Disturbance Of Calcium Homeostasis Research Articles

Aberrance of GAP43/p-GAP43 Closely Associates with the Pathology of Neuron Loss in Prion-Infected Rodent Models.

Prion diseases are fatal neurodegenerative disorders characterized by neuron damage and loss. Growth-associated protein 43 (GAP43) functions in neuronal plasticity and synaptic function, but its role in prion diseases is not fully elucidated. In this study, we investigated the changes of GAP43 in the central nerve system (CNS) of several prion-infected rodent models and explored the potential relationship of GAP43 with PrPSc deposit and neuron loss using various methods. We found that GAP43 levels were significantly decreased in the brain tissues of scrapie-infected rodent models at the terminal stage of the disease. Immunohistochemical analysis showed that GAP43 colocalized with NeuN-positive cells morphologically, indicating the presence of GAP43 in mature neurons. On contrary, the levels of GAP43 and p-GAP43 increased in a prion-infected cell line SMB-S15 in vitro, accompanying with the increase of intracellular calcium. Stimulation of lipopolysaccharide (LPS) upregulated while removal of PrPSc propagation downregulated the level of GAP43 in SMB-S15 cells. Morphological colocalization and molecular interaction between GAP43 and PrPSc have been addressed in the brains of prion-infected rodents and prion-infected cell line. Histological assays of the serial sections of the whole brains of prion-infected mice proposed that the reduced GAP43 level correlated with large amount of PrPSc deposits and notable neuron damage and loss showing cell crumpled and nuclear pyknosis. The impairment of GAP43 signaling and disturbance of calcium homeostasis by aberrance of brain GAP43/p-GAP43 not only reflect but also likely contribute to the pathology of severe neuron loss at the end of prion disease.

Impact of occupational lead exposure on the comprehensive health status of gas cutter workers

BackgroundOccupational exposure to hazardous substances, particularly in involving metal cutting and welding industries, poses critical public health concern. This study assesses the health status of gas cutter workers, focusing on Pb exposure. MethodIn this cross-sectional study, 40 participants with BLL ≥20 μg/dL were recruited from workers engaged in oxy-acetylene metal cutting. These workers were compared to an age-, sex-, and sociodemographic-matched control group (n = 42) from the same workplace. Health assessments including routine clinical and laboratory investigations along with BLL, and markers of calcium homeostasis were carried out. ResultsGas cutters exhibited significantly higher mean systolic BP and elevated SGOT levels, with similar prevalence of respiratory symptoms and musculoskeletal disorders in both groups. No significant differences were found in most hematological, liver, and renal parameters. However, gas cutters had significantly higher PTH levels and lower serum vitamin D levels. Pulmonary function tests indicated significantly reduced FVC, FEV1, FEV1/FVC ratio, FEF25-75 %, and PEFR in gas cutters, as well as markedly higher CRP levels. ConclusionGas cutters experience significant health impacts compared to controls, including elevated systolic BP, impaired pulmonary function, and disturbance in calcium homeostasis due to occupational Pb exposure. Higher CRP levels suggest notable inflammatory responses. These findings highlight the urgent need for targeted interventions and regular monitoring to mitigate health risks associated with Pb exposure among gas cutter workers.

Regulatory Peptide Pro-Gly-Pro Accelerates Neuroregeneration of Primary Neuroglial Culture after Mechanical Injury in Scratch Test

The scratch test is used as an experimental in vitro model of mechanical damage to primary neuronal cultures to study the mechanisms of cell death in damaged areas. The involvement of NMDA receptors in processes leading to delayed neuronal death, due to calcium dysregulation and synchronous mitochondrial depolarization, has been previously demonstrated. In this study, we explored the neuroregenerative potential of Pro-Gly-Pro (PGP)—an endogenous regulatory peptide with neuroprotective and anti-inflammatory properties and a mild chemoattractant effect. Mechanical injury to the primary neuroglial culture in the form of a scratch caused acute disruption of calcium homeostasis and mitochondrial functions. This was accompanied by neuronal death alongside changes in the profile of neuronal markers (BDNF, NSE and GFAP). In another series of experiments, under subtoxic doses of glutamate (Glu, 33 μM), delayed changes in [Ca2+]i and ΔΨm, i.e., several days after scratch application, were more pronounced in cells in damaged neuroglial cultures. The percentage of cells that restored the initial level of [Ca2+]i (p < 0.05) and the rate of recovery of ΔΨm (p < 0.01) were decreased compared with undamaged cells. Prophylactic application of PGP (100 μM, once) prevented the increase in [Ca2+]i and the sharp drop in mitochondrial potential [ΔΨm] at the time of scratching. Treatment with PGP (30 μM, three or six days) reduced the delayed Glu-induced disturbances in calcium homeostasis and cell death. In the post-glutamate period, the surviving neurons more effectively restored the initial levels of [Ca2+]i (p < 0.001) and Ψm (p < 0.0001). PGP also increased intracellular levels of BDNF and reduced extracellular NSE. In the context of the peptide’s therapeutic effect, the recovery of the damaged neuronal network occurred faster due to reduced astrogliosis and increased migration of neurons to the scratch area. Thus, the peptide PGP has a neuroprotective effect, increasing the survival of neuroglial cells after mechanical trauma in vitro by reducing cellular calcium overload and preventing mitochondrial dysfunction. Additionally, the tripeptide limits the post-traumatic consequences of mechanical damage: it reduces astrogliosis and promotes neuronal regeneration.

The phosphorylation of Smad3 by CaMKIIγ leads to the hepatocyte pyroptosis under perfluorooctane sulfonate exposure

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant and accumulated in the liver of mammals. PFOS exposure is closely associated with the development of pyroptosis. Nevertheless, the underlying mechanism is unclear. We found here that PFOS induced pyroptosis in the mice liver and L-02 cells as demonstrated by activation of the NOD-like receptor protein 3 inflammasome, gasdermin D cleavage and increased release of interleukin-1β and interleukin-18. The level of cytoplasmic calcium was accelerated in hepatocytes upon exposure to PFOS. The phosphorylated/activated form of calcium/calmodulin-dependent protein kinase II (CaMKII) was augmented by PFOS in vivo and in vitro. PFOS-induced pyroptosis was relieved by CaMKII inhibitor. Among various CaMKII subtypes, we identified that CaMKIIγ was activated specifically by PFOS. CaMKIIγ interacted with Smad family member 3 (Smad3) under PFOS exposure. PFOS increased the phosphorylation of Smad3, and CaMKII inhibitor or CaMKIIγ siRNA alleviated PFOS-caused phosphorylation of Smad3. Inhibiting Smad3 activity was found to alleviate PFOS-induced hepatocyte pyroptosis. This study puts forward that CaMKIIγ-Smad3 is the linkage between calcium homeostasis disturbance and pyroptosis, providing a mechanistic explanation for PFOS-induced pyroptosis.

NIR photoactivated electron intersystem crossing to evoke calcium-mediated lysosome-dependent cell death and immunotherapy

The efficacy of photodynamic therapy (PDT) highly depends on the photosensitizer (PS). How to rationally design PS with an efficient inter-system crossing (ISC) rate to enable the capacity for reactive oxygen species (ROS) production, remains a great challenge. Herein, we have successfully provided two isomers at two positions of the BODIPY core with a decoration of cyclometalated Ir(III) fragment to avoid the disadvantages of themselves as PS for PDT. With the theoretical and experimental investigations, the intact connection with BODIPY and Ir(III) fragment has been confirmed to facilitate the ISC process to produce ROS. PS could be accumulated in the lysosome, and excited with a near-infrared wavelength light (630 nm). Due to the severe ROS production upon irradiation, the lysosome membrane permeabilization (LMP) was activated. The calcium homeostasis has been subsequently disrupted with the release of the lysosomal contents, resulting in acidosis and calcium-mediated lysosome-dependent cell death (autophagy blockage and mitochondrial apoptosis). The photodynamic immunotherapy was also evoked with the disturbed calcium homeostasis, which has been demonstrated with the bilateral tumor models in vivo. This study not only provided a superior NIR photosensitizer but also presented an effective strategy to reduce the energy gap via electron intersystem crossing to boost photodynamic immunotherapy.

Risk Factors for Transient and Permanent Hypoparathyroidism Following Thyroidectomy: A Comprehensive Review.

Hypoparathyroidism is a common complication following thyroidectomy, resulting in significant disturbances in calcium homeostasis due to low parathyroid hormone (PTH) levels. This comprehensive review examines the risk factors associated with transient and permanent hypoparathyroidism post-thyroidectomy, emphasizing surgical, patient-related, and perioperative factors. Transient hypoparathyroidism, characterized by temporary hypocalcemia resolving within weeks to months, is often managed with short-term calcium and vitamin D supplementation. In contrast, permanent hypoparathyroidism persists beyond six months post-surgery, necessitating lifelong supplementation and potentially PTH replacement therapy. The review delves into the anatomy and physiology of the parathyroid glands, mechanisms leading to hypoparathyroidism, and incidence rates. Surgical factors such as the extent of thyroidectomy, surgeon expertise, and intraoperative parathyroid gland preservation are critical in determining the risk of hypoparathyroidism. Patient factors, including age, sex, pre-existing conditions, and perioperative management, influence outcomes. Diagnostic and monitoring strategies, along with management protocols for both transient and permanent hypoparathyroidism, are discussed. Prevention strategies, emerging research, future surgical techniques, and intraoperative monitoring directions are highlighted to improve clinical outcomes. This review aims to enhance understanding, inform surgical practices, and optimize postoperative care to minimize the incidence and impact of hypoparathyroidism in thyroidectomy patients.

Vulnerability of Store-Operated Calcium Entry to Inhibitors and Microenvironment in Cells of Different Breast Cancer Subtypes.

The incidence and development of cancer are highly dependent on pathological disturbances in calcium homeostasis of the cell. One of the major pathways for calcium entry is store-operated calcium entry (SOCE), which functions in virtually all cell types. Changes in the expression level of the main proteins organizing SOCE are observed during the development of various cancer types, particularly breast cancer (BC). This leads to unique SOCE with characteristics individual for each type of BC and requires particular therapeutic approaches. In this study, we tested the sensitivity of SOCE in various BC cells to selective ORAI channel inhibitors and the less selective compounds Leflunomide and Teriflunomide, approved by the FDA for clinical use. We also analyzed the vulnerability of SOCE to the influence of factors typical of the tumor microenvironment: hypoxia and acidification. We have observed that the SOCE inhibitors Leflunomide and Teriflunomide suppress SOCE in the triple-negative BC cell line MDA-MB-231, but not in the luminal A BC cell line MCF-7. MDA-MB-231 cells also demonstrate higher pH dependence of SOCE compared to MCF-7 cells. In addition, the oxygen scavenger sodium dithionide also affects SOCE, stimulating it in MDA-MB-231 cells but inhibiting in MCF-7 cells. Overall, our data highlight the importance of considering the different sensitivities of various BC cell types to inhibitors and to microenvironmental factors such as hypoxia and acidification when developing targeted drugs.

Expect the unexpected: Brown tumor of the mandible as the first manifestation of primary hyperparathyroidism.

Hyperparathyroidism (HPT) is a condition in which one or more parathyroid glands produce increased levels of parathyroid hormone (PTH), causing disturbances in calcium homeostasis. Most commonly HPT presents with asymptomatic hypercalcemia but the clinical spectrum may include disturbances reflecting the combined effects of increased PTH secretion and hypercalcemia. Brown tumors are rare, benign, tumor-like bone lesions, occurring in 1.5% to 4.5% of patients with HPT, as a complication of an uncontrolled disease pathway, and are nowadays rarely seen in clinical practice. The tumor can appear either as a solitary or multifocal lesion and usually presents as an asymptomatic swelling or a painful exophytic mass. Furthermore, it can cause a pathological fracture or skeletal pain and be radiologically described as a lytic bone lesion. The diagnosis of a brown tumor in HPT is typically confirmed by assessing the levels of serum calcium, phosphorus, and PTH. Although when present, brown tumor is quite pathognomonic for HPT, the histologic finding often suggests a giant cell tumor, while clinical presentation might suggest other more frequent pathologies such as metastatic tumors. Treatment of brown tumors frequently focuses on managing the underlying HPT, which can often lead to regression and resolution of the lesion, without the need for surgical intervention. However, in refractory cases or when dealing with large symptomatic lesions, surgical treatment may be necessary.

Pyridaben induces apoptosis and inflammation in bovine mammary epithelial cells by disturbance of calcium homeostasis and upregulation of MAPK cascades

Pyridaben is a widely used pyridazinone insecticide used to protect crops against insects and mites. The toxicity of pyridaben has been reported in mice, zebrafish, the human reproductive system, nervous system, and respiratory system. Pyridaben can also be ingested by dairy cattle through feed. However, the toxicity of pyridaben in cattle has not been investigated on. Thus, this study focuses on demonstrating the toxicity of pyridaben in the bovine mammary glands and with the generation milk in the bovine mammary epithelial cells, as it is crucial to the continuance of the amount and the quality of the milk produced. We started by analyzing the intracellular toxicity along with the impact of pyridaben on the cell cycle distribution and the transcription of associated genes. Pyridaben treatment induced cell cycle arrest accompanied the disruption in G1 and S phases with imbalanced cytosolic and mitochondrial calcium ion homeostasis, and caused a destruction of mitochondrial membrane potential. This eventually led to apoptosis of MAC-T cells. We also investigated in the impact that pyridaben has on MAPK signaling proteins, where phosphorylation of ERK1/2, JNK, and p38 were upregulateed. Moreover, examination of the effect of pyridaben in the inflammatory genes revealed hyperactivation of the inflammatory gene transcription. This is the first research to assess the negative outcomes that pyridaben could impose on dairy cattle and milk production.

Case Series of Congenital Heart Block: Mothers With anti-Ro Autoantibodies and the Risks to Their Offspring

Introduction: Cardiac manifestation of congenital heart block (CHB) in neonates following maternal anti-Ro and anti-La autoantibodies is a serious complication of neonatal lupus with a prevalence of 1: 22000 live birth and is associated with high morbidity and mortality. Disturbance of calcium homeostasis which leads to electrical conduction abnormality and eventually fibrosis of the heart tissue is the well-known pathogenesis of CHB. Most of the babies with CHB ended up with third-degree heart block and need a pacemaker as it is an irreversible injury. Case series: Here, we reported four case series of neonatal lupus with cardiac manifestation in mothers with positive anti-Ro or anti-La which have been detected during pregnancy within 24 to 32 weeks of gestation. All four cases of newborns ended up with third-degree heart block which required a permanent pacemaker by the latest age of two months old. Conclusion: A better understanding of the aetiology of the development of CHB and identifying the risk factors in mothers is crucial for the outcomes of CHB newborns. Early diagnosis through early screening, enhanced diagnostic tools for CHB, and timely treatment of the mother may aid clinicians in better management and improve the survival rate of infants with CHB.

Calcium’s Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions

Calcium research, since its pivotal discovery in the early 1800s through the heating of limestone, has led to the identification of its multi-functional roles. These include its functions as a reducing agent in chemical processes, structural properties in shells and bones, and significant role in cells relating to this review: cellular signaling. Calcium signaling involves the movement of calcium ions within or between cells, which can affect the electrochemical gradients between intra- and extracellular membranes, ligand binding, enzyme activity, and other mechanisms that determine cell fate. Calcium signaling in muscle, as elucidated by the sliding filament model, plays a significant role in muscle contraction. However, as organisms age, alterations occur within muscle tissue. These changes include sarcopenia, loss of neuromuscular junctions, and changes in mineral concentration, all of which have implications for calcium’s role. Additionally, a field of study that has gained recent attention, cellular senescence, is associated with aging and disturbed calcium homeostasis, and is thought to affect sarcopenia progression. Changes seen in calcium upon aging may also be influenced by its crosstalk with other minerals such as iron and zinc. This review investigates the role of calcium signaling in aging muscle and cellular senescence. We also aim to elucidate the interactions among calcium, iron, and zinc across various cells and conditions, ultimately deepening our understanding of calcium signaling in muscle aging.

Inhibition of Autophagy in Heat-Stressed Sperm of Adult Mice: A Possible Role of Catsper1, 2 Channel Proteins.

Various phenomena guarantee gamete maturation and formation at all stages of evolution, one of which is autophagy playing a critical role in the final morphology of gametes, particularly sperms. Autophagy is influenced by oxidative stress, disturbances of calcium homeostasis, and hyperthermia conditions. The current study aimed to assess the autophagy-related proteins along with the activity of sperm calcium channel (CatSper) proteins following the induction of heat stress (HS). The study sample includes two groups of adult mice: sham and HS groups. In the HS group, the right testis was transferred to the abdominal cavity for 120 hours and then returned to the scrotum where it remained for 7 days. After 7 days, the testis and epididymis were removed to conduct real-time, immunohistochemical studies, sperm parameter evaluation, and seminiferous tubule assessment. In this study, the expression and distribution of autophagy proteins were measured. Plus, CatSper1 and CatSper2 were evaluated as proteins of calcium channels. The results of the present study demonstrated that the expression intensity of autophagy indices in seminiferous tubules decreased significantly after HS induction, which was associated with a decrease in the distribution of CatSper proteins in the sperms. HS led to morphological changes in sperm, reduced motility and viability of sperm, and decreased spermatogenesis indices. In this study, following heat stress, the decrease in CatSper protein distribution may lead to the structural disorder of CatSper channels, which could strongly affect autophagic activity. Also, disruption of spermatogenesis and sperm parameters may be the consequence of decreased autophagy activity.

Study on myocardial toxicity induced by lead halide perovskites nanoparticles

Lead halide perovskites (LHPs) are outstanding candidates for next-generation optoelectronic materials, with considerable prospects of use and commercial value. However, knowledge about their toxicity is scarce, which may limit their commercialization. Here, for the first time, we studied the cardiotoxicity and molecular mechanisms of representative CsPbBr3 nanoparticles in LHPs. After their intranasal administration to Institute of Cancer Research (ICR) mice, using advanced synchrotron radiation, mass spectrometry, and ultrasound imaging, we revealed that CsPbBr3 nanoparticles can severely affect cardiac systolic function by accumulating in the myocardial tissue. RNA sequencing and Western blotting demonstrated that CsPbBr3 nanoparticles induced excessive oxidative stress in cardiomyocytes, thereby provoking endoplasmic reticulum stress, disturbing calcium homeostasis, and ultimately leading to apoptosis. Our findings highlight the cardiotoxic effects of LHPs and provide crucial toxicological data for the product.

Numerical investigations and simulation of calcium distribution in the alpha-cell

The α-cells are a part of islets of Langerhans located in the pancreas and are responsible for glucagon secretion. Calcium signaling is crucial for the regulation of the functions and structure of these α-cells and the same is still not well understood. Here a mathematical model is framed to obtain more insights into calcium signaling in α-cells. The non-linear reaction-diffusion equation for calcium signaling along with boundary conditions is employed to propose the model for a one-dimensional steady-state case. The numerical solutions were obtained using the Newton-Raphson method and the cubic spline method. The combination of Newton-Raphson and cubic spline has proved to be quite effective in numerical simulations and in generating deeper insights into calcium regulation in an α-cell under various conditions. The results provide information about changes in source influx, buffers, ER leak, and SERCA pump leading to disturbances in calcium homeostasis, which can be responsible for the development of diabetes and other metabolic disorders.

Stromal Interaction Molecule 1-Mediated Store-Operated Calcium Entry Promotes Autophagy Through AKT/Mammalian Target of Rapamycin Pathway in Hippocampal Neurons After Ischemic Stroke

The pathophysiological process of neuronal injury due to cerebral ischemia is complex among which disturbance of calcium homeostasis and autophagy are two major pathogenesis. However, it remains ambiguous whether the two factors are independent. Stromal interaction molecule 1 (STIM1) is the most important Ca2+ sensor mediating the store-operated Ca2+ entry (SOCE) through interacting with Orai1 and has recently been proven to participate in autophagy in multiple cells. In this study, we aimed to investigate the potential role of STIM1-induced SOCE on autophagy and whether its regulator function contributes to neuronal injury under hypoxic conditions using in vivo transient middle cerebral artery occlusion (tMCAO) model and in vitro oxygen and glucose deprivation (OGD) primary cultured neuron model respectively. The present data indicated that STIM1 induces autophagic flux impairment in neurons through promoting SOCE and inhibiting AKT/mTOR signaling pathway. Pharmacological inhibition of SOCE or downregulation of STIM1 with siRNA suppressed the autophagic activity in neurons. Moreover, stim1 knockdown attenuated neurological deficits and brain damage after tMCAO, which could be reversed by AKT/mTOR pathway inhibitor AZD5363. Together, the modulation of STIM1 on autophagic activation indicated the potential link between Ca2+ homeostasis and autophagy which provided evidence that STIM1 could be a promising therapeutic target for ischemic stroke.

In vitro aging of stallion spermatozoa during prolonged storage at 5°C.

Artificial insemination with chilled stallion semen is hampered by a limited period of maximum fertility maintenance (24-48 h). This study used multiparametric flow cytometry to simultaneously measure reactive oxygen species (ROS) production, mitochondrial function or [Ca2+ ]i and plasma membrane fluidity in viable, acrosome-intact spermatozoa, with the aim of providing insight into changes in sperm function during storage at 5°C. High proportions of viable and acrosome-intact spermatozoa (71 ± 8%) remained after 96 h of storage demonstrating that the basic integrity of the cells was well preserved (n=17 stallions). In addition, more than 90% of viable, acrosome-intact spermatozoa had active mitochondria and low intra-cellular or mitochondrial ROS levels. By contrast, the percentage of viable, acrosome-intact sperm with low plasma membrane fluidity and low [Ca2+ ]i decreased over time (1h: 63 ± 16%, 96 h: 29 ± 18%; p < 0.05). The [Ca2+ ]i in viable sperm rose 3.1-fold (p < 0.05) over the 4 days, and fewer spermatozoa responded to bicarbonate stimulation (1h: 46 ± 17%, 96 h: 19 ± 12%) with an increase in plasma membrane fluidity following prolonged storage. Overall, prolonged storage of stallion semen at 5°C resulted in disturbed calcium homeostasis and increased plasma membrane fluidity. The decline in fertility of stallion semen during cooled-storage may therefore relate to aspects of in vitro aging (changes in plasma membrane fluidity and intracellular calcium) which impairs capacitation-associated cell functions.

NCX1 disturbs calcium homeostasis and promotes RANKL-induced osteoclast differentiation by regulating JNK/c-Fos/NFATc1 signaling pathway in multiple myeloma

Although several types of calcium channels abnormalities have been shown to promote myeloma bone disease (MBD), the relationship between Na+/Ca2+ exchanger 1 (NCX1) and MBD remains unexplored. Here, we examined the role of NCX1 in the development of multiple myeloma (MM), with a special focus on the underlying effects involved osteoclast differentiation. Firstly, we detected NCX1 protein highly expressed in BM tissues of MM patients, and its expression was positively correlated with serum calcium and the percentage of BM CD138+ cells. In vitro, NCX1 suppression with the inhibitor KB-R7943 reduced cell viability of MM cells and caused apoptosis. Extracellular high Ca2+ environment increased the level of intracellular Ca2+ in MM cells through gating the calcium influx, with subsequently promoting the expression of NCX1 and osteoclastogenesis-related genes (receptor activator of nuclear factor-κB (RANKL), nuclear factor of activated T cell cytoplasmic 1 (NFATc1), and proto-oncogene Fos (c-Fos). This phenomenon could be reversed by KB-R7943 or calcium chelation. Furthermore, NCX1 overexpression in MM cells accelerated osteoclastogenesis, while NCX1 knockdown or suppression resulted in the opposite effect. Mechanistically, we further investigated the related mechanisms of NCX1 regulating osteoclast differentiation using RNA sequencing, western blotting and Enzyme linked immunosorbent assay, and found that NCX1 modulated osteoclast differentiation in MM though JNK/c-Fos/NFATc1 signaling pathway. In conclusion, the Ca2+/NCX1-mediated signaling participates in the osteoclasts-myeloma cell interactions, which represents a promising target for future therapeutic intervention in MBD.

ANTIOXIDANT ROLE OF DJ-1 PROTEIN IN THE PATHOGENESIS OF PARKINSON'S DISEASE

Parkinson's disease is a progressive age-related neurodegenerative disease, and oxidative stress is an important mediator in its pathogenesis. Loss of neurons in the midbrain region (Substantia nigra) causes dopamine deficiency and leads to the formation of intracellular inclusions containing α-synuclein aggregates. Both of these phenomena are considered neuropathological features of Parkinson's disease. Although the clinical diagnosis is based on the presence of bradykinesia and other major motor signs, Parkinson's disease is associated with many non-motor symptoms that contribute and complicate the disease. The underlying molecular pathogenesis involves several pathways and mechanisms: α-synuclein proteostasis, mitochondrial dysfunction, oxidative stress, disturbances in calcium homeostasis, and neuroinflammation.&#x0D; Mutations in the PARK7 gene resulting in loss of function of the encoded DJ-1 protein have been identified as the cause of one of several forms of the inherited form of Parkinson's disease. The DJ-1 protein is attributed the role of an antioxidant based on experiments in cellular model systems. The active site of DJ-1 contains a highly reactive cysteine residue (Cys106) which is oxidized under oxidative stress. It is assumed that Cys106 plays a critical role in the biological function of DJ-1, regulating antioxidant protection depending on the oxidation state of Cys106, i.e. acts as a sensor of oxidative stress. Thus, the level of oxidized DJ-1 (oxDJ-1) may serve as a possible biomarker of oxidative stress.

4-PBA rescues hyperoxaluria induced nephrolithiasis by modulating urinary glycoproteins: Cross talk between endoplasmic reticulum, calcium homeostasis and mitochondria

AimUrinary glycoproteins such as Tamm Horsfall Protein (THP) and Osteopontin (OPN) are well established key regulators of renal stone formation. Additionally, recent revelations have highlighted the influence of Endoplasmic Reticulum (ER) and mitochondria of crucial importance in nephrolithiasis. However, till date conclusive approach highlighting the influence of ER stress on urinary glycoproteins and chaperone in nephrolithiasis remains elusive. Therefore, the present study was focussed on deciphering the possible effect of 4-PBA mitigating ER stress on urinary glycoproteins and calnexin (chaperone) with emphasis on interlinking calcium homeostasis in hyperoxaluric rats. Material and methodsPost 9 days of treatment, animals were sacrificed, and renal tissues were investigated for urinary glycoproteins, calnexin, calcium homeostasis, ER environment, redox status, and mitochondrial linkage. Key findings4-PBA appreciably reversed the altered levels of THP, OPN, and calnexin observed along with curtailing the disrupted calcium homeostasis when assessed for SERCA activity and intra-cellular calcium levels. Additionally, significant improvement in the perturbed ER environment as verified by escalated ER stress markers, disturbed protein folding-aggregation-degradation (congo red assay) pathway, and redox status was found post 4-PBA intervention. Interestingly, linkage of ER stress and mitochondria was established under hyperoxaluric conditions when assessed for protein levels of VDAC1 and GRP75. Significance4-PBA treatment resulted in rectifying the repercussions of ER-mitochondrial caused distress when assessed for protein folding/aggregation/degradation events along with disturbed calcium homeostasis. The present study advocates the necessity to adopt a holistic vision towards hyperoxaluria with emphasis on glycoproteins and ER environment.

Systematic assessment of pathophysiological mechanisms and their interrelation in progression of Alzheimer’s disease

Alzheimer’s disease (AD) consists of 60-80% of all dementia cases, thus is recognized as the commonest form of dementia. The current challenge to clinicians and researchers in the field of AD is development of treatment plans that can target the progression of pathology at molecular level as well newer diagnostic techniques for early detection and prevention of AD. This could be achieved by enhancing our understanding of the underlying pathophysiology of AD. This is systematic and concise review of various pathophysiological mechanisms contributing to AD. Legitimate indexing portals and search websites were used to carry out the literature search for this article. A combination of MeSH terms and Boolean operators were used. Obtained research articles were carefully assessed first by reading title and abstract and finally by reading the whole text. A set of inclusion and exclusion criteria were used to select the reference articles.: In our literature search 75 articles were obtained from PubMed, Google scholar and Cochrane Library after removing duplicate records. These were screened using titles and abstract. 23 articles were excluded from the study as per the exclusion criteria. Full text of 52 articles were read. 7 articles were excluded, 45 were studied thoughrouly and 30 were referenced during the writing of this review.Various risk factors – old age, diabetes, smoking, mutation etc contribute to Aβ plaque accumulation due to cleavage of APP protein by α and ϒ secretase. Aβ plaque further contributes to accumulation of neurofibrillary tangles, neuroinflammation and oxidative stress. This together with disturbance in Calcium homeostasis and excitotoxicity at glutamate receptors contribute to neurodegeneration and synaptic toxicity.