Parkinson's disease (PD) is one of the most common neurodegenerative disorders with limited clinical interventions. A number of epidemiological as well as case-control studies have revealed an association between pesticide exposure, especially of paraquat (PQ) and occurrence of PD. Hsp70, a molecular chaperone by function, has been shown as one of the modulators of neurological disorders. However, paucity of information regarding the protective role of Hsp70 on PQ-induced PD like symptoms led us to hypothesize that modulation of hsp70 expression in the dopaminergic neurons would improve the health of these cells. We took advantage of Drosophila, which is a well-established model for neurological research and also possesses genetic tools for easy manipulation of gene expression with limited ethical concern. Over-expression of hsp70 was found to reduce PQ-induced oxidative stress along with JNK and caspase-3 mediated dopaminergic neuronal cell death in exposed organism. Further, anti-apoptotic effect of hsp70 was shown to confer better homeostasis in the dopaminergic neurons of PQ-exposed organism as evidenced by their improved locomotor performance and survival. The study has merit in the context of human concern since we observed protection of dopaminergic neurons in PQ-exposed organism by over-expressing a human homologue of hsp70, HSPA1L, in these cells. The effect was parallel to that observed with Drosophila hsp70. These findings reflect the potential therapeutic applicability of hsp70 against PQ-induced PD like symptoms in an organism.

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Paraquat (PQ) exposure causes degeneration of the dopaminergic neurons in an exposed organism while altered metabolism has a role in various neurodegenerative disorders. Therefore, the study presented here was conceived to depict the role of altered metabolism in PQ-induced Parkinson-like symptoms and to explore Drosophila as a potential model organism for such studies. Metabolic profile was generated in control and in flies that were fed PQ (5, 10, and 20 mM) in the diet for 12 and 24 h concurrent with assessment of indices of oxidative stress, dopaminergic neurodegeneration, and behavioral alteration. PQ was found to significantly alter 24 metabolites belonging to different biological pathways along with significant alterations in the above indices. In addition, PQ attenuated brain dopamine content in the exposed organism. The study demonstrates that PQ-induced alteration in the metabolites leads to oxidative stress and neurodegeneration in the exposed organism along with movement disorder, a phenotype typical of Parkinson-like symptoms. The study is relevant in the context of Drosophila and humans because similar alteration in the metabolic pathways has been observed in both PQ-exposed Drosophila and in postmortem samples of patients with Parkinsonism. Furthermore, this study provides advocacy towards the applicability of Drosophila as an alternate model organism for pre-screening of environmental chemicals for their neurodegenerative potential with altered metabolism.

Over the past few decades, mechanisms of programmed cell death have attracted the scientific community because they are involved in diverse human diseases. Initially, apoptosis was considered as a crucial mechanistic pathway for programmed cell death; recently, an alternative regulated mode of cell death was identified, mimicking the features of both apoptosis and necrosis. Several lines of evidence have revealed that dysregulation of necroptosis leads to pathological diseases such as cancer, cardiovascular, lung, renal, hepatic, neurodegenerative, and inflammatory diseases. Regulated forms of necrosis are executed by death receptor ligands through the activation of receptor-interacting protein kinase (RIPK)-1/3 and mixed-lineage kinase domain-like (MLKL), resulting in the formation of a necrosome complex. Many papers based on genetic and pharmacological studies have shown that RIPKs and MLKL are the key regulatory effectors during the progression of multiple pathological diseases. This review focused on illuminating the mechanisms underlying necroptosis, the functions of necroptosis-associated proteins, and their influences on disease progression. We also discuss numerous natural and chemical compounds and novel targeted therapies that elicit beneficial roles of necroptotic cell death in malignant cells to bypass apoptosis and drug resistance and to provide suggestions for further research in this field.

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder with limited clinical treatments. The occurrence of PD includes both genetic and environmental toxins, such as the pesticides paraquat (PQ), as major contributors to PD pathology in both invertebrate and mammalian models. Calycosin, an isoflavone phytoestrogen, has multiple pharmacological properties, including neuroprotective activity. However, the paucity of information regarding the neuroprotective potential of calycosin on PQ-induced neurodegeneration led us to explore whether calycosin can mitigate PD-like phenotypes and the underlying molecular mechanisms. We used a PQ-induced PD model in Drosophila as a cost-effective in vivo screening platform to investigate the neuroprotective efficacy of natural compounds on PD. We reported that calycosin shows a protective role in preventing dopaminergic (DA) neuronal cell death in PQ-exposed Canton S flies. Calycosin-fed PQ-exposed flies exhibit significant resistance against PQ-induced mortality and locomotor deficits in terms of reduced oxidative stress, loss of DA neurons, the depletion of dopamine content, and phosphorylated JNK-caspase-3 levels. Additionally, mechanistic studies show that calycosin administration improves PQ-induced mitochondrial dysfunction and stimulates mitophagy and general autophagy with reduced pS6K and p4EBP1 levels, suggestive of a maintained energy balance between anabolic and catabolic processes, resulting in the inhibition of neuronal cell death. Collectively, this study substantiates the protective effect of calycosin against PQ-induced neurodegeneration by improving DA neurons’ survival and reducing apoptosis, likely via autophagy induction, and it is implicated as a novel therapeutic application against toxin-induced PD pathogenesis.

Periodontitis is the most prevalent chronic inflammatory oral disease that is characterized by tooth loss and is commonly associated with several systemic inflammatory diseases. Some epidemiological studies suggest that those suffering from periodontitis might be at a greater risk of developing gastric Helicobacter pylori (Hp) infection; however, evidence that showing the association between periodontitis and the risk of gastric Hp infection is less clear. We conducted a large-scale, population-based study in Taiwan with a 13-year follow-up period to evaluate the risk of gastric Hp in a periodontitis patient cohort. To conduct this study, we used epidemiological data from the Taiwanese Longitudinal National Health Insurance Research Database (NHIRD) from 2000 to 2013. We selected 134,474 participants (64,868 males and 69,606 females with a minimum age of 20 years), with and without periodontitis, and matched patient cohort groups for age, sex, index year, and co-morbidities. The Cox proportional hazards regression model was used to examine the risk of gastric Hp infection in patients with periodontitis. Patients with periodontitis exhibited a higher risk of developing gastric Hp infection compared to those individuals/groups without periodontitis (1.35 vs. 0.87 per 1000 person-years, adjusted the hazards ratio (aHR 1.52), and 95% confidence intervals (CIs) 1.38–1.67, p < 0.001). The risk of gastric Hp infection persisted even after stratifying by age (aHR = 1.96 (1.79–2.13) for 50–64 years and 1.70 (1.49–1.94) for ≥65 years), gender (aHR = 1.20 (1.11–1.29) for men), and presence of comorbidities of hypertension (aHR = 1.24 (1.11–1.38)), hyperlipidemia (aHR = 1.28 (1.14–1.42)), COPD (aHR = 1.45 (1.31–1.61)), CLD (aHR = 1.62 (1.47–1.77)) and CKD (aHR = 1.44 (1.04–1.99)). Overall, our findings showed that periodontitis patients have a greater risk for gastric Hp than individuals without periodontitis. Clinicians should perform regular good oral hygiene practices, along with newer treatments, for patients with periodontitis, especially those at higher risk of gastric Hp infection.

Hexavalent chromium [Cr(VI)] is a genotoxic chemical, and in the chemical‐exposed organism, oxidative stress is one of the leading causative mechanisms of genotoxicity. Heat shock protein‐70 (Hsp70) is reported to be modulated in environmental chemical exposed organisms. Inadequate information on the protective role of Hsp70 in chemical‐induced DNA lesions prompted us to investigate this possibility in a well‐studied genetically tractable in vivo model Drosophila melanogaster. In the midgut cells of Cr(VI)‐exposed hsp70‐knockout (KO), ‐knockdown (KD), and ‐overexpression Drosophila strains, no significant change in double‐strand breaks generation was observed in comparison to similarly exposed w 1118 and the respective genetic control strain after 48 h. Therefore, the role of hsp70 was investigated on oxidative DNA damage induction in the exposed organisms after 24 h. Oxidized DNA lesions (particularly oxidized purine‐based lesions), 8‐oxo‐dG level, and oxidative stress endpoints were found to be significantly elevated in hsp70‐KO and ‐KD strains in comparison to similarly exposed w 1118 and respective genetic control strain. On the contrary, in ubiquitous hsp70‐overexpression strain exposed to Cr(VI), these endpoints were significantly lowered concurrently with increased GSH level through elevated gclc, and gclm expression, Gclc level, and GCL activity. The study suggests that as a consequence of hsp70 overexpression, the augmented GSH level in cells vis‐a‐vis GSH de novo synthesis can counteract Cr(VI)‐induced oxidized DNA lesions.

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