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1.
Acta Psychol (Amst) ; 248: 104384, 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38981311

ABSTRACT

Accredited Social Health Activists (ASHAs) in India are the subjects of this study, which explores the complex relationships between emotional labor (EL) and unstable work environments and how these relationships affect organizational commitment (OC). The study also looked at how organizational virtuousness (OV) and perceived social value mediated the relationship between precarious work (PW), EL, and OC. This study included a total sample size of N = 467 ASHA personnel from a variety of healthcare settings. Hierarchical regression analysis was used to look at the moderating effects using the Hayes Process Macro. The findings suggest that there are noteworthy negative associations between EL, PW, and the OC of ASHA workers. Nevertheless, OV and perceived social worth (PSW) emerged as significant moderators. More precisely, elevated levels of PSW and OV mitigated the adverse effects of PW and EL on the OC of ASHA workers.

2.
Article in English | MEDLINE | ID: mdl-38885137

ABSTRACT

Background: The rickettsioses, except for typhus fever and scrub typhus (ST), were not really recognized as distinct clinical entities until the early 20th century. Only when specific rickettsial serologic testing was introduced in the 1940s could the precise etiologies of various rickettsial diseases (RDs) be determined with certainty. Although ST is a well- recognized zoonotic disease entity, but non-scrub typhus rickettsial infection like spotted fever group and typhus group are not well studied in India and are still underestimated. Methods: We report cases who had shown seropositivity of spotted fever and typhus fever RD in IgM and IgG ELISA whose samples were referred from various hospitals of Delhi/National Capital Region in which clinicians had strong suspicion of rickettsiosis other than ST or Weil-Felix test found positive for any of the OX2, 19, and K antigens. Results: We reported 18 cases of SFG and TGRD with mostly cases presented with fever followed by hepato-intestinal symptoms. Conclusion: The vast variability and nonspecific presentation of rickettsiosis in spotted and typhus fever at times have often made it difficult to diagnose clinically. Prompt antibiotic therapy shortens the course of the disease, lowers the risk of complications, and in turn, reduces morbidity and mortality owing to RDs. There is a distinct need for physicians and health care workers at all levels of care in India to be aware of the clinical features, available diagnostic tests and their interpretation, and the therapy for these infections.

3.
Ind Psychiatry J ; 33(1): 108-115, 2024.
Article in English | MEDLINE | ID: mdl-38853815

ABSTRACT

Background: Adaptive behavior plays a crucial role in daily functioning, involving a complex interplay between individuals and their environment. In India, the Vineland Social Maturity Scale (VSMS) has been the preferred assessment tool for measuring adaptive behaviors, despite its age of over 85 years. However, periodic evaluation is necessary to ensure its continued relevance. Aim: This study aims to critically evaluate selected items of the Indian version of the VSMS. Materials and Methods: A survey form was developed through a focus group discussion (FGD), comprising 20 items from the Indian adaptation of the VSMS. The form was converted into a Google Form and distributed to medical and rehabilitation specialists across India. The responses were collected, recorded, and analyzed in an Excel sheet. Results: Of the 107 responses received, 14 were incomplete and excluded, leaving 93 complete for analysis. The analysis revealed that less than half of the surveyed items and domains received ratings of disagreement from over a quarter of the respondents concerning their frequency, relevance, and diagnostic value. Conclusion: This study underscores the need for a dynamic approach to defining and assessing adaptive behavior, especially in the Indian context. It highlights the importance of revising existing scales, incorporating technology-related items, and considering societal and cultural norms shifts. While acknowledging its limitations, this research sets the stage for future investigations to gain a more nuanced understanding of adaptive behaviors amidst changing societal dynamics. Ultimately, these efforts aim to develop more comprehensive and relevant assessment tools for adaptive behavior in today's rapidly evolving world.

6.
Acta Psychol (Amst) ; 243: 104136, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38244371

ABSTRACT

Workplace Ostracism is known to be a physically and emotionally painful experience. Even if it has a temporary and minor impact, it strongly predicts employee turnover intentions. Therefore, the purpose of this paper is to examine the moderating effects of perceptions of Organizational Virtuousness (OV) and Authentic Leadership (AL) in explaining the relationship between Workplace Ostracism (WO) and employees' Turnover Intentions (TI). Data were collected from 686 full-time employees using a non-probabilistic convenience sampling in India's Information Technology (IT) companies. The reliability and validity of scales were assessed using confirmatory factor analysis. Multiple hierarchical regression modeling was used to test the proposed hypotheses using IBM SPSS 23.0 with Process Macro 3.5. The present study's findings suggest that workplace ostracism is significantly related to employees' turnover intentions. Furthermore, perceptions of organizational virtuousness and authentic leadership moderated the relationship between workplace ostracism and employee turnover intentions. Employee turnover is a gigantic problem for IT firms in India. The present study offers valuable insights to managers to create awareness of workplace ostracism. Implementing managerial strategies rooted in positive psychology can help organizations create a more inclusive, supportive, and psychologically healthy work environment. This, in turn, can reduce the occurrence of workplace ostracism and turnover intentions.


Subject(s)
Intention , Leadership , Humans , Ostracism , Personnel Turnover , Reproducibility of Results , Workplace/psychology , Working Conditions
7.
Biochim Biophys Acta Mol Basis Dis ; 1870(2): 166932, 2024 02.
Article in English | MEDLINE | ID: mdl-37926360

ABSTRACT

Several converging lines of evidence from our group support a potential role of RLIP76 (AKA Rlip) in neurodegenerative disorders, including Alzheimer's Disease (AD). However, the role of Rlip in Alzheimer's and other neurodegenerative diseases is not well understood. The purpose of the present study is to determine the role of Rlip in the brains of AD patients and control subjects. To achieve our goals, we used frozen tissues and formalin-fixed paraffin-embedded postmortem brains from AD patients of different Braak stages and age-matched control subjects. Our immunohistology and immunoblotting blotting analysis revealed that expression of Rlip protein gradually and significantly decreased (p = 0.0001) with AD progression, being lowest in Braak stage IV-V. Rlip was colocalized with Amyloid beta (Aß) and phosphorylated tau (p-Tau) as observed by IHC staining and co-immunoprecipitation studies. Lipid peroxidation (4-HNE generation) and H2O2 production were significantly higher (p = 0.004 and 0.0001 respectively) in AD patients compared to controls, and this was accompanied by lower ATP production in AD (p = 0.0009). Oxidative DNA damage was measured by 8-Hydroxyguanosine (8-OHdG) in tissue lysates by ELISA and COMET assay. AD 8-OHdG levels were significantly higher (p = 0.0001) compared to controls. COMET assay was performed in brain cells, isolated from frozen postmortem samples. The control samples showed minimal DNA in comets representing few DNA strand breaks (<20 %), (score-0-1). However, the AD group showed an average of 50 % to 65 % of DNA in comet tails (score-4-5) indicating numerous DNA strand breaks. The difference between the two groups was significant (p = 0.001), as analyzed by Open Comet by ImageJ. Elevated DNA damage was further examined by western blot analysis for phosphorylated histone variant H2AX (γH2AX). Induction of γH2AX was very significant (p < 0.0001) and confirmed the presence of double-strand breaks in DNA. Overall, our results indicate an important role for Rlip in maintaining neuronal health and homeostasis by suppressing cellular oxidative stress and DNA damage. Based on our findings, we cautiously conclude that Rlip is a promising therapeutic target for Alzheimer's disease.


Subject(s)
Alzheimer Disease , Mitochondrial Diseases , Humans , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Autopsy , Brain/metabolism , DNA/metabolism , Hydrogen Peroxide/metabolism , Mitochondrial Diseases/metabolism , Oxidative Stress/physiology
8.
Front Immunol ; 14: 1258873, 2023.
Article in English | MEDLINE | ID: mdl-37860001

ABSTRACT

Breast cancer is the second most common cancer among women in the United States in which the standard of care treatment is surgery with adjunctive therapy. Cryoablation, which destroys the tumor using extremely cold temperatures while preserving the potential tumor antigens, is a promising alternative to surgical resection. It is less invasive, cosmetically appeasing, cost-effective, and capable of contributing to the abscopal effect - the immune response targeting potential distant metastasis. However, to maximize the immunologic benefit of cryoablation in biologically high-risk breast cancers, combination with therapies that enhance immune activation, such as immune checkpoint inhibitors (ICIs) may be necessary. This mini review describes the fundamentals of cryoablation and treatment with ICIs, as well as discuss the caveats in both strategies and current clinical trials aimed to improve this approach to benefit patients.


Subject(s)
Cryosurgery , Triple Negative Breast Neoplasms , Humans , Female , Triple Negative Breast Neoplasms/drug therapy , Immunotherapy
9.
Indian J Psychiatry ; 65(7): 742-748, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37645365

ABSTRACT

Introduction: Tobacco use is a major causative factor for head and neck cancers (HNC). Continued use of tobacco even after cancer diagnosis is common and is associated with all-cause and cancer-specific mortality, cancer recurrence and poor treatment response. Evidence suggests that behavioral interventions, help achieve greater smoking cessation rates in HNC patients. However, intervention studies focussed on HNC patients using smokeless tobacco, which is more common than smoking in India, are sparse. Materials and Methods: We conducted a parallel arm randomized controlled trial (RCT) on dyads of patients with recently diagnosed HNC and a close relative. The experimental arm received a brief tobacco cessation intervention (BTCI) and the control arm received treatment as usual (TAU); 27 and 25 dyads in each arm completed the trial. Results: Overall for the dyads using SLT, the relative risk of continuing to use SLT was 3.23 times higher (odds ratio = 7.01) if BTCI was not undertaken at one-month follow-up and 4.43 times higher (odds ratio = 8.65) at 3-months follow-up. For patients only, the relative risk of continuing to use SLT at one-month and 3-months follow-ups was 4.99 and 12.04 times higher, respectively, if BTCI was not undertaken. For relatives only, the corresponding relative risk values were 2.14 and 2.2. Conclusion: We conclude that BTCI delivered to patient-relative dyads, compared to TAU, is effective in enhancing the discontinuation rates of the use of SLT in newly diagnosed patients with HNC. This form of intervention is significantly effective for discontinuing SLT use in the relatives too.

10.
Cells ; 12(12)2023 06 16.
Article in English | MEDLINE | ID: mdl-37371116

ABSTRACT

RalBP1 (Rlip) is a stress-activated protein that is believed to play a large role in aging and neurodegenerative diseases such as Alzheimer's disease (AD) and other tauopathies. The purpose of our study was to understand the role of Rlip in mutant Tau-expressed immortalized hippocampal HT22 cells. In the current study, we used mutant Tau (mTau)-expressed HT22 neurons and HT22 cells transfected with Rlip-cDNA and/or silenced RNA, and studied the cell survival, mitochondrial respiration, mitochondrial function, immunoblotting, and immunofluorescence analysis of synaptic and mitophagy proteins and the colocalization of Rlip and mTau proteins. We found Rlip protein levels were reduced in mTau-HT22 cells, Rlip silenced HT22 cells, and mTau + Rlip RNA silenced HT22 cells; on the other hand, increased Rlip levels were observed in Rlip cDNA transfected HT22 cells. We found cell survival was decreased in mTau-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mTau-HT22 cells. A significantly reduced oxygen consumption rate (OCR) was found in mTau-HT22 cells and in RNA-silenced Rlip-HT22 cells, with an even greater reduction in mTau-HT22 + Rlip RNA-silenced HT22 cells. A significantly increased OCR was found in Rlip-overexpressed HT22 cells and in all groups of cells that overexpress Rlip cDNA. Mitochondrial function was defective in mTau-HT22 cells, RNA silenced Rlip in HT22 cells, and was further defective in mTau-HT22 + Rlip RNA-silenced HT22 cells; however, it was rescued in Rlip overexpressed in all groups of HT22 cells. Synaptic and mitophagy proteins were decreased in mTau-HT22 cells, and further reductions were found in RNA-silenced mTau-HT22 cells. However, these were increased in mTau + Rlip-overexpressed HT22 cells. An increased number of mitochondria and decreased mitochondrial length were found in mTau-HT22 cells. These were rescued in Rlip-overexpressed mTau-HT22 cells. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reverses these defects. Overall, our findings revealed that Rlip is a promising new target for aging, AD, and other tauopathies/neurological diseases.


Subject(s)
Alzheimer Disease , Tauopathies , Humans , DNA, Complementary/metabolism , Alzheimer Disease/metabolism , Neurons/metabolism , Tauopathies/metabolism , Mitochondria/metabolism , Oxidative Stress , RNA/metabolism , Hippocampus/metabolism
11.
Biochim Biophys Acta Mol Basis Dis ; 1869(7): 166759, 2023 10.
Article in English | MEDLINE | ID: mdl-37225106

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disease that affects a large proportion of the aging population. RalBP1 (Rlip) is a stress-activated protein that plays a crucial role in oxidative stress and mitochondrial dysfunction in aging and neurodegenerative diseases but its precise role in the progression of AD is unclear. The purpose of our study is to understand the role of Rlip in the progression and pathogenesis of AD in mutant APP/amyloid beta (Aß)-expressed mouse primary hippocampal (HT22) hippocampal neurons. In the current study, we used HT22 neurons that express mAPP, transfected with Rlip-cDNA and/or RNA silenced, and studied cell survival, mitochondrial respiration, mitochondrial function, immunoblotting & immunofluorescence analysis of synaptic and mitophagy protein's and colocalization of Rlip and mutant APP/Aß proteins and mitochondrial length and number. We also assessed Rlip levels in autopsy brains from AD patients and control subjects. We found cell survival was decreased in mAPP-HT22 cells and RNA-silenced HT22 cells. However, cell survival was increased in Rlip-overexpressed mAPP-HT22 cells. Oxygen consumption rate (OCR) was decreased in mAPP-HT22 cells and RNA-silenced Rlip-HT22 cells. OCR was increased in Rlip-overexpressed in mAPP-HT22 cells. Mitochondrial function was defective in mAPP-HT22 cells and RNA silenced Rlip in HT22 cells, however, it was rescued in Rlip overexpressed mAPP-HT22 cells. Synaptic and mitophagy proteins were decreased in mAPP-HT22 cells, further reducing RNA-silenced Rlip-HT22 cells. However, these were increased in mAPP+Rlip-HT22 cells. Colocalization analysis revealed Rlip is colocalized with mAPP/Aß. An increased number of mitochondria and decreased mitochondrial length were found in mAPP-HT22 cells. These were rescued in Rlip overexpressed mAPP-HT22 cells. Reduced Rlip levels were found in autopsy brains from AD patients. These observations strongly suggest that Rlip deficiency causes oxidative stress/mitochondrial dysfunction and Rlip overexpression reduced these defects.


Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Mice , Animals , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Neurodegenerative Diseases/pathology , Oxidative Stress , Mitochondria/metabolism , RNA/metabolism
12.
Life Sci Space Res (Amst) ; 37: 78-87, 2023 May.
Article in English | MEDLINE | ID: mdl-37087182

ABSTRACT

PURPOSE: Astronauts on missions beyond low Earth orbit will be exposed to galactic cosmic radiation, and there is concern about potential adverse cardiovascular effects. Most of the research to identify cardiovascular risk of space radiation has been performed in rodent models. To aid in the translation of research results to humans, the current study identified long-term effects of high-energy charged particle irradiation on cardiovascular function and structure in a larger non-rodent animal model. MATERIALS AND METHODS: At the age of 12 months, male New Zealand white rabbits were exposed to whole-body protons (250 MeV) or oxygen ions (16O, 600 MeV/n) at a dose of 0 or 0.5 Gy and were followed for 12 months after irradiation. Ultrasonography was used to measure in vivo cardiac function and blood flow parameters at 10- and 12-months post-irradiation. At 12 months after irradiation, blood cell counts and blood chemistry values were assessed, and cardiac tissue and aorta were collected for histological as well as molecular and biochemical analyses. Plasma was used for metabolomic analysis and to quantify common markers of cardiac injury. RESULTS: A small but significant decrease in the percentage of circulating lymphocytes and an increase in neutrophil percentage was seen 12 months after 0.5 Gy protons, while 16O exposure resulted in an increase in monocyte percentage. Markers of cardiac injury, cardiac troponin I (cTnI) and N-Terminal pro-B-type Natriuretic Peptide were modestly increased in the proton group, and cTnI was also increased after 16O. On the other hand, metabolomics on plasma at 12 months revealed no changes. Both types of irradiation demonstrated alterations in cardiac mitochondrial morphology and an increase in left ventricular protein levels of inflammatory cell marker CD68. However, changes in cardiac function were only mild. CONCLUSION: Low dose charged particle irradiation caused mild long-term changes in inflammatory markers, cardiac function, and structure in the rabbit heart, in line with previous studies in mouse and rat models.


Subject(s)
Cosmic Radiation , Protons , Humans , Rabbits , Male , Rats , Mice , Animals , Infant , Oxygen , Ions , Heart/radiation effects , Dose-Response Relationship, Radiation
13.
Int J Mol Sci ; 23(11)2022 May 29.
Article in English | MEDLINE | ID: mdl-35682775

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and is the most common cause of dementia in older people. AD is associated with the loss of synapses, oxidative stress, mitochondrial structural and functional abnormalities, microRNA deregulation, inflammatory responses, neuronal loss, accumulation of amyloid-beta (Aß) and phosphorylated tau (p-tau). AD occurs in two forms: early onset, familial AD and late-onset, sporadic AD. Causal factors are still unknown for a vast majority of AD patients. Genetic polymorphisms are proposed to contribute to late-onset AD via age-dependent increases in oxidative stress and mitochondrial abnormalities. Recent research from our lab revealed that reduced levels of Rlip76 induce oxidative stress, mitochondrial dysfunction and synaptic damage, leading to molecular and behavioral phenotypes resembling late-onset AD. Rlip76 is a multifunctional 76 kDa protein encoded by the RALBP1 gene, located on chromosome 18. Rlip is a stress-protective ATPase of the mercapturic acid pathway that couples clathrin-dependent endocytosis with the efflux of glutathione-electrophile conjugates. Rlip is evolutionarily highly conserved across species and is ubiquitously expressed in all tissues, including AD-affected brain regions, the cerebral cortex and hippocampus, where highly active neuronal metabolisms render the cells highly susceptible to intracellular oxidative damage. In the current article, we summarize molecular and cellular features of Rlip and how depleted Rlip may exacerbate oxidative stress, mitochondrial dysfunction and synaptic damage in AD. We also discuss the possible role of Rlip in aspects of learning and memory via axonal growth, dendritic remodeling, and receptor regulation. We conclude with a discussion of the potential for the contribution of genetic polymorphisms in Rlip to AD progression and the potential for Rlip-based therapies.


Subject(s)
Alzheimer Disease , Aged , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Amyloid beta-Peptides/metabolism , Humans , Mitochondria/genetics , Mitochondria/metabolism , Oxidative Stress , Synapses/metabolism
14.
Indian J Psychiatry ; 64(2): 192-198, 2022.
Article in English | MEDLINE | ID: mdl-35494335

ABSTRACT

Background: The time of cancer diagnosis is considered as a teaching moment with regard to tobacco cessation. Aim: In view of the limited studies focussing on smokeless tobacco (SLT), we aimed to assess the patterns of SLT use, attitudes toward SLT use in the context of cancer diagnosis, and factors associated with quitting SLT in dyads consisting newly diagnosed patients with head and neck cancers and their relatives. Material and Method: A total of 106 such dyads were assessed on cross-sectional study design. The patients included in the study were above 18 years of age of either sex with a recent (i.e., <6 months) diagnosis of head and neck (lip, tongue, mouth, oropharynx, hypopharynx, pharynx, and larynx) cancer (HNC), not having undergone any surgical intervention for the same and having used SLT for at least 6 months continuously prior to diagnosis of HNC. For each patient, one family member who was aged 18 years or above and lived for at least past 1 year with the patient was included. Result: We found that 60.4% of patients and 6.53% of relatives quit SLT use after the diagnosis of cancer. However, motivation to quit was greater despite continued SLT use, in both patients and relatives. Reasonable number of patients and relatives reported awareness regarding health warnings and long-term consequences of SLT use on cancer. For patients, use of only one form of SLT, presence of 2 or more males in the family using SLT, and presence of another tobacco-related medical disorder in the family were significantly higher in those who quit. Conclusion: The diagnosis of cancer might indeed act as a "teaching moment" for many users but this effect is not extendable on to their relatives.

15.
Cancers (Basel) ; 14(3)2022 Jan 21.
Article in English | MEDLINE | ID: mdl-35158795

ABSTRACT

Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses malignancy and causes global reversion of characteristic CpG island methylomic and transcriptomic aberrations in the p53-null mouse model of spontaneous carcinogenesis through incompletely defined signaling and transcriptomic mechanisms. The methylome and transcriptome are normally regulated by the concerted actions of several mechanisms that include chromatin remodeling, promoter methylation, transcription factor interactions, and miRNAs. The present studies investigated the interaction of Rlip depletion or inhibition with the promoter methylation and transcription of selected cancer-related genes identified as being affected by Rlip depletion in our previous studies. We constructed novel promoter CpG island/luciferase reporter plasmids that respond only to CpG methylation and transcription factors. We found that Rlip depletion regulated expression by a transcription factor-based mechanism that functioned independently of promoter CpG methylation, lipid peroxidation, and p53 status.

17.
Article in English | MEDLINE | ID: mdl-36816155

ABSTRACT

On January 30, 2020, the COVID-19 epidemic was declared an international public health emergency by the World Health Organization. Given the growing impact of the pandemic, there is great interest in finding potential targets for treating infected or hospitalized COVID-19 patients. Therapeutic studies have been conducted on pre-existing drugs, which vary by country, including anti-malarial agents, antiviral agents, and convalescent plasma. However, many of these agents are ineffective at reducing mortality or only shorten the severity or duration of COVID-19 illness in hospitalized patients. As such, other alternatives for treating COVID-19 are being investigated. One such target of interest has been clathrin-dependent endocytosis (CDE). Clathrin-dependent endocytosis is the most commonly observed mechanism of viral entry into cells. However, there have been no published studies to date on CDE inhibition strategies against COVID-19. One such target is Rlip or RLIP76 (human gene RALBP1, 18p11.22). Among its many functions, Rlip is a stress-protective, Ral-regulated ATPase of the mercapturic acid pathway that transports glutathione-electrophile conjugates of electrophilic toxins, which are precursors of mercapturic acid that precedes de-glutamylation by gamma-glutamyl transferase. Rlip is also regulated by several G-proteins that coordinate movement of cells, organelles, membranes, cytoskeleton, macromolecules, and other small molecules. Previous studies have link Rlip in the pathogenesis of several viral illness. In this paper, we want to propose that RLIP76 (Rlip or RALBP1) may be a novel target for treating SARS-CoV-2 viral infections.

18.
Cancers (Basel) ; 13(24)2021 Dec 20.
Article in English | MEDLINE | ID: mdl-34944997

ABSTRACT

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.

19.
Cells ; 10(11)2021 11 10.
Article in English | MEDLINE | ID: mdl-34831336

ABSTRACT

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/- mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/pathology , GTPase-Activating Proteins/metabolism , Mitochondria/pathology , Oxidative Stress , Animals , Antioxidants/metabolism , Behavior, Animal , Cyclic AMP Response Element-Binding Protein/metabolism , Disease Models, Animal , GTPase-Activating Proteins/deficiency , Gene Expression Regulation , Mice , Mitochondria/metabolism , Mitochondria/ultrastructure , Mitochondrial Dynamics/genetics , Models, Biological , Organelle Biogenesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction , Synapses/genetics
20.
Cancer Control ; 28: 10732748211042125, 2021.
Article in English | MEDLINE | ID: mdl-34473004

ABSTRACT

OBJECTIVES: Breast cancer is the second highest female mortality rate in Texas for all races and ethnicities, except for Hispanics. Interestingly, Hale County is a rural underserved county in West Texas which experiences a lower rate of cancer, has higher age-adjusted mortality rates (26.2/100 000), on average, compared to all of Texas (23.1/100 000). The purpose of this study was to determine the relationship between sociodemographic variables and breast cancer outcomes in underserved Hale County which contributed to the highest mortality rate in Texas. METHODS: Hale County breast cancer data (1995-2014) were obtained from the Texas Cancer Registry. Statistical methods independent samples t-test, Kaplan-Meier curve, and Cox proportional hazard were used to describe the significant relationship between survival time, sociodemographic, and prognostic variables. RESULTS: Women with breast cancer in Hale County were more likely to be White non-Hispanics (n = 266, 65.5%) and had the highest longevity (2753.6 ± 2073.5 days). White Hispanics experienced the worst survival (2369.6 ± 2060.2 days) and were more likely to develop a serious grade of cancer. Significant relationships were found between the stage of cancer and insurance status with survival time for both White non-Hispanics and White Hispanics (P < .001). Patients in grades II and III were found to be significantly (P < .01) associated with breast cancer death, and grades II and III which had around five-fold and eleven-fold increased risk of death, respectively, compared with the referent group, grade I. CONCLUSION: Determining the impact of sociodemographic variables on breast cancer outcome is essential to addressing issues of geographic disparities and integrating such variables may guide relevant policy interventions to reduce breast cancer's incidence in rural underserved communities in West Texans.


Subject(s)
Breast Neoplasms/epidemiology , Cancer Survivors/statistics & numerical data , Neoplasm Staging/methods , Rural Population , Aged , Breast Neoplasms/diagnosis , Cross-Sectional Studies , Female , Humans , Incidence , Middle Aged , Retrospective Studies , Survival Rate/trends , Texas/epidemiology
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