Quality of life and thalassemia in India: A scoping review.

In recent years, a multitude of studies have been conducted to investigate the assessment of quality of life (QoL) among individuals affected by thalassemia. This scoping review aimed to examine the existing knowledge regarding the QoL and its associated factors among individuals with thalassemia in India. Databases, such as PubMed, SCOPUS, Web of Science, and the Preferred Reporting Items for Systematic Review and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) guidelines, were searched. A total of nine articles were included in the review. The included studies mainly investigated children. The Pediatric Quality of Life Inventory (PedsQL) is the most common instrument used most often. Overall, the research findings indicate that individuals who underwent blood transfusion exhibited a lower QoL than those who did not receive blood transfusion. Additionally, it was observed that children diagnosed with thalassemia reported a lower QoL than adults. Nevertheless, the studies exhibited notable methodological deficiencies that constrained the validity and generalizability of the results. Hence, it is imperative to undertake comprehensive QoL research encompassing all regions of India and various thalassemia populations within the country to bridge this evidentiary void.

Prevalence and Associated Risk Factors of Hypertension Among Tribal Population Aged 15-49 in India: Evidence from National Family Health Survey, 2019-2021.

BACKGROUND: Approximately 10% of non-communicable diseases (NCDs) can be attributed to hypertension. The prevalence of hypertension is steadily increasing among urban, rural, and tribal populations alike. There has been a growing incidence of hypertension within underprivileged groups; however, there is a scarcity of research focusing on the risks of hypertension within Indian tribes. The current study aimed to estimate the pooled prevalence of hypertension among tribes and the risk factors of hypertension. METHODS: This study uses data from the fifth phase of the National Family Health Survey (NFHS-5) in India, covering 2,843,917 individuals in 636,699 households. A total of 69,176 individuals belonging to tribal communities aged between 15 and 49, encompassing both males and females, have been incorporated into our study. The study utilized bivariate and multivariable binary logistic regression analyses, which were conducted using the R statistical software. RESULTS: Among 69,176 tribal populations between 15 and 49 years, the overall prevalence of hypertension was 12.54% (8676/69176; 95% CI, 12.29%, 12.79%). The prevalence of hypertension among males was 16.4% and 12.07% among females. Age, gender, education, marital status, smoking, and alcohol consumption were found to be the significant predictors of hypertension among tribes. CONCLUSION: The rising prevalence and potential dangers of hypertension within Indian tribes highlight their epidemiological transition burdened by significant cardiometabolic health concerns, necessitating prompt and ongoing monitoring and surveillance.

Epitranscriptomic Reader YTHDF2 Regulates SEK1( MAP2K4 )-JNK-cJUN Inflammatory Signaling in Astrocytes during Neurotoxic Stress.

As the most abundant glial cells in the CNS, astrocytes dynamically respond to neurotoxic stress, however, the key molecular regulators controlling the inflammatory status of these sentinels during neurotoxic stress have remained elusive. Herein, we demonstrate that the m6A epitranscriptomic mRNA modification tightly regulates the pro-inflammatory functions of astrocytes. Specifically, the astrocytic neurotoxic stresser, manganese (Mn), downregulated the m6A reader YTHDF2 in human and mouse astrocyte cultures and in the mouse brain. Functionally, YTHDF2 knockdown augmented, while its overexpression dampened, neurotoxic stress induced proinflammatory response, suggesting YTHDF2 serves as a key upstream regulator of inflammatory responses in astrocytes. Mechnistically, YTHDF2 RIP-sequencing identified MAP2K4 ( MKK4; SEK1) mRNA as a YTHDF2 target influencing inflammatory signaling. Our target validation revealed Mn-exposed astrocytes mediates proinflammatory response by activating the phosphorylation of SEK1, JNK, and cJUN signaling. Collectively, YTHDF2 serves a key upstream 'molecular switch' controlling SEK1( MAP2K4 )-JNK-cJUN proinflammatory signaling in astrocytes.

Aggregation-Inhibiting scFv-Based Therapies Protect Mice against AAV1/2-Induced A53T-α-Synuclein Overexpression.

To date, there is no cure for Parkinson's disease (PD). There is a pressing need for anti-neurodegenerative therapeutics that can slow or halt PD progression by targeting underlying disease mechanisms. Specifically, preventing the build-up of alpha-synuclein (αSyn) and its aggregated and mutated forms is a key therapeutic target. In this study, an adeno-associated viral vector loaded with the A53T gene mutation was used to induce rapid αSyn-associated PD pathogenesis in C57BL/6 mice. We tested the ability of a novel therapeutic, a single chain fragment variable (scFv) antibody with specificity only for pathologic forms of αSyn, to protect against αSyn-induced neurodegeneration, after unilateral viral vector injection in the substantia nigra. Additionally, polyanhydride nanoparticles, which provide sustained release of therapeutics with dose-sparing properties, were used as a delivery platform for the scFv. Through bi-weekly behavioral assessments and across multiple post-mortem immunochemical analyses, we found that the scFv-based therapies allowed the mice to recover motor activity and reduce overall αSyn expression in the substantia nigra. In summary, these novel scFv-based therapies, which are specific exclusively for pathological aggregates of αSyn, show early promise in blocking PD progression in a surrogate mouse PD model.

Environmental neurotoxic pesticide exposure induces gut inflammation and enteric neuronal degeneration by impairing enteric glial mitochondrial function in pesticide models of Parkinson's disease: Potential relevance to gut-brain axis inflammation in Parkinson's disease pathogenesis.

Despite the growing recognition that gastrointestinal (GI) dysfunction is prevalent in Parkinson's disease (PD) and occurs as a major prodromal symptom of PD, its cellular and molecular mechanisms remain largely unknown. Among the various types of GI cells, enteric glial cells (EGCs), which resemble astrocytes in structure and function, play a critical role in the pathophysiology of many GI diseases including PD. Thus, we investigated how EGCs respond to the environmental pesticides rotenone (Rot) and tebufenpyrad (Tebu) in cell and animal models to better understand the mechanism underlying GI abnormalities. Both Rot and Tebu induce dopaminergic neuronal cell death through complex 1 inhibition of the mitochondrial respiratory chain. We report that exposing a rat enteric glial cell model (CRL-2690 cells) to these pesticides increased mitochondrial fission and reduced mitochondrial fusion by impairing MFN2 function. Furthermore, they also increased mitochondrial superoxide generation and impaired mitochondrial ATP levels and basal respiratory rate. Measurement of LC3, p62 and lysosomal assays revealed impaired autolysosomal function in ECGs during mitochondrial stress. Consistent with our recent findings that mitochondrial dysfunction augments inflammation in astrocytes and microglia, we found that neurotoxic pesticide exposure also enhanced the production of pro-inflammatory factors in EGCs in direct correlation with the loss in mitochondrial mass. Finally, we show that pesticide-induced mitochondrial defects functionally impaired smooth muscle velocity, acceleration, and total kinetic energy in a mixed primary culture of the enteric nervous system (ENS). Collectively, our studies demonstrate for the first time that exposure to environmental neurotoxic pesticides impairs mitochondrial bioenergetics and activates inflammatory pathways in EGCs, further augmenting mitochondrial dysfunction and pro-inflammatory events to induce gut dysfunction. Our findings have major implications in understanding the GI-related pathogenesis and progression of environmentally linked PD.

Understanding the trends of tribal research in India through bibliometric analysis.

Tribes are the most vulnerable, particularly in healthcare. Health research in a population helps to understand the trends of various diseases and other social determinants causing them. Our study aims to perform a bibliometric analysis of Tribal research in India from its status quo. Materials and Methods: Research articles on tribal health were retrieved from Scopus and analyzed using MS Office, VOS viewer, and Word Cloud generator from January 2000 to December 2020. The number of research publications published each year, the clustering pattern of contributing authors, the most popular journals, the leading publication, document type, domain research areas, and commonly used keywords were all considered in the study. Results: As a result of the search, 1249 research publications were found. According to our selection criteria, only 395 research papers were included in the analysis. Approximately 43 research publications were published in 2020, but only three articles were published in 2000. Almost 35.7% of articles were published in traditional medicine, and 15.7% and 14.7% of articles were published in nutrition and infectious diseases. Less than 1% of articles were published in Health Policy, and 1.5% were published in Health Systems. Conclusions: The study results showed that the research on tribes has now been improving in the following years. Research into tribal mental health and health care systems should be encouraged. Collaboration and funding may assist academic institutions in raising awareness of health issues in these populations.

Chronic Manganese Exposure and the Enteric Nervous System: An in Vitro and Mouse in Vivo Study.

BACKGROUND: Chronic environmental exposure to manganese (Mn) can cause debilitating damage to the central nervous system. However, its potential toxic effects on the enteric nervous system (ENS) have yet to be assessed. OBJECTIVE: We examined the effect of Mn on the ENS using both cell and animal models. METHOD: Rat enteric glial cells (EGCs) and mouse primary enteric cultures were exposed to increasing concentrations of Mn and cell viability and mitochondrial health were assessed using various morphological and functional assays. C57BL/6 mice were exposed daily to a sublethal dose of Mn (15mg/kg/d) for 30 d. Gut peristalsis, enteric inflammation, gut microbiome profile, and fecal metabolite composition were assessed at the end of exposure. RESULTS: EGC mitochondria were highly susceptible to Mn neurotoxicity, as evidenced by lower mitochondrial mass, adenosine triphosphate-linked respiration, and aconitase activity as well as higher mitochondrial superoxide, upon Mn exposure. Minor differences were seen in the mouse model: specifically, longer intestinal transit times and higher levels of colonic inflammation. CONCLUSION: Based on our findings from this study, Mn preferentially induced mitochondrial dysfunction in a rat EGC line and in vivo resulted in inflammation in the ENS. https://doi.org/10.1289/EHP7877.

PKC Delta Activation Promotes Endoplasmic Reticulum Stress (ERS) and NLR Family Pyrin Domain-Containing 3 (NLRP3) Inflammasome Activation Subsequent to Asynuclein-Induced Microglial Activation: Involvement of Thioredoxin-Interacting Protein (TXNIP)/Thioredoxin (Trx) Redoxisome Pathway.

A classical hallmark of Parkinson's disease (PD) pathogenesis is the accumulation of misfolded alpha-synuclein (αSyn) within Lewy bodies and Lewy neurites, although its role in microglial dysfunction and resultant dopaminergic (DAergic) neurotoxicity is still elusive. Previously, we identified that protein kinase C delta (PKCδ) is activated in post mortem PD brains and experimental Parkinsonism and that it participates in reactive microgliosis; however, the relationship between PKCδ activation, endoplasmic reticulum stress (ERS) and the reactive microglial activation state in the context of α-synucleinopathy is largely unknown. Herein, we show that oxidative stress, mitochondrial dysfunction, NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, and PKCδ activation increased concomitantly with ERS markers, including the activating transcription factor 4 (ATF-4), serine/threonine-protein kinase/endoribonuclease inositol-requiring enzyme 1α (p-IRE1α), p-eukaryotic initiation factor 2 (eIF2α) as well as increased generation of neurotoxic cytokines, including IL-1ß in aggregated αSynagg-stimulated primary microglia. Importantly, in mouse primary microglia-treated with αSynagg we observed increased expression of Thioredoxin-interacting protein (TXNIP), an endogenous inhibitor of the thioredoxin (Trx) pathway, a major antioxidant protein system. Additionally, αSynagg promoted interaction between NLRP3 and TXNIP in these cells. In vitro knockdown of PKCδ using siRNA reduced ERS and led to reduced expression of TXNIP and the NLRP3 activation response in αSynagg-stimulated mouse microglial cells (MMCs). Additionally, attenuation of mitochondrial reactive oxygen species (mitoROS) via mito-apocynin and amelioration of ERS via the eIF2α inhibitor salubrinal (SAL) reduced the induction of the ERS/TXNIP/NLRP3 signaling axis, suggesting that mitochondrial dysfunction and ERS may act in concert to promote the αSynagg-induced microglial activation response. Likewise, knockdown of TXNIP by siRNA attenuated the αSynagg-induced NLRP3 inflammasome activation response. Finally, unilateral injection of αSyn preformed fibrils (αSynPFF) into the striatum of wild-type mice induced a significant increase in the expression of nigral p-PKCδ, ERS markers, and upregulation of the TXNIP/NLRP3 inflammasome signaling axis prior to delayed loss of TH+ neurons. Together, our results suggest that inhibition of ERS and its downstream signaling mediators TXNIP and NLRP3 might represent novel therapeutic avenues for ameliorating microglia-mediated neuroinflammation in PD and other synucleinopathies.

Characterization of nonmotor behavioral impairments and their neurochemical mechanisms in the MitoPark mouse model of progressive neurodegeneration in Parkinson's disease.

Mitochondrial dysfunction has been implicated as a key player in the pathogenesis of Parkinson's disease (PD). The MitoPark mouse, a transgenic mitochondrial impairment model developed by specific inactivation of TFAM in dopaminergic neurons, spontaneously exhibits progressive motor deficits and neurodegeneration, recapitulating several features of PD. Since nonmotor symptoms are now recognized as important features of the prodromal stage of PD, we comprehensively assessed the clinically relevant motor and nonmotor deficiencies from ages 8-24 wk in both male and female MitoPark mice and their littermate controls. As expected, motor deficits in MitoPark mice began around 12-14 wk and became severe by 16-24 wk. Interestingly, MitoPark mice exhibited olfactory deficits in the novel and social scent tests as early as 10-12 wk as compared to age-matched littermate controls. Additionally, male MitoPark mice showed spatial memory deficits before female mice, beginning at 8 wk and becoming most severe at 16 wk, as determined by the Morris water maze. MitoPark mice between 16 and 24 wk spent more time immobile in forced swim and tail suspension tests, and made fewer entries into open arms of the elevated plus maze, indicating a depressive and anxiety-like phenotype, respectively. Importantly, depressive behavior as determined by immobility in forced swim test was reversible by antidepressant treatment with desipramine. Neurochemical and mechanistic studies revealed significant changes in CREB phosphorylation, BDNF, and catecholamine levels as well as neurogenesis in key brain regions. Collectively, our results indicate that MitoPark mice progressively exhibit deficits in olfactory discrimination, cognitive learning and memory, and anxiety- and depression-like behaviors as well as key neurochemical signaling associated with nonmotor deficits in PD. Thus, MitoPark mice can serve as an invaluable model for studying nonmotor deficits in addition to studying the motor deficits related to pathology in PD.

NANOTECHNOLOGY-MEDIATED THERAPEUTIC STRATEGIES AGAINST SYNUCLEINOPATHIES IN NEURODEGENERATIVE DISEASE.

Synucleinopathies are a subset of debilitating neurodegenerative disorders for which clinically approved therapeutic options to either halt or retard disease progression are currently unavailable. Multiple synergistic pathological mechanisms in combination with the characteristic misfolding of proteins are attributable to disease pathogenesis and progression. This complex interplay, as well as the difficult and multiscale nature of therapeutic delivery into the central nervous system, make finding effective treatments difficult. Nanocarriers (NCs) are a class of materials that can significantly improve therapeutic brain delivery and enable multifunctional therapies. In this review, an update on the known pathology of synucleinopathies is presented. Then, NC-enabled therapeutics designed to target the multiple mechanisms by combination therapies and multiscale targeting methods is reviewed. The implications of these strategies are synthesized and evaluated to suggest opportunities for the rational design of anti-neurodegenerative NC therapeutics.

Kv1.3 modulates neuroinflammation and neurodegeneration in Parkinson's disease.

Characterization of the key cellular targets contributing to sustained microglial activation in neurodegenerative diseases, including Parkinson's disease (PD), and optimal modulation of these targets can provide potential treatments to halt disease progression. Here, we demonstrated that microglial Kv1.3, a voltage-gated potassium channel, was transcriptionally upregulated in response to aggregated α-synuclein (αSynAgg) stimulation in primary microglial cultures and animal models of PD, as well as in postmortem human PD brains. Patch-clamp electrophysiological studies confirmed that the observed Kv1.3 upregulation translated to increased Kv1.3 channel activity. The kinase Fyn, a risk factor for PD, modulated transcriptional upregulation and posttranslational modification of microglial Kv1.3. Multiple state-of-the-art analyses, including Duolink proximity ligation assay imaging, revealed that Fyn directly bound to Kv1.3 and posttranslationally modified its channel activity. Furthermore, we demonstrated the functional relevance of Kv1.3 in augmenting the neuroinflammatory response by using Kv1.3-KO primary microglia and the Kv1.3-specific small-molecule inhibitor PAP-1, thus highlighting the importance of Kv1.3 in neuroinflammation. Administration of PAP-1 significantly inhibited neurodegeneration and neuroinflammation in multiple animal models of PD. Collectively, our results imply that Fyn-dependent regulation of Kv1.3 channels plays an obligatory role in accentuating the neuroinflammatory response in PD and identify Kv1.3 as a potential therapeutic target for PD.

MitoPark transgenic mouse model recapitulates the gastrointestinal dysfunction and gut-microbiome changes of Parkinson's disease.

Gastrointestinal (GI) disturbances are one of the earliest symptoms affecting most patients with Parkinson's disease (PD). In many cases, these symptoms are observed years before motor impairments become apparent. Hence, the molecular and cellular underpinnings that contribute to this early GI dysfunction in PD have actively been explored using a relevant animal model. The MitoPark model is a chronic, progressive mouse model recapitulating several key pathophysiological aspects of PD. However, GI dysfunction and gut microbiome changes have not been categorized in this model. Herein, we show that decreased GI motility was one of the first non-motor symptoms to develop, evident as early as 8 weeks with significantly different transit times from 12 weeks onwards. These symptoms were observed well before motor symptoms developed, thereby paralleling PD progression in humans. At age 24 weeks, we observed increased colon transit time and reduced fecal water content, indicative of constipation. Intestinal inflammation was evidenced with increased expression of iNOS and TNFα in the small and large intestine. Specifically, iNOS was observed mainly in the enteric plexi, indicating enteric glial cell activation. A pronounced loss of tyrosine hydroxylase-positive neurons occurred at 24 weeks both in the mid-brain region as well as the gut, leading to a corresponding decrease in dopamine (DA) production. We also observed decreased DARPP-32 expression in the colon, validating the loss of DAergic neurons in the gut. However, the total number of enteric neurons did not significantly differ between the two groups. Metabolomic gas chromatography-mass spectrometry analysis of fecal samples showed increased sterol, glycerol, and tocopherol production in MitoPark mice compared to age-matched littermate controls at 20 weeks of age while 16 s microbiome sequencing showed a transient temporal increase in the genus Prevotella. Altogether, the data shed more light on the role of the gut dopaminergic system in maintaining intestinal health. Importantly, this model recapitulates the chronology and development of GI dysfunction along with other non-motor symptoms and can become an attractive translational animal model for pre-clinical assessment of the efficacy of new anti-Parkinsonian drugs that can alleviate GI dysfunction in PD.

Organophosphate pesticide chlorpyrifos impairs STAT1 signaling to induce dopaminergic neurotoxicity: Implications for mitochondria mediated oxidative stress signaling events.

The organophosphate (OP) pesticide chlorpyrifos (CPF), used in agricultural settings, induces developmental and neurological impairments. Recent studies using in vitro cell culture models have reported CPF exposure to have a positive association with mitochondria-mediated oxidative stress response and dopaminergic cell death; however, the mechanism by which mitochondrial reactive oxygen species (ROS) contribute to dopaminergic cell death remains unclear. Therefore, we hypothesized that STAT1, a transcription factor, causes apoptotic dopaminergic cell death via mitochondria-mediated oxidative stress mechanisms. Here we show that exposure of dopaminergic neuronal cells such as N27 cells (immortalized murine mesencephalic dopaminergic cells) to CPF resulted in a dose-dependent increase in apoptotic cell death as measured by MTS assay and DNA fragmentation. Similar effects were observed in CPF-treated human dopaminergic neuronal cells (LUHMES cells), with an associated increase in mitochondrial dysfunction. Moreover, CPF (10 µM) induced time-dependent increase in STAT1 activation coincided with the collapse of mitochondrial transmembrane potential, increase in ROS generation, proteolytic cleavage of protein kinase C delta (PKCδ), inhibition of the mitochondrial basal oxygen consumption rate (OCR), with a concomitant reduction in ATP-linked OCR and reserve capacity, increase in Bax/Bcl-2 ratio and enhancement of autophagy. Additionally, by chromatin immunoprecipitation (ChIP), we demonstrated that STAT1 bound to a putative regulatory sequence in the NOX1 and Bax promoter regions in response to CPF in N27 cells. Interestingly, overexpression of non-phosphorylatable STAT1 mutants (STAT1Y701F and STAT1S727A) but not STAT1 WT construct attenuated the cleavage of PKCδ and ultimately cell death in CPF-treated cells. Furthermore, small interfering RNA knockdown demonstrated STAT1 to be a critical regulator of autophagy and mitochondria-mediated proapoptotic cell signaling events after CPF treatment in N27 cells. Finally, oral administration of CPF (5 mg/kg) in postnatal rats (PNDs 27-61) induced motor deficits, and nigrostriatal dopaminergic neurodegeneration with a concomitant induction of STAT1-dependent proapoptotic cell signaling events. Conversely, co-treatment with mitoapocynin (a mitochondrially-targeted antioxidant) and CPF rescued motor deficits, and restored dopaminergic neuronal survival via abrogation of STAT1-dependent proapoptotic cell signaling events. Taken together, our study identifies a novel mechanism by which STAT1 regulates mitochondria-mediated oxidative stress response, PKCδ activation and autophagy. In this context, the phosphorylation of Tyrosine 701 and Serine 727 in STAT1 was found to be essential for PKCδ cleavage. By attenuating mitochondrial-derived ROS, mitoapocynin may have therapeutic applications for reversing CPF-induced dopaminergic neurotoxicity and associated neurobehavioral deficits as well as neurodegenerative diseases.

Manganese exposure exacerbates progressive motor deficits and neurodegeneration in the MitoPark mouse model of Parkinson's disease: Relevance to gene and environment interactions in metal neurotoxicity.

Parkinson's disease (PD) is now recognized as a neurodegenerative condition caused by a complex interplay of genetic and environmental influences. Chronic manganese (Mn) exposure has been implicated in the development of PD. Since mitochondrial dysfunction is associated with PD pathology as well as Mn neurotoxicity, we investigated whether Mn exposure augments mitochondrial dysfunction and neurodegeneration in the nigrostriatal dopaminergic system using a newly available mitochondrially defective transgenic mouse model of PD, the MitoPark mouse. This unique PD model recapitulates key features of the disease including progressive neurobehavioral changes and neuronal degeneration. We exposed MitoPark mice to a low dose of Mn (10mg/kg, p.o.) daily for 4 weeks starting at age 8 wks and then determined the behavioral, neurochemical and histological changes. Mn exposure accelerated the rate of progression of motor deficits in MitoPark mice when compared to the untreated MitoPark group. Mn also worsened olfactory function in this model. Most importantly, Mn exposure intensified the depletion of striatal dopamine and nigral TH neuronal loss in MitoPark mice. The neurodegenerative changes were accompanied by enhanced oxidative damage in the striatum and substantia nigra (SN) of MitoPark mice treated with Mn. Furthermore, Mn-treated MitoPark mice had significantly more oligomeric protein and IBA-1-immunoreactive microglia cells, suggesting Mn augments neuroinflammatory processes in the nigrostriatal pathway. To further confirm the direct effect of Mn on impaired mitochondrial function, we also generated a mitochondrially defective dopaminergic cell model by knocking out the TFAM transcription factor by using a CRISPR-Cas9 gene-editing method. Seahorse mitochondrial bioenergetic analysis revealed that Mn decreases mitochondrial basal and ATP-linked respiration in the TFAM KO cells. Collectively, our results reveal that Mn can augment mitochondrial dysfunction to exacerbate nigrostriatal neurodegeneration and PD-related behavioral symptoms. Our study also demonstrates that the MitoPark mouse is an excellent model to study the gene-environment interactions associated with mitochondrial defects in the nigral dopaminergic system as well as to evaluate the contribution of potential environmental toxicant interactions in a slowly progressive model of Parkinsonism.

Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinson's disease.

The NLRP3 inflammasome signaling pathway is a major contributor to the neuroinflammatory process in the central nervous system. Oxidative stress and mitochondrial dysfunction are key pathophysiological processes of many chronic neurodegenerative diseases, including Parkinson's disease (PD). However, the inter-relationship between mitochondrial defects and neuroinflammation is not well understood. In the present study, we show that impaired mitochondrial function can augment the NLRP3 inflammasome-driven proinflammatory cascade in microglia. Primary mouse microglia treated with the common inflammogen LPS increased NLRP3 and pro-IL-1ß expression. Interestingly, exposure of LPS-primed microglial cells to the mitochondrial complex-I inhibitory pesticides rotenone and tebufenpyrad specifically potentiated the NLRP3 induction, ASC speck formation and pro-IL-1ß processing to IL-1ß in a dose-dependent manner, indicating that mitochondrial impairment heightened the NLRP3 inflammasome-mediated proinflammatory response in microglia. The neurotoxic pesticide-induced NLRP3 inflammasome activation was accompanied by bioenergetic defects and lysosomal dysfunction in microglia. Furthermore, the pesticides enhanced mitochondrial ROS generation in primary microglia, while amelioration of mitochondria-derived ROS by the mitochondria-targeted antioxidant mito-apocynin completely abolished IL-1ß release, indicating mitochondrial ROS drives potentiation of the NLRP3 inflammasome in microglia. Exposure to conditioned media obtained from mitochondrial inhibitor-treated, LPS-primed microglial cells, but not unprimed cells, induced dopaminergic neurodegeneration in cultured primary mesencephalic and human dopaminergic neuronal cells (LUHMES). Notably, our in vivo results with chronic rotenone rodent models of PD further support the activation of proinflammatory NLRP3 inflammasome signaling due to mitochondrial dysfunction. Collectively, our results demonstrate that mitochondrial impairment in microglia can amplify NLRP3 inflammasome signaling, which augments the dopaminergic neurodegenerative process.

Dimensions of social capital of families with thalassemia in an indigenous population in Tamil Nadu, India - a qualitative study.

BACKGROUND: Studies have shown that social capital is positively associated with health, and the association is context-based. Indigenous populations with poor access to health care largely depend on social capital for their health care needs. This study was conducted to explore the dimensions and types of social capital and its utilization by families with thalassemia for their health and well-being in an indigenous population in Tamil Nadu, India. METHODS: The participants in the study were parents who had children with thalassemia, belonged to an indigenous community in Tamil Nadu, were poor and marginalized, and had poor access to health care. Different dimensions and types of social capital were examined with the help of qualitative in-depth interviews using a phenomenological approach. A total of 8 in-depth interviews were conducted and transcribed. Thematic analysis of the data was performed. RESULTS: The social capital identified through the in-depth interviews consisted of various levels of family support, financial support from relatives and neighbors, the provision of information from formal and informal networks, and trust in the physician. Indigenous communities are close-knit due to their geographical remoteness and limited accessibility. Family ties were a form of social capital that encouraged bonding, and provided support and care to the children affected by thalassemia. The bonding also helped to meet the regular requirement of blood donation for the children. Relatives and neighbors were an asset that served as a bridge for the families affected, helping them in times of immediate and urgent financial need, making it easier to sustain long-term treatment and providing emotional support. There were informal networks that bridged parents belonging to indigenous and non-indigenous communities, with the latter providing the former with information to help them choose better health care at an affordable cost. The other formal links were the ties between the parents and nongovernmental organizations, such as the local thalassemia association, which connected members belonging to different areas. It was these ties that were of the greatest assistance to the families affected in coping with the disease, enabling them to sustain the treatment, and assisting them to choose and carry out the complicated bone marrow transplantation, which is the definitive treatment for this condition. CONCLUSION: The bonding, bridging, and linking dimensions of social capital help communities cope with thalassemia, the more so in indigenous and marginalized communities.