolic and neurodegenerative diseases. So, targeting autophagy and mitophagy might be a potential therapeutic strategy for a variety of health conditions. � 2022Item 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. HemachandraType 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.Item 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. HemachandraType 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.Item 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. HemachandraThe 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.