Mitochondria

Antibiotic induced changes to mitochondria result in potential contributions to carcinogenesis, heart pathologies, other medical conditions and ecosystem risks

Published on: 2nd October, 2020

OCLC Number/Unique Identifier: 8689024240

With the discovery by Calghatgi (2013) that three common antibiotics (Abs) increased mitochondrial reactive oxygen (ROS) and lipid peroxide (LP) and depleted their natural absorbant glutathione led me to investigate further the potential impacts of these genotoxic substances on carcinogenesis. The range of impacts on mitochondria and cellular DNA varied by antibiotic to those consistent with known prior contributions to carcinogenesis. Specific cancers probably increased by these changes were HCC, RCC (KCC), CRC, cancer of the esophagus. Tumor suppressor gene mutations resulting from LP were noteworthy in this regard and mutations induced in CRC were consistent with those found in carcinogenesis of CRC. In addition depression of short chain fatty acids in microbiomes were found which depress the immune system increasing risk of all cancers. Many cancers were increased according to epidemiological studies linking Abs with elevated odds ratios, with one concern in particular, fatal breast cancer. The impact of loss of functionality of the mitochondria was also linked to depression of the citric acid cycle and therefore ATP which deflected metabolism to glycolysis, the Warburg mechanism also increasing risk of all cancers, favoured by cancer cells. In conclusion, some portion of many cancer types are probably increased in likelihood by number, type and frequency of Abs treatment and chronic residue exposure which varies from individual to individual. This led me to propose a three pronged carcinogenesis mechanism for Abs. 1. Cancer critical mutations 2. Immune depression 3. loss of mitochondrial functionality leading to Warburg effects. Damage to mitochondria were also noted by common pesticides tested in China and cancer associations were also found for many pesticides supporting a similar contributory etiology. Heart health concerns were raised by these findings because of the myriad mitochondria in the heart and because of long term reliability needs. Studies suggesting hearts were affected by Abs and pesticide exposure were presented. Because of their geographical ubiquitousness and the huge range of diseases associated with mitochondrial dysfunction, antibiotics and pesticides and bacteriocidal biocides are of concern for biodiversity and life in general. I propose research steps to evaluate Abs safety and suggest directions for further research and make suggestions on ways to ameliorate Abs toxicity.
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Hepatic adenomatosis: A clinically challenging rare liver disease

Published on: 11th July, 2018

OCLC Number/Unique Identifier: 7828397085

43-year-old lady presented with incidentally discovered liver lesions while she was being managed for her complaints of menorrhagia. CT and MRI showed hepatomegaly with multiple lesions in both lobes of the liver with vascular element in the background of diffuse fatty infiltration. Patient underwent laparoscopic core biopsy. Histopathology showed extensive steatosis, intracytoplasmic giant mitochondria and absence of portal tracts, features highly suggestive of hepatic adenomatosis. IHC staining showed membranous and cytoplasmic positivity in hepatocytes for B-catenin consistent with multiple hepatic adenomatosis. Hepatic adenomatosis is a new clinical entity in the hepatological practice characterized by the presence of 10 or more nodules in the liver known for its major complication of bleeding. Hepatic adenomatosis is managed by regular imaging and resection of large (> 5cm) superficial and painful adenomas along with liver function tests and tumor markers to rule out malignant transformation. However, the potential cure being the liver transplantation.
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Transcriptional profile of bovine preimplantation development selected based on G6PDH activity

Published on: 8th April, 2021

OCLC Number/Unique Identifier: 9026744769

The oocyte is the female gamete that contributes not only half of the genetic material but also all of the cytoplasm to the zygote, supplying the transcripts, proteins, mitochondria and other components necessary for early embryonic development. The intrinsic oocyte quality is one of the main factors affecting the embryo yield, the implantation rate and the rate of healthy offspring. It is obvious that a fertilized oocyte must reach the blastocyst stage within 6–9 days in the proper culture conditions to have a significant chance of inducing a pregnancy and producing an offspring. The ability to sustain the first week of embryonic development is clearly influenced by the follicular status from which the oocyte is obtained indicating that this developmental potential is inherent within certain oocytes. Since most early embryos that do not reach the blastocyst stage are blocked at or close to the maternal to zygotic transition (MZT)-stage, which occurs at the eight-cell stage in cattle, one could speculate that incompetent oocytes fail to appropriately activate the embryonic genome. Oocyte selection based on glucose-6-phosphate dehydrogenase (G6PDH) activity has been successfully used to differentiate between competent and incompetent bovine oocytes. Recently, molecular regulation of genes regulating biological process of Brilliant Cresyl Blue staining (BCB) selected oocytes and embryos was investigated to explain their variation in quality and developmental potentiality. This short review will highlights some of these efforts that have been done in this interesting area of research.
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Chlorhexidine and oral cancer: A short review

Published on: 18th February, 2020

OCLC Number/Unique Identifier: 8535180883

Owing to the ever westernizing lifestyles in developing countries like India, the escalation of oral cancer patients are in need of urgent plan of action. With tobacco being the commonest cause for causation of oral cancer, Global Adult Tobacco Survey, 2016-17 revealed that almost 28% of whole population of India is consuming tobacco in either smoking or smokeless form. With these increasing numbers, the expected death toll to be expected to touch 1-2 million mark by the year 2035 [1]. Although, the current Onco-medicine fraternity excels in rendering care to oral cancer patients in the form of surgeries, chemotherapy and radiation-therapy. Often, these treatment modalities impart some unwanted adverse effects like, docetaxel (DCT) is known for its hepatotoxicity [2,3] whereas, one of the commonly used cisplatin (CIS) presents with nephrotoxicity, neurotoxicity, bone marrow suppression and vomiting [4,5]. Literature suggests of many non conventional medicaments being tested in past for their anti onco-genic effect, where few being effective and others being questionable ones. Chlorhexidine being one among them showing some how promising anti onco-genic activity with feeble amount of studies being conducted in past. Chlorhexidine, one of the most commonly prescribed mouthrinse in the field of dentistry, with varying concentrations of 0.12% and 0.2% concentrations. Although, apart from being broad spectrum antibiotic, its capability to dismantle the protein – protein bond between anti – apoptotic Bcl-2 family protein Bcl-xL and its pro – apoptotic binding partners [6]. The current study was conducted on three cell lines of squamous cell carcinoma (SCC-4, SCC-9, SCC -15) and two pharynx carcinoma cell lines (FaDu and Detroit 562). The compounds induced apoptosis through mitochondria dependent apoptotic pathway in oral tumour cell lines. Another study conducted to assess the similar anti – oncogenic activites of chlorhexidine mouthrinse along with cranberry [7]. It was evident from results that, with increasing concentrations of chlorhexidine mouthrinse, there was increase in mean percent growth inhibition. The authors concluded saying, chlorhexidine has showed both anti cancerous as well as anti bacterial activity required to tackle common oral infections, part of common anti cancer therapy. Fernando Martínez-Pérez et al (2019) conducted study, where antitumor activity of Lipophilic Bismuth Nanoparticles (BisBAL NPs) and chlorhexidine on human squamous cell carcinoma was assessed using energy dispersive X – ray spectroscopy in conjunction with scanning electron microscopy (EDS-SEM). Study revealed, BisBAL NPs and chlorhexidine both showed cell growth inhibition on both cancer cell line (CAL-27) and human gingival fibroblasts (HGFs). Although, chlorhexidine showed non specific cytotoxicity for both tumoral and non tumoral control cells. The suggestive mechanism of action might be loss of cell membrane integrity [8]. Although Eliot MN (2013) conducted study, to assess the risk of head and neck squamous cell carcinoma secondary to use of alcohol containing and non alcoholic mouthwashes including chlorhexidine. The study was concluded with an assumption based on chlorhexidine mouthwash alters the oral flora [9], thus resulting in increasing risk exponentially through diverse change in oral bacteria and altered immune response with contribution towards genesis or promotion of cancer [10]. On the contrary, alcohol consumption and smoking are predisposing factors towards upper digestive tract cancer. The main causative factor being the first metabolite of alcohol, acetaldehyde. And much higher levels are derived from oral bacteria and thus, same can be altered in favour through usage of chlorhexidine mouthwash, to avoid excessive production of acetaldehyde intra orally. In conclusion, chlorhexidine mouthwash has been into dental practice since long and the role it plays in either ways has to be assessed by a multi dimensional study with cell lines including that of control to derive better compared conclusions.
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The Bacterial Heterotrimeric Amidotransferase GatCAB: functions, structures and mechanism-based inhibitors

Published on: 1st May, 2017

OCLC Number/Unique Identifier: 7317595685

tRNA-dependent amidotransferases (AdT) are essential enzymes for protein biosynthesis in many bacteria and in all archaea. As AdT is essential for a number of pathogenic bacteria, and it is absent from mammalian cytoplasm, it is considered as a putative target for novel inhibitors that could be lead compounds to develop a new class of antibiotics. Besides GatFAB of Saccharomyces cerevisiae mitochondria and GatAB of Plasmodium falciparum apicoplast, all reported AdT can be divided into two groups: heterodimeric GatDE and heterotrimeric GatCAB. The latter is required to catalyze the conversion of Glu-tRNAGln and/or Asp-tRNAAsn into Gln-tRNAGln and/or Asn-tRNAAsn in many pathogenic bacteria. Recently determined high resolution crystal structures of several GatCAB could be used to design new inhibitors. In this review, we highlight the essential role of AdT for the faithful translation of glutamine and/or asparagine codons, we describe important features of the crystal structures of several GatCAB as well as tRNA/AdT/aaRS complexes for the formation of Gln-tRNAAsn and Asn-tRNAAsn, we finally summarize discoveries of AdT inhibitors based on their analogy to glutamine, adesosine tripoliphosphate and 3’-end of tRNA.
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The review of the relationship between UCP2 and obesity: Focusing on inflammatory-obesity

Published on: 19th January, 2021

OCLC Number/Unique Identifier: 8895645747

Understanding the obesity-related genes may provide future therapeutic strategies to modulate disease progression. UCP2 separates oxidative phosphorylation (OXPHOS) from ATP production in the inner mitochondria. Figure 1 shows the differences among UCP1, 2, 3. The main role of UCP2 is controlling the metabolism of energy in the cells [1-3]. Besides that, the expression of UCP2 is associated with chronic inflammation due to reactive oxygen species (ROS). In this regard, in injured cells and tissues, ROS could be decreased by reducing the proton motor force by the anti-inflammatory effect of UCP2 [4].
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Protection from the Pathogenesis of Neurodegenerative Disorders, including Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, Huntington’s Disease, and Parkinson’s Diseases, through the Mitigation of Reactive Oxygen Species

Published on: 4th November, 2019

OCLC Number/Unique Identifier: 8302209826

The biological changes caused by oxidative stress (OS) are known to be involved in the etiology of neurodegenerative disorders, including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and Parkinson’s disease. The brain is particularly vulnerable to OS due to its high lipid content and extensive consumption of oxygen. OS processes, particularly the excessive production of reactive oxygen species (ROS), play a critical role in how neurodegenerative disorders develop. This is evidenced by in vivo studies investigating various biomolecules related to OS, such as products of lipid and DNA oxidation. Accordingly, ROS can also cause oxidative-related damage in neurodegenerative disorders, including dopamine auto-oxidation, mitochondrial dysfunction, glial cell activation, α-synuclein aggregation, excessive free iron, and changes in calcium signaling. Furthermore, excessive levels of cellular oxidants reduce antioxidant defenses, which in turn propagate the cycle of OS. As such, it is increasingly important to determine the linkage between a high intake of antioxidants through dietary interventions and a lower risk of developing neurodegenerative diseases. Indeed, in addition to modulating the immune system, optimal nutritional status is capable of changing various processes of neuroinflammation known to be involved in the pathogenesis of neurodegeneration. Accordingly, a better understanding of the role ROS plays in the etiology of neurodegeneration is needed, along with the identification of dietary interventions that may lead to improved therapeutic strategies for both the treatment and prevention of neurodegenerative disorders. Therefore, this review presents a comprehensive summary of the role of ROS in the pathogenesis of neurodegenerative disorders. In addition, nutrients believed to be useful for mitigating and counteracting ROS are discussed. 
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Differential diagnosis of POLG related disorders: What to keep in mind when multiorgan system is involved?

Published on: 9th June, 2021

Mitochondrial and lysosomal dysfunction accounts for a large group of inherited metabolic disorders most of which are due to a dysfunctional mitochondrial respiratory chain (MRC) leading to deficient energy production and defects in phagocytosis in endosomal-lysosomal pathway respectively. MRC function depends on the coordinated expression of both nuclear (nDNA) and mitochondrial (mtDNA) genomes. Thus, mitochondrial diseases can be caused by genetic defects in either the mitochondrial or the nuclear genome, or in the cross-talk between the two. The mitochondrial DNA depletion syndromes (MDSs) are a clinically heterogeneous group of disorders with an autosomal recessive pattern of inheritance that have onset in infancy or early childhood and are characterized by a reduced number of copies of mtDNA in affected tissues and organs. In this review article, we summarized the spectrum of mtDNA depletion disorders along with minor learning of lysosomal storage diseases. This current article offers a perspective on the role of genetics in medical practice and how this role may evolve over the next several years.
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An update in the utilization of N-acetyl cysteine & vitamin c for tackling the oxidative stress in acute kidney injury secondary to robust sepsis - A systematic review

Published on: 1st February, 2022

OCLC Number/Unique Identifier: 9414669659

The commonest etiology of acute kidney injury (AKI) is Sepsis that results in an escalation of morbidity and mortality in the hospital intensive care units. Existentially, the therapy of septic AKI rather than being definitive or curative is just supportive, without tackling the pathophysiology. Usually, Sepsis gets correlated with systemic inflammation, along with the escalated generation of Reactive oxygen species (ROS), in particular superoxide. Simultaneously liberation of nitric oxide (NO) subsequently reacts with the superoxide, thus, resulting in the generation of reactive nitrogen species (RNS), that is mostly peroxynitrite. This sepsis stimulated generation of ROS in addition to RNS might cause a reduction in the bioavailability of NO that modulates microcirculation aberrations, localized tissue hypoxia as well as mitochondrial impairment, thus starting a vicious cycle of cellular damage which results in AKI. Here we conducted a systematic review utilizing search engine PubMed, Google scholar; Web of science; Embase; Cochrane review library utilizing the MeSH terms like septic AKI; ROS; inducible nitric oxide synthase (iNOS); nicotinamide adenine nucleotide phosphate(NADPH)oxidase complex; Oxidative stress; Renal medullary hypoxia; Hypoxia inducible factor1; hypoxia responsive enhancer A; mitochondrial impairment; Intrarenal oxygenation; urinary oxygenation; erythropoietin gene; RRT; NAC; Vitamin C from 1950 to 2021 till date. We found a total of 6500 articles out of which we selected 110 articles for this review. No meta-analysis was done. Thus here we detail the different sources of ROS, at the tie of sepsis, besides their pathophysiological crosstalk with the immune system, microcirculation as well as mitochondria that can result in the generation of AKI. Furthermore, we detail the therapeutic utility of N-acetylcysteine (NAC), besides the reasons for its success in ovine as well as porcine models of AKI. Moreover, we discuss preclinical along with clinical for evaluation of Vitamin C’s antioxidant effects as well as pleiotropic effects as a stress hormone that might aid in abrogation of septic AKI.
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Viscosity-sensitive mitochondrial fluorescent probes and their bio-applications

Published on: 26th August, 2022

As a vital index of the mitochondrial micro-environment, mitochondrial micro-viscosity plays a fundamental role in cell life activities. Normal mitochondrial viscosity is a necessary condition for the maintenance of normal life activities of mitochondria. Abnormal mitochondrial viscosity can lead to a series of mitochondria-related diseases. Therefore, it is essential to observe mitochondrial viscosity for physiological and pathological processes. Given the conventional viscosity measurement methods (viscometer, etc.) cannot monitor the changes in mitochondrial viscosity, the fluorescence method supplemented with the fluorescent probe is widely used to observe the changes in mitochondrial viscosity. In view of the booming development in this area, this review describes the applications of viscosity-responsive mitochondrial fluorescent probes in biological samples from the cellular and tissue levels. We hope that this review will deepen our understanding of mitochondrial viscosity and related fields, and promote the development of viscosity-sensitive mitochondrial probes and other organelle fluorescence probes.
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Nutritional interventions for the prevention and treatment of neurological disorders such as anxiety, bipolar disorder, depression, epilepsy, multiple sclerosis, and schizophrenia

Published on: 11th November, 2022

Neurological disorders are a significant cause of mortality and disability across the world. The current aging population and population expansion have seen an increase in the prevalence of neurological and psychiatric disorders such as anxiety, bipolar disorder, depression, epilepsy, multiple sclerosis and schizophrenia. These pose a significant societal burden, especially in low - and middle-income countries. Many neurological disorders have complex mechanisms and lack definitive cures; thus, improving our understanding of them is essential. The pathophysiology of neurological disorders often includes inflammation, mitochondrial dysfunction and oxidative stress. Oxidative stress processes, especially the generation of reactive oxygen species, are key mechanisms in the development of neurological disorders. Oxidative stress refers to an imbalance between the production of reactive oxygen species and antioxidants that can counteract them. Through their impacts on the pathophysiology of neurological disorders, nutrients with anti-inflammatory, neuroprotective and antioxidative properties have been suggested to prevent or mitigate these disorders. Certain vitamins, minerals, polyphenols and flavonoids may have therapeutic effects as adjuvant treatments for neurological disorders. Diet quality is also a risk factor for some neurological and psychiatric disorders and addressing nutritional deficiencies may alleviate symptoms. Therefore, optimizing nutritional intake may represent a potential treatment or prevention strategy. This review summarizes a selection of promising nutrients for the prevention and amelioration of neurological disorders to provide a summary for scientists, clinicians and patients, which may improve understanding of the potential benefits of nutrients in the treatment of neurological disorders.
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Forensic analysis of raw meat adulteration using mtDNA

Published on: 29th December, 2022

Meat species identification has become essential with the increasing events of frauds like the illegal slaughter of cows, meat adulteration, and substitution. Food scam directly influences public well-being, trade, and wildlife. In Pakistan, donkey meat is used as adulterants for cow meat and is considered Haram in Islamic concepts. In this study PCR, based detection methods are used for identification purposes. The mitochondrial gene cytochrome b has been used in this study to identify the origin of meat specie. Specie-specific primers of cyt b of cow and donkey were used for identification. DNA from different binary ratios of cow and donkey meat was extracted by the phenol-chloroform method. Ratios were made from 1-10 and extracted DNA was subjected to PCR to amplify the target fragment of the cyt b gene. Primers were sensitive to identifying species origin in all meat ratios. Multiplex PCR was designed to identify both species and the results were analyzed by gel electrophoresis. Fragment size of 309bp for cow and 475bp for donkey was observed.Results of the current study conclude that PCR assays, including multiplex PCR, is efficient and has a high sensitivity for even small amount of meat. It is concluded that multiplex PCR is useful and reliable for adulterated meat detection.
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In the pursuit of a new route on acute myeloid leukemia treatment

Published on: 29th December, 2021

Acute myeloid leukaemia (AML) is the forefront disorder of the bone marrow among others that disrupt the normal production of blood cells and platelets. The bone marrow microenvironment or the bone marrow niche (BM niche) that orchestrates the proliferation and survival of Leukaemic stem cells (LSC) is the reason for relapse after complete remission and also chemotherapy drug resistance. As for most cancers oxidative phosphorylation, a fundamental mitochondrial process of energy production, is under focus for the treatment of AML and a novel strategy of targeting heat shock proteins appears as a promising route for further research.
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The Neuroprotective Role of TERT Influences the Expression of SOD1 in Motor Neurons and Mouse Brain: Implications for fALS

Published on: 14th October, 2023

Amyotrophic lateral sclerosis (ALS) disease is characterized by degeneration of motor neurons and elevation of brain oxidative stress. Previous studies demonstrated the neuroprotective effects of Telomerase reverse transcriptase (TERT) from oxidative stress. We showed that increasing TERT expression in the brain of the Tg hSOD1G93A mouse ALS model attenuated the disease pathology and increased the survival of motor neurons exposed to oxidative stress. How TERT increased the survival of motor neurons exposed to oxidative stress is not yet clear. Here we investigated the consequence of TERT depletion in motor neuron cells under normal and oxidative stress conditions and in mouse brains of TERT knockout mice, on the expression and activity of SOD1 and catalase enzymes. Depletion of mouse TERT caused mitochondrial dysfunction and impaired catalase and SOD1 activity. Compensation with hTERT restored the activity of SOD1. SOD1 expression increased in the brain of TERT KO and in ALS mice and decreased in the brain of WT mice treated with telomerase-increasing compounds. We suggest that the ability of TERT to protect neurons from oxidative stress affects the expression and activity of SOD1, in a TERT-dependent manner, and supports the notion of TERT as a therapeutic target for neurodegenerative diseases like ALS.
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Association of Cytokine Gene Polymorphisms with Inflammatory Responses and Sepsis Outcomes in Surgical and Trauma Patients

Published on: 19th February, 2024

Sepsis, a life-threatening condition triggered by infection, poses a significant healthcare challenge with high mortality rates. The interplay between genetics and the immune response in sepsis, particularly in surgical and trauma patients, is complex and critical. Genetic polymorphisms, particularly in cytokine genes like TNF-α, IL-6, and IL-8, have been extensively studied for their influence on sepsis susceptibility, severity, and outcomes. Polymorphisms can alter gene expression and cytokine production, leading to variations in immune responses. Studies have also explored polymorphisms concerning sepsis in genes encoding CD86, TLR4, and SIRT6. This review highlights the association between genetic polymorphisms and inflammatory responses, focusing on their impact on sepsis outcomes in surgical and trauma patients. Genetic variations play a significant role in sepsis risk, severity, and prognosis, with potential implications for personalized therapeutic strategies. Biomarkers such as cytokine gene polymorphisms may aid in predicting sepsis risk and guiding treatment decisions. Complementary therapies like acupuncture and novel biomarkers like microvesicles carrying mitochondrial content provide additional avenues for personalized sepsis management. Furthermore, multiomics approaches offer promise in predicting postoperative outcomes in surgical patients. Understanding the genetic basis of sepsis is essential for improving prevention, diagnosis, and treatment, ultimately leading to better clinical outcomes. Combining genomics, bioinformatics, and clinical expertise, precision medicine can revolutionize sepsis management by tailoring interventions to individual genetic profiles, thus enhancing patient care and outcomes.
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The Potential Use of Dimethyltryptamine against Ischemia-reperfusion Injury of the Brain

Published on: 19th April, 2024

Ischemia-Reperfusion Injury (IRI) is the outcome of two intertwined pathological processes resulting from the shortage of blood flow to tissues and the subsequent restoration of circulation to a previously ischemic area. IRI (sometimes just one side of the dyad) remains one of the most challenging problems in several branches of emergency medicine. Mitochondrial and endoplasmic reticulum dysfunction is a crucial pathological factor involved in the development of IRI. The sigma-1 receptor (Sig1-R) is an intracellular chaperone molecule located between the mitochondria and endoplasmic reticulum with an apparent physiological role in regulating signaling between these cell organelles and serves as a safety mechanism against cellular stress. Therefore, amelioration of IRI is reasonably expected by the activation of the Sig1-R chaperone. Indeed, under cellular stress, Sig1-R agonists improve mitochondrial respiration and optimize endoplasmic reticulum function by sustaining high-energy phosphate synthesis. The discovery that N, N-dimethyltryptamine (DMT) is an endogenous agonist of the Sig1-R may shed light on yet undiscovered physiological mechanisms and therapeutic potentials of this controversial hallucinogenic compound. In this article, the authors briefly overview the function of Sig1-R in cellular bioenergetics with a focus on the processes involved in IRI and summarize the results of their in vitro and in vivo DMT studies aiming at mitigating IRI. The authors conclude that the effect of DMT may involve a universal role in cellular protective mechanisms suggesting therapeutic potentials against different components and types of IRIs emerging in local and generalized brain ischemia after stroke or cardiac arrest.
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