Mitochondria

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.

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.

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.

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.

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.

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].

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. 

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.

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.