Melatonin as a regulator of apoptosis in leukaemia: molecular mechanism and therapeutic perspectives.

Leukaemia is a dangerous malignancy that causes thousands of deaths every year throughout the world. The rate of morbidity and mortality is significant despite many advancements in therapy strategies for affected individuals. Most antitumour medications used now in clinical oncology use apoptotic signalling pathways to induce cancer cell death. Accumulated data have shown a direct correlation between inducing apoptosis in cancer cells with higher tumour regression and survival. Until now, the efficacy of melatonin as a powerful antitumour agent has been firmly established. A change in melatonin concentrations has been reported in multiple tumours such as endometrial, hematopoietic, and breast cancers. Findings show that melatonin's anticancer properties, such as its prooxidation function and ability to promote apoptosis, indicate the possibility of utilizing this natural substance as a promising agent in innovative cancer therapy approaches. Melatonin stimulates cell apoptosis via the regulation of many apoptosis facilitators, including mitochondria, cytochrome c, Bcl-2, production of reactive oxygen species, and apoptosis receptors. This paper aimed to further assess the anticancer effects of melatonin through the apoptotic pathway, considering the role that cellular apoptosis plays in the pathogenesis of cancer. The effect of melatonin may mean that it is appropriate for use as an adjuvant, along with other therapeutic approaches such as radiotherapy and chemotherapy.

Evaluation of expression pattern of cellular miRNAs (let-7b, miR-29a, miR-126, miR-34a, miR-181a-5p) and IL-6, TNF-α, and TGF-ß in patients with pseudoexfoliation syndrome.

Pseudoexfoliation syndrome (PEX) is a critical clinical and biological extracellular matrix systemic disorder. Despite the unknown nature of PEX etiopathogenesis, it is proven to be associated with various genes and factors. The present research focused on analyzing the expression of miR and inflammatory cytokines in PEX. Serum and aqueous humor (AH) were collected prior to cataract surgery or trabeculectomy from 99 participants (64 with PEX glaucoma, and 35 controls). Real-time PCR was used for assessing the expression pattern of some miRNAs namely let-7b, miR-29a, miR-126, miR-34a, and miR-181a-5p. ELISA was carried out to explore the transcription of some inflammatory cytokines such as TGF-ß, TNF-α, and IL-6. The indication of our results was a significant enhancement in the expression of let-7, miR-34a, and miR-181a-5p in PEX in contrast to the control group. Notwithstanding a significant suppression in miR-29a, and miR-126 expression levels in PEX in contrast to the control group. Analysis of ROC curve revealed that miR-29a and miR-34a are able to act as useful markers in order to discriminate the PEX group from the PEX negative subjects which were determined as the control group. According to the results obtained, the mean levels of TGF-ß, TNF-α, and IL-6 upregulated among PEX subjects in contrast to control samples. In conclusion, our findings indicated that the selected cytokines alongside the selected miRNAs could be introduced as a biomarker panel in the diagnosis of PEX.

Non-coding RNAs and exosomal non-coding RNAs in pituitary adenoma.

Pituitary adenoma (PA) is the third most common primary intracranial tumor in terms of overall disease incidence. Although they are benign tumors, they can have a variety of clinical symptoms, but are mostly asymptomatic, which often leads to diagnosis at an advanced stage when surgical intervention is ineffective. Earlier identification of PA could reduce morbidity and allow better clinical management of the affected patients. Non-coding RNAs (ncRNAs) do not generally code for proteins, but can modulate biological processes at the post-transcriptional level through a variety of molecular mechanisms. An increased number of ncRNA expression profiles have been found in PAs. Therefore, understanding the expression patterns of different ncRNAs could be a promising method for developing non-invasive biomarkers. This review summarizes the expression patterns of dysregulated ncRNAs (microRNAs, long non-coding RNAs, and circular RNAs) involved in PA, which could one day serve as innovative biomarkers or therapeutic targets for the treatment of this neoplasia. We also discuss the potential molecular pathways by which the dysregulated ncRNAs could cause PA and affect its progression.

Role of non-coding RNAs in neuroblastoma.

Neuroblastoma is known as the most prevalent extracranial malignancy in childhood with a neural crest origin. It has been widely accepted that non-coding RNAs (ncRNAs) play important roles in many types of cancer, including glioma and gastrointestinal cancers. They may regulate the cancer gene network. According to recent sequencing and profiling studies, ncRNAs genes are deregulated in human cancers via deletion, amplification, abnormal epigenetic, or transcriptional regulation. Disturbances in the expression of ncRNAs may act either as oncogenes or as anti-tumor suppressor genes, and can lead to the induction of cancer hallmarks. ncRNAs can be secreted from tumor cells inside exosomes, where they can be transferred to other cells to affect their function. However, these topics still need more study to clarify their exact roles, so the present review addresses different roles and functions of ncRNAs in neuroblastoma.

Apoptosis and myocardial infarction: role of ncRNAs and exosomal ncRNAs.

ncRNAs, particularly miRNAs, lncRNAs and circRNAs, are a group of RNAs which, although they do not encode proteins (however, recent evidence shows that certain circRNAs are translatable), play a major role in regulating gene expression and, therefore, affect multiple cellular processes, in particular apoptosis. Apoptosis is proven to mediate myocardial infarction physiopathology in addition to ischemic necrosis and, therefore, has recently gained great interest as a target to improve MI outcomes. The current work reviews studies that have assessed ncRNAs with the ability to promote or suppress apoptosis in the process of MI and, therefore, may introduce new therapeutic targets for MI treatment.

Paxlovid (Nirmatrelvir/Ritonavir): A new approach to Covid-19 therapy?

Despite the need for novel, effective therapeutics for the COVID-19 pandemic, no curative regimen is yet available, therefore patients are forced to rely on supportive and nonspecific therapies. Some SARS-CoV-2 proteins, like the 3 C-like protease (3CLpro) or the major protease (Mpro), have been identified as promising targets for antiviral drugs. The Mpro has major a role in protein processing as well as pathogenesis of the virus, and could be a useful therapeutic target. The antiviral drug nirmatrelvir can keep SARS-CoV-2 from replicating through inhibiting Mpro. Nirmatrelvir was combined with another HIV protease inhibitor, ritonavir, to create Paxlovid (Nirmatrelvir/Ritonavir). The metabolizing enzyme cytochrome P450 3 A is inhibited by ritonavir to lengthen the half-life of nirmatrelvir, so rintonavir acts as a pharmacological enhancer. Nirmatrelvir exhibits potent antiviral activity against current coronavirus variants, despite significant alterations in the SARS-CoV-2 viral genome. Nevertheless, there are still several unanswered questions. This review summarizes the current literature on nirmatrelvir and ritonavir efficacy in treating SARS-CoV-2 infection, and also their safety and possible side effects.

Non-coding RNAs and Exosomal Non-coding RNAs in Traumatic Brain Injury: the Small Player with Big Actions.

Nowadays, there is an increasing concern regarding traumatic brain injury (TBI) worldwide since substantial morbidity is observed after it, and the long-term consequences that are not yet fully recognized. A number of cellular pathways related to the secondary injury in brain have been identified, including free radical production (owing to mitochondrial dysfunction), excitotoxicity (regulated by excitatory neurotransmitters), apoptosis, and neuroinflammatory responses (as a result of activation of the immune system and central nervous system). In this context, non-coding RNAs (ncRNAs) maintain a fundamental contribution to post-transcriptional regulation. It has been shown that mammalian brains express high levels of ncRNAs that are involved in several brain physiological processes. Furthermore, altered levels of ncRNA expression have been found in those with traumatic as well non-traumatic brain injuries. The current review highlights the primary molecular mechanisms participated in TBI that describes the latest and novel results about changes and role of ncRNAs in TBI in both clinical and experimental research.

Potential of natural products in the treatment of myocardial infarction: focus on molecular mechanisms.

Although conventional drugs are widely used in the prevention and treatment of cardiovascular disease (CVD), they are being used less frequently due to concerns about possible side effects over the long term. There has been a renewed research interest in medicinal plant products, and their role in protecting the cardiovascular system and treating CVD, which are now being considered as potential alternatives to modern drugs. The most important mechanism causing damage to the myocardium after heart attack and reperfusion, is increased levels of free radicals and oxidative stress. Therefore, treatment approaches often focus on reducing free radicals or enhancing antioxidant defense mechanism. It has been previously reported that bioactive natural products can protect the heart muscle in myocardial infarction (MI). Since these compounds are readily available in fruits and vegetables, they could prevent the risk of MI if they are consumed daily. Although the benefits of a healthy diet are well known, many scientific studies have focused on whether pure natural compounds can prevent and treat MI. In this review we summarize the effects of curcumin, resveratrol, quercitin, berberine, and tanshinone on MI and CVD, and focus on their proposed molecular mechanisms of action.

Epigenetic regulation in myocardial infarction: Non-coding RNAs and exosomal non-coding RNAs.

Myocardial infarction (MI) is one of the leading causes of deaths globally. The early diagnosis of MI lowers the rate of subsequent complications and maximizes the benefits of cardiovascular interventions. Many efforts have been made to explore new therapeutic targets for MI, and the therapeutic potential of non-coding RNAs (ncRNAs) is one good example. NcRNAs are a group of RNAs with many different subgroups, but they are not translated into proteins. MicroRNAs (miRNAs) are the most studied type of ncRNAs, and have been found to regulate several pathological processes in MI, including cardiomyocyte inflammation, apoptosis, angiogenesis, and fibrosis. These processes can also be modulated by circular RNAs and long ncRNAs via different mechanisms. However, the regulatory role of ncRNAs and their underlying mechanisms in MI are underexplored. Exosomes play a crucial role in communication between cells, and can affect both homeostasis and disease conditions. Exosomal ncRNAs have been shown to affect many biological functions. Tissue-specific changes in exosomal ncRNAs contribute to aging, tissue dysfunction, and human diseases. Here we provide a comprehensive review of recent findings on epigenetic changes in cardiovascular diseases as well as the role of ncRNAs and exosomal ncRNAs in MI, focusing on their function, diagnostic and prognostic significance.

Effects of microRNAs and long non-coding RNAs on chemotherapy response in glioma.

Glioma is the most prevalent invasive primary tumor of the central nervous system. Glioma cells can spread and infiltrate into normal surrounding brain tissues. Despite the standard use of chemotherapy and radiotherapy after surgery in glioma patients, treatment resistance is still a problem, as the underlying mechanisms are still not fully understood. Non-coding RNAs are widely involved in tumor progression and treatment resistance mechanisms. In the present review, we discuss the pathways by which microRNAs and long non-coding RNAs can affect resistance to chemotherapy and radiotherapy, as well as offer potential therapeutic options for future glioma treatment.

Role of non-coding RNAs and exosomal non-coding RNAs in retinoblastoma progression.

Retinoblastoma (RB) is a rare aggressive intraocular malignancy of childhood that has the potential to affect vision, and can even be fatal in some children. While the tumor can be controlled efficiently at early stages, metastatic tumors lead to high mortality. Non-coding RNAs (ncRNAs) are implicated in a number of physiological cellular process, including differentiation, proliferation, migration, and invasion, The deregulation of ncRNAs is correlated with several diseases, particularly cancer. ncRNAs are categorized into two main groups based on their length, i.e. short and long ncRNAs. Moreover, ncRNA deregulation has been demonstrated to play a role in the pathogenesis and development of RB. Several ncRNAs, such as miR-491-3p, miR-613,and SUSD2 have been found to act as tumor suppressor genes in RB, but other ncRNAs, such as circ-E2F3, NEAT1, and TUG1 act as tumor promoter genes. Understanding the regulatory mechanisms of ncRNAs can provide new opportunities for RB therapy. In the present review, we discuss the functional roles of the most important ncRNAs in RB, their interaction with the genes responsible for RB initiation and progression, and possible future clinical applications as diagnostic and prognostic tools or as therapeutic targets.

Exosomal long non-coding RNAs: novel molecules in gastrointestinal cancers' progression and diagnosis.

Gastrointestinal (GI) cancers arise in the GI tract and accessory organs, including the mouth, esophagus, stomach, liver, biliary tract, pancreas, small intestine, large intestine, and rectum. GI cancers are a major cause of cancer-related morbidity and mortality worldwide. Exosomes act as mediators of cell-to-cell communication, with pleiotropic activity in the regulation of homeostasis, and can be markers for diseases. Non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs), can be transported by exosomes derived from tumor cells or non-tumor cells. They can be taken by recipient cells to alter their function or remodel the tumor microenvironment. Moreover, due to their uniquely low immunogenicity and excellent stability, exosomes can be used as natural carriers for therapeutic ncRNAs in vivo. Exosomal lncRNAs have a crucial role in regulating several cancer processes, including angiogenesis, proliferation, drug resistance, metastasis, and immunomodulation. Exosomal lncRNA levels frequently alter according to the onset and progression of cancer. Exosomal lncRNAs can therefore be employed as biomarkers for the diagnosis and prognosis of cancer. Exosomal lncRNAs can also monitor the patient's response to chemotherapy while also serving as potential targets for cancer treatment. Here, we discuss the role of exosomal lncRNAs in the biology and possible future treatment of GI cancer.

Role of exosomes in malignant glioma: microRNAs and proteins in pathogenesis and diagnosis.

Malignant gliomas are the most common and deadly type of central nervous system tumors. Despite some advances in treatment, the mean survival time remains only about 1.25 years. Even after surgery, radiotherapy and chemotherapy, gliomas still have a poor prognosis. Exosomes are the most common type of extracellular vesicles with a size range of 30 to 100 nm, and can act as carriers of proteins, RNAs, and other bioactive molecules. Exosomes play a key role in tumorigenesis and resistance to chemotherapy or radiation. Recent evidence has shown that exosomal microRNAs (miRNAs) can be detected in the extracellular microenvironment, and can also be transferred from cell to cell via exosome secretion and uptake. Therefore, many recent studies have focused on exosomal miRNAs as important cellular regulators in various physiological and pathological conditions. A variety of exosomal miRNAs have been implicated in the initiation and progression of gliomas, by activating and/or inhibiting different signaling pathways. Exosomal miRNAs could be used as therapeutic agents to modulate different biological processes in gliomas. Exosomal miRNAs derived from mesenchymal stem cells could also be used for glioma treatment. The present review summarizes the exosomal miRNAs that have been implicated in the pathogenesis, diagnosis and treatment of gliomas. Moreover, exosomal proteins could also be involved in glioma pathogenesis. Exosomal miRNAs and proteins could also serve as non-invasive biomarkers for prognosis and disease monitoring. Video Abstract.