Safety and efficacy of platelet-derived mitochondrial transplantation in ischaemic heart disease.

BACKGROUND: Acute ST-elevation myocardial infarction (STEMI) remains a globally significant health challenge in spite of improvement in management strategy. Being aware that mitochondrial dysfunction plays a crucial role in ischaemia-reperfusion injury (IRI) modulation, empirical evidence suggests functional mitochondrial transplantation strikes as a reliable therapeutic approach for patients with acute myocardial infarction. METHODS AND RESULTS: We conducted a prospective, triple-blinded, parallel-group, blocked randomised clinical trial to investigate the therapeutic effects and clinical outcomes of platelet-derived mitochondrial transplantation in 30 patients with acute STEMI, such that the 15 subjects in the control group were given standard of care treatment, whereas the subjects in the intervention group received autologous platelet-derived mitochondria through the intracoronary injection. We observed that within 40 days, the intervention group had a slightly greater improvement in the left ventricular ejection fraction (LVEF) compared to the control group and experienced a significant enhancement in the exercise capacity (p < 0.001). Moreover, major adverse cardiac events (MACE), arrhythmia, fever, and tachycardia were compared between the groups and lack of significant difference marks the safety of mitochondrial transplantation (p > 0.05). Furthermore, the two groups were not significantly distinct as regards the average length of stay for a hospitalisation (p > 0.05). CONCLUSION: We suggest platelet-derived mitochondrial transplantation appears as a beneficial and highly promising therapeutic option for patients of ischaemic heart disease (IHD); however, we are aware that further in-depth studies with larger sample sizes along with longer follow-up periods are necessary for validating the clinical implications of our findings.

Study of Three Potential Diagnostic Biomarkers in Nasopharyngeal Carcinoma Samples from Guilan, North of Iran

Abstract Introduction Finding biomarkers for highly lethal cancers is a priority. Objective The current study was designed to understand the clinical significance of vascular endothelial growth factor (VEGF), latent membrane protein 1 (LMP1), and tumor necrosis factor-α (TNF-α) expression as the biomarkers, and evaluate their correlation with each other, in nasopharyngeal carcinoma (NPC) in the province of Guilan, North of Iran. Methods Gene expression was evaluated in 25 formalin-fixed paraffin-embedded (FFPE) blocks from cases of confirmed NPC and 20 FFPE samples of non-NPC by quantifying messenger ribonucleic acid (mRNA) and protein levels, using real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC) methods, respectively. Furthermore, the correlations among the protein levels of different genes, along with the patients' demographic characteristics were assessed. Results Our findings on mRNA and protein levels demonstrated that the expression of the LMP1 gene in the NPC group was significantly elevated compared with that of the non-NPC group. In addition, the protein levels in the NPC group indicated a positive and significant correlation between LMP1 and VEGF expression. It was noted that both protein and mRNA levels showed no significant differences in the expression of TNF-α and VEGF genes between the NPC and control groups. Furthermore, there was no significant relationship between the expression of these proteins and the demographic characteristics of NPC patients. Conclusion Overall, a significant increase in LMP1 expression was observed in NPC patients, which may serve as a diagnostic biomarker for NPC. Also, LMP1 might be involved in NPC progression by inducing VEGF gene expression.

Study of Three Potential Diagnostic Biomarkers in Nasopharyngeal Carcinoma Samples from Guilan, North of Iran.

Introduction Finding biomarkers for highly lethal cancers is a priority. Objective The current study was designed to understand the clinical significance of vascular endothelial growth factor (VEGF), latent membrane protein 1 (LMP1), and tumor necrosis factor-α (TNF-α) expression as the biomarkers, and evaluate their correlation with each other, in nasopharyngeal carcinoma (NPC) in the province of Guilan, North of Iran. Methods Gene expression was evaluated in 25 formalin-fixed paraffin-embedded (FFPE) blocks from cases of confirmed NPC and 20 FFPE samples of non-NPC by quantifying messenger ribonucleic acid (mRNA) and protein levels, using real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC) methods, respectively. Furthermore, the correlations among the protein levels of different genes, along with the patients' demographic characteristics were assessed. Results Our findings on mRNA and protein levels demonstrated that the expression of the LMP1 gene in the NPC group was significantly elevated compared with that of the non-NPC group. In addition, the protein levels in the NPC group indicated a positive and significant correlation between LMP1 and VEGF expression. It was noted that both protein and mRNA levels showed no significant differences in the expression of TNF-α and VEGF genes between the NPC and control groups. Furthermore, there was no significant relationship between the expression of these proteins and the demographic characteristics of NPC patients. Conclusion Overall, a significant increase in LMP1 expression was observed in NPC patients, which may serve as a diagnostic biomarker for NPC. Also, LMP1 might be involved in NPC progression by inducing VEGF gene expression.

Human umbilical cord-derived mesenchymal stem cells-harvested mitochondrial transplantation improved motor function in TBI models through rescuing neuronal cells from apoptosis and alleviating astrogliosis and microglia activation.

Each year, traumatic brain injury (TBI) causes a high rate of mortality throughout the world and those who survive have lasting disabilities. Given that the brain is a particularly dynamic organ with a high energy consumption rate, the inefficiency of current TBI treatment options highlights the necessity of repairing damaged brain tissue at the cellular and molecular levels, which according to research is aggravated due to ATP deficiency and reactive oxygen species surplus. Taking into account that mitochondria contribute to generating energy and controlling cellular stress, mitochondrial transplantation as a new treatment approach has lately reduced complications in a number of diseases by supplying healthy and functional mitochondria to the damaged tissue. For this reason, in this study, we used this technique to transplant human umbilical cord-derived mesenchymal stem cells (hUC-MSCs)-derived mitochondria as a suitable source for mitochondrial isolation into rat models of TBI to examine its therapeutic benefit and the results showed that the successful mitochondrial internalisation in the neuronal cells significantly reduced the number of brain cells undergoing apoptosis, alleviated astrogliosis and microglia activation, retained normal brain morphology and cytoarchitecture, and improved sensorimotor functions in a rat model of TBI. These data indicate that human umbilical cord-derived mesenchymal stem cells-isolated mitochondrial transplantation improves motor function in a rat model of TBI via rescuing neuronal cells from apoptosis and alleviating astrogliosis and microglia activation, maybe as a result of restoring the lost mitochondrial content.

Mitochondrial transfer in PC-3 cells fingerprinted in ferroptosis sensitivity: a brand new approach targeting cancer metabolism.

Despite recent therapeutic advancements, cancer remains one of the leading causes of death worldwide, with mitochondrial dysfunction being associated with cancer initiation and progression, along with chemotherapeutic resistance and ferroptotic cell death failure; however, the significance of mitochondria in various cancer types remains a matter of debate for the moment. The aim of this study is to ascertain the outcome of transferring healthy mitochondria into the aggressive and rapidly proliferating prostate cancer (PC-3) cells and afterwards evaluate the efficacy of combination therapy with or without the ferroptosis inducer erastin. In this sense, normal mitochondria were first isolated from human umbilical cord-derived mesenchymal stem cells, human umbilical vein endothelial cells, and human embryonic kidney cells and were later transferred into PC-3 cells and rhodamine 6G-treated PC-3 cells exhibiting mitochondrial dysfunction. Next, cell proliferation and sensitivity to cisplatin were measured using Cell Counting Kit-8 and the Malondialdehyde Assay Lipid Peroxidation Kit, respectively, along with ferroptotic damage. Transferring the healthy mitochondria into PC-3 cells was observed to increase cell proliferation and rescue the cisplatin-induced cell death, but not the erastin-induced ferroptosis, as in mitochondrial transfer effectively enhanced erastin-mediated ferroptosis in PC-3 cells. Hence, the introduction of healthy mitochondria into the highly aggressive and proliferating cancer cells would be deemed a brand new therapeutic strategy for a variety of cancers.

Mitochondria: how eminent in ageing and neurodegenerative disorders?

Numerous factors are implicated in the onset and progression of ageing and neurodegenerative disorders, with defects in cell energy supply and free radicals regulation designated as being the main functions of mitochondria and highly accentuated in plentiful studies. Hence, analysing the role of mitochondria as one of the main factors implicated in these disorders could undoubtedly come in handy with respect to disease prevention and treatment. In this review, first, we will explore how mitochondria account for neurodegenerative disorders and ageing and later will draw the various pathways contributing to mitochondrial dysfunction in their distinct way. Also, we will discuss the deviation-countering mechanisms, particularly mitophagy, a subset of autophagy known as a much larger cellular defence mechanism and regulatory system, along with its potential therapeutic effects. Last but not least, we will be highlighting the mitochondrial transfer experiments with animal models of neurodegenerative disorders.

Plumping up a Cushion of Human Biowaste in Regenerative Medicine: Novel Insights into a State-of-the-Art Reserve Arsenal.

Major breakthroughs and disruptive methods in disease treatment today owe their thanks to our inch by inch developing conception of the infinitive aspects of medicine since the very beginning, among which, the role of the regenerative medicine can on no account be denied, a branch of medicine dedicated to either repairing or replacing the injured or diseased cells, organs, and tissues. A novel means to accomplish such a quest is what is being called "medical biowaste", a large assortment of biological samples produced during a surgery session or as a result of physiological conditions and biological activities. The current paper accentuating several of a number of promising sources of biowaste together with their plausible applications in routine clinical practices and the confronting challenges aims at inspiring research on the existing gap between clinical and basic science to further extend our knowledge and understanding concerning the potential applications of medical biowaste.

Non-coding RNAs in ferroptotic cancer cell death pathway: meet the new masters.

Despite the recent advances in cancer therapy, cancer chemoresistance looms large along with radioresistance, a major challenge in dire need of thorough and minute investigation. Not long ago, cancer cells were reported to have proven refractory to the ferroptotic cell death, a newly discovered form of regulated cell death (RCD), conspicuous enough to draw attention from scholars in terms of targeting ferroptosis as a prospective therapeutic strategy. However, our knowledge concerning the underlying molecular mechanisms through which cancer cells gain immunity against ferroptosis is still in its infancy. Of late, the implication of non-coding RNAs (ncRNAs), including circular RNAs (circRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) in ferroptosis has been disclosed. Nevertheless, precisely explaining the molecular mechanisms behind the contribution of ncRNAs to cancer radio/chemotherapy resistance remains a challenge, requiring further clarification. In this review, we have presented the latest available information on the ways and means of regulating ferroptosis by ncRNAs. Moreover, we have provided important insights about targeting ncRNAs implicated in ferroptosis with the hope of opening up new horizons for overcoming cancer treatment modalities. Though a long path awaits until we make this ambitious dream come true, recent progress in gene therapy, including gene-editing technology will aid us to be optimistic that ncRNAs-based ferroptosis targeting would soon be on stream as a novel therapeutic strategy for treating cancer.

Pharmacological Targeting of Ferroptosis in Cancer Treatment.

Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.

Cashing in on ferroptosis against tumor cells: Usher in the next chapter.

Ferroptosis is a new type of non-apoptotic regulated cell death (RCD) driven by unrestricted lethal lipid peroxidation, which is totally distinct from other forms of RCD in genetic and biochemical characteristics. It is generally believed that iron dependency, malfunction of the redox system, and excessive lipid peroxidation are the main hallmarks of ferroptosis. Accumulating pieces of evidence over the past few years have shown that ferroptosis is tightly related to various types of diseases, especially cancers. Ferroptosis has recently attracted great attention in the field of cancer research. A plethora of evidence shows that employing ferroptosis as a powerful weapon can remarkably enhance the efficacy of tumor cell annihilation. Better knowledge of the ferroptosis mechanisms and their interplay with cancer biology would enable us to use this fashionable tool in the best way. Herein, we will briefly present the relevant mechanisms of ferroptosis, the multifaceted relation between ferroptosis and cancer, encompassing tumor immunity, overcoming chemoresistance, and epithelial to mesenchymal transition. In the end, we will also briefly discuss the potential approaches to ferroptosis-based cancer therapy, such as using drugs and small molecules, nanoparticles, mitochondrial targeting, and photodynamic therapy.

Taming of Covid-19: potential and emerging application of mesenchymal stem cells.

Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has turned out to cause a pandemic, with a sky scraping mortality. The virus is thought to cause tissue injury by affecting the renin-angiotensin system. Also, the role of the over-activated immune system is noteworthy, leading to severe tissue injury via the cytokine storms. Thus it would be feasible to modulate the immune system response in order to attenuate the disease severity, as well as treating the patients. Today different medicines are being administered to the patients, but regardless of the efficacy of these treatments, adverse effects are pretty probable. Meanwhile, mesenchymal stem cells (MSCs) prove to be an effective candidate for treating the patients suffering from COVID-19 pneumonia, owing to their immunomodulatory and tissue-regenerative potentials. So far, several experiments have been conducted; transplanting MSCs and results are satisfying with no adverse effects being reported. This paper aims to review the recent findings regarding the novel coronavirus and the conducted experiments to treat patients suffering from COVID-19 pneumonia utilizing MSCs.

IFN-γ and TNF-α Gene Polymorphisms in Multiple Sclerosis Patients in Northwest Iran.

BACKGROUND: Cytokines are polypeptides that play critical roles in immune responses. Gene polymorphisms occurring in the inflammatory cytokines are taking a role in autoimmune diseases, including multiple sclerosis (MS), which may induce inappropriate immune responses. OBJECTIVE: The aim of this study was to investigate the allelic and genotypic frequencies of interferon gamma gene (IFN-γ) at +874A/T locus and tumor necrosis factor (TNF-α) at+308A/G locus in MS patients of Azeri population. METHODS: At first, a questionnaire was prepared for each of 240 healthy, non-relative, and 152 Azeri MS patients before obtaining the blood sample from all subjects. After DNA extraction, the frequency of alleles and genotypes of the IFN-γ and TNF-α genes at +874A/T and -308G/A loci, respectively, were determined by allele-specific PCR method. Finally, the frequencies were compared between control and MS patients by chi-square test (x2-test) and p<0.05 was considered significant. RESULTS: In the IFN-γ +874A/T gene single nucleotide polymorphism (SNP), the most allelic and genotypic frequencies in MS patients were the A allele, 55.26% (p=0.04) and the AT genotype, 52.63% (p=0.048). In healthy individuals, it was 65.42% for the A allele and 45.42% for the AA genotype. For the TNF-α 308 G/A SNP, the highest allelic and genotypic frequencies in MS patients were the G allele with 55.92% (p<0.001) and AG genotype with 61.84%, and in healthy subjects, the allelic and genotypic frequencies were 84.2% and 70.8% for the G allele and GG genotype, respectively. CONCLUSION: Head trauma, the infection with the herpes virus and Mycoplasma pneumonia, frequent colds and high consumption of canned foods provide grounds for MS. The T allele in the IFN-γ gene (+874) and the genotypes of AA and AG at the TNF-α gene (-308) at the position-308 were considered as potential risk factors for MS. Therefore, the polymorphisms in cytokine genes and following changes in their expression levels can be effective in susceptibility to MS.