Blood Features Associated with Viral Infection Severity: An Experience from COVID-19-Pandemic Patients Hospitalized in the Center of Iran, Yazd.

Pandemics such as coronavirus disease 2019 (COVID-19) can manifest as systemic infections that affect multiple organs and show laboratory manifestations. We aimed to analyze laboratory findings to understand possible mechanisms of organ dysfunction and risk stratification of hospitalized patients in these epidemics. Methods. This retrospective study was conducted among patients admitted to COVID-19 referral treatment center, Shahid Sadoughi Hospital, Yazd, Iran, from April 21 to November 21, 2021. It was the fifth peak of COVID-19 in Iran, and Delta (VOC-21APR-02; B.1-617.2) was the dominant and most concerning strain. All cases were positive for COVID-19 by RT-PCR test. Lab information of included patients and association of sex, age, and outcome were analyzed, on admission. Results. A total of 466 COVID-19 patients were included in the study, the majority of whom were women (68.9%). The average age of hospitalized patients in male and female patients was 57.68 and 41.32 years, respectively (p < 0.01). During hospitalization, abnormality in hematological and biochemical parameters was significant and was associated with the outcome of death in patients. There was incidence of lymphopenia, neutrophilia, anemia, and thrombocytopenia. The changes in neutrophil/lymphocyte (N/L) and hematocrit/albumin (Het/Alb) ratio and potassium and calcium levels were significant. Conclusion. Based on these results, new biochemical and hematological parameters can be used to predict the spread of infection and the underlying molecular mechanism. Viral infection may spread through blood cells and the immune system.

Dual role of glycans and binding receptors in pathogenesis of enveloped viruses (by mainly focusing on two recent pandemics).

A period of about a decade has been estimated to pass for the emergence of a new infectious strain of a virus that may lead to the occurrence of a pandemic one. It is now suggested that the variants of the 1918 H1N1 and coronavirus disease-19 pandemics could have existed in humans after the initial cross-species introduction to humans and underwent multiple low-level seasonal epidemics before the occurrence of their outbreaks. They share similarities in the continuation, widespreadness due to high transmissibility, high fatality rate and clinical symptoms. They are assumed to share a similar principle of a zoonotic source and a cross-species pathway for transmission. They show some similarities in their pathogenesis with other enveloped viruses: Severe Acute Respiratory Syndrome Coronavirus-1 (SARS-CoV-1), Middle East respiratory syndrome coronavirus (MERS-CoV), human immunodeficiency virus, Ebola, Lassa and measles viruses. The highly pathogenic nature of these viruses and their genetic variants may depend on their binding affinity for host cell receptors, whereby they efficiently circumvent or block host cell immune responses triggered by cytokines (interferon). High transmission rates and viral pathogenicity are attributed to glycan moieties that facilitate virus binding to host multiple receptors and cell entry, thereby helping viruses to evade immune recognition and response. Also, mucosa glycotopes are a matter of concern that play as primary sites for virus attachment and body entry. Finding general lectins or ligands that block the viral-host receptors interaction or identifying individual glycotopes is the therapeutic and prognosis topic that demands the main focus.

Extrachromosomal Circular DNAs, Amplified Oncogenes, and CRISPR-Cas9 System.

Structurally rearranged extrachromosomal circular DNAs (eccDNAs) have been identified in tumor cells, many of which carry regions related to recurrent cancer driver oncogenes (e.g., CCND1, EGFR, and MYC). In a tumor cell, eccDNAs are carrying regions associated with oncogene amplification (>10-fold amplified-copy numbers in human tumors) and poor outcome across multiple cancers. Even though dual-delivery of pairs of CRISPR and CRISPR-associated protein 9 (Cas9) guiding RNAs into normal human cells was reported to induce circularization of genes and chromosomes, in bacteria, the CRISPR-Cas9 system primarily targets extrachromosomal rearranged elements. Likewise, in cancer cells, it is expected that a designed CRISPR-Cas9 system would be able to target extrachromosomal copy number amplifications and produce double strand breaks detrimental to cellular fitness by dictating gene-independent copy number loss-of-fitness effects and antiproliferative responses. A system designed against amplified amplicons may provide a novel approach for cancer therapy and propose a practical implication for CRISPR-Cas9 pairs as a pathway in therapeutic strategies of cancer. SIGNIFICANCE STATEMENT: Structurally rearranged extrachromosomal circular DNAs (eccDNAs) have been identified in tumor cells. Many eccDNAs are carrying regions related to recurrent cancer driver oncogenes (e.g. CCND1, EGFR and MYC). It is expected that a designed CRISPR-Cas9 system would able to target extrachromosomal recurrent oncogenes.

Molecular Basis for Pathogenicity of Human Coronaviruses.

Over the past years, several zoonotic viruses have crossed the species barrier into humans and have been causing outbreaks of severe, and often fatal, respiratory illness. The 21st century has seen the worldwide spread of three recognized coronaviruses (CoVs) which can cause pneumonia and severe acute respiratory symptoms (SARSs), SARS, MERS, and recently SARS-CoV-2. Herein, it is raising concerns about the dissemination of another new and highly lethal pandemic outbreak. Preparing for a pandemic outbreak involves a great deal of awareness necessary to stop initial outbreaks, through recognizing the molecular mechanisms underlying virus transmission and pathogenicity. CoV spike protein S is the key determinant of host tropism and viral pathogenicity which can undergo variations and makes the CoV a highly pathogenic and diffusible virus capable of sustained human-to-human transmission and spread easily. The three mentioned CoVs exhibit some similarities in S protein whereby constitute a promising target for the development of prophylactics and therapeutics in the future.

Molecular Targeting and Rational Chemotherapy in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a molecularly complex disease with multiple aberrant genetic pathways involved in its pathogenesis. Approximately one-third to one-half of patients with AML would relapse, and no standard therapy is established for relapsing and/or refractory AML (RR-AML) yet. It is unlikely that blockage of only one specific pathway will lead to prolonged remissions and cures in all fractions of the AML patients population. Nowadays, novel therapeutic agents with rational combination are being recognized which improve the cure rate for relapsed AML. These drugs and their metabolites impart unique properties in the interaction with each of the intracellular targets and metabolic enzymes whereby resulting in unique clinical activity. To date, most of the combinations have used a targeted agent combined with standard agents such as anthracyclines, cytarabine, or hypomethylating agents to improve the outcome. Rational combinations of DNA damage-inducing therapies with DNA methyltransferase and histone deacetylase inhibitors synergistically enhance the DNA damage, growth inhibition and apoptosis of myeloid cells. This review makes a thorough look at current antineoplastic agents for AML with emphasis on its genetics and molecular mechanisms of action and the role of combination regimens.

Genetic Characterization and Risk Stratification of Acute Myeloid Leukemia.

The most common acute leukemia in adults is acute myeloid leukemia (AML). The pathophysiology of the disease associates with cytogenetic abnormalities, gene mutations and aberrant gene expressions. At the molecular level, the disease manifests as changes in both epigenetic and genetic signatures. At the clinical level, two aspects of AML should be taken into account. First, the molecular changes occurring in the disease are important prognostic and predictive markers of AML. Second, use of novel therapies targeting these molecular changes. Currently, cytogenetic abnormalities and molecular alterations are the common biomarkers for the prognosis and choice of treatment for AML. Finding a panel of multiple biomarkers is a crucial diagnostic step for patient classification and serves as a prerequisite for individualized treatment strategies. Furthermore, the most important way of identifying relevant targets for new treatment approaches is defining specific patterns or a spectrum of driver gene mutations occurring in AML. Then, an algorithm can be established by the use of several biomarkers, to be used for personalized medicine. This review deals with molecular alterations, risk stratification, and relevant therapeutic decision-making in AML.

Sirt1 and Parp1 as epigenome safeguards and microRNAs as SASP-associated signals, in cellular senescence and aging.

Cellular senescence (CS) is underlying mechanism of organism aging and is closely interconnected with age-related diseases (ARDs). Thus, any attempt that influences CS, may be undertaken to reverse or inhibit senescence, whereby could prolong healthy life span. Until now, two main proposes are epigenetic and genetic modifications of cell fate. The first one concerns rejuvenation through effective reprogramming in cells undergoing senescence, or derived from very old or progeroid patients, by which is effective in vitro in induced pluripotent stem cells (iPSCs). The second approach concerns modification of senescence signaling pathways like as IGF-induced agents. However, senescence research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of senescence is controlled, at least to some extent, by epigenetic pathways and biochemical processes conserved in evolution. In this review we try to concentrate on very specific pathways (DNA damage response, DDR, and epigenetic modifiers) and very specific determinants (senescence-associated secretory phenotype, SASP-miRNAs) of human premature aging. A major challenge is to dissect the interconnectedness between the candidate elements and their relative contributions to aging, with the final goal of identifying new opportunities for design of novel anti-aging treatments or avoidance of age-associated manifestations. While knowing that aging is unavoidable and we cannot expect its elimination, but prolonging healthy life span is a goal worth serious consideration.

Underlying mechanisms and chemical/biochemical therapeutic approaches to ameliorate protein misfolding neurodegenerative diseases.

Protein misfolding and inclusion body formations are common events in neurodegenerative diseases characterized by deposition of misfolded proteins inside or outside of neurons, and are commonly referred to as "protein misfolding neurodegenerative diseases" (PMNDs). These phenotypically diverse but biochemically similar aggregates suggest a highly conserved molecular mechanism of pathogenesis. These challenges are magnified by presence of mutations that render individual proteins subject to misfolding and/or aggregation. Cell proteostasis network and molecular chaperoning are maintaining cell proteome to preserve the protein folding, refolding, oligomerization, or disaggregation, and play formidable tasks to maintain the health of organism in the face of developmental changes, environmental insults, and rigors of aging. Maintenance of cell proteome requires the orchestration of major pathways of the cellular proteostasis network (heat shock response (HSR) in the cytosol and the unfolded protein response (UPR) in the endoplasmic reticulum). Proteostasis responses culminate in transcriptional and post-transcriptional programs that up-regulate the homeostatic mechanisms. Proteostasis is strongly influenced by the general properties of individual proteins for folding, misfolding, and aggregation. We examine a growing body of evidence establishing that when cellular proteostasis goes awry, it can be reestablished by deliberate chemical and biological interventions. We first try to introduce some new chemical approaches to prevent the misfolding or aggregation of specific proteins via direct binding interactions. We then start with approaches that employ chemicals or biological agents to enhance the general capacity of the proteostasis network. We finish with evidence that synergy is achieved with the combination of mechanistically distinct approaches to reestablish organ proteostasis. © 2016 BioFactors, 43(6):737-759, 2017.

Comparison of miRNA signature versus conventional biomarkers before and after off-pump coronary artery bypass graft.

Circulating levels of microRNAs (miRNAs) and their expression patterns are supposed to serve as signatures for diagnosis or prognosis of cardiovascular events. The present study aimed at determining if there is any correlation between the release pattern of 2 miRNAs and the plasma levels of conventional biomarkers cardiac troponin I (cTnI), creatine kinase (CK) and uric acid (UA) in patients undergoing their first off-pump coronary artery bypass graft (OCABG). Seventy OCABG patients (69% men, aged 59.2±8.2years) were enrolled. Emergencies, re-operations, abnormal preoperative serum cTnI and combined procedures were excluded from this study. Pre-operative mean ejection fraction was 45.8±8.6%, the average number of grafts was 3±0.87/patient, and the internal mammary artery was used for all. Beside conventional clinical assays, we performed real-time quantitative PCR to analyze the circulating levels of miR-155, miR-126 and miR-499 at 1day before surgery as well as 4days after surgery. Importantly, there was no report of myocardial infarction in our patients, pre- or post-operatively. In contrast to conventional biomarkers cTnI and CK, circulating levels of miRNAs decreased significantly (P<0.01) after revascularization surgery. A significant positive correlation was seen between the cTnI and miR-499 (r∼0.53, P<0.01) and between miR-126 and UA (r∼0.5, P<0.01). Time course study of circulating miR-499, miR-126 and miR-155 in cardiac surgery clarified their advantage and correlations to the traditional biomarkers cTnI, total CK, CK-MB and UA. Our results suggest that this signature is a novel, early biomarker which indicates myocardial ischemia in cardiac surgery. It could be postulated that the application of these miRNAs may be considered for monitoring of response to pharmacological interventions aimed at reducing cardiac ischemia, especially in OCABG candidates.

THE PREVALENCE OF CELIAC DISEASE IN PATIENTS WITH IRON-DEFICIENCY ANEMIA IN CENTER AND SOUTH AREA OF IRAN

Background - Celiac disease is an immune-mediated enteropathy due to a permanent sensitivity to gluten in genetically susceptible people. Iron-deficiency anemia is the most widely experienced anemia in humans. Iron-deficiency anemia additionally is a common extra intestinal manifestation of celiac disease. Objective - To investigate correlation between tTg levels and histological alterations and then to determine the prevalence of celiac disease in Center and South area patients of Iran with iron deficiency anemia. Methods - A total of 402 patients aged 12-78 years who presented with iron-deficiency anemia were included in this study. Hemoglobin, mean corpuscular volume and serum ferritin were determined. Venous blood samples for anti-tissue transglutaminase antibody immunoglobuline A and G were obtained from these patients. Upper gastrointestinal endoscopy was recommended to patients who had positive serology. Results - Of 402 patients with iron-deficiency anemia, 42 (10.4%) had positive serology for celiac disease. The small intestine biopsy of all patients with positive serology showed pathological changes (Marsh I, II & III). There was not significant difference in the mean hemoglobin level between iron-deficiency anemia patients with celiac disease and without celiac disease, duodenal biopsy results did not show significant relationship between the severity of pathological changes and levels of anti-tTG IgG (P -value: 0/869) but significant relationship was discovered between pathological changes and levels of anti-tTG IgA (P -value: 0/004). Conclusion - Screening of celiac disease by anti-tissue transglutaminase antibody should be completed as a routine investigation in patients with iron-deficiency anemia. Also physicians must consider celiac disease as a possible reason of anemia in all patients with iron deficiency anemia.

Contexto - A doença celíaca é uma enteropatia imunomediada, devido a uma sensibilidade permanente ao glúten em pessoas geneticamente suscetíveis. A anemia por deficiência de ferro é a anemia mais frequente em seres humanos e, além disso, é uma manifestação extra intestinal comum da doença celíaca. Objetivo - Investigar a correlação entre níveis de imunoglobulina de anticorpos anti-transglutaminase tissular A (anti-tTG IgA) e G (IgG anti-tTG) e alterações histológicas e, em seguida, determinar a prevalência de doença celíaca no Centro e Sul do Irã em pacientes com anemia por deficiência de ferro. Métodos - Foram incluídos neste estudo um total de 402 pacientes com idades entre 12-78 anos, que apresentavam anemia por deficiência de ferro. Hemoglobina, volume corpuscular médio e ferritina sérica foram determinados. Amostras de sangue venoso para imunoglobulina de anti-tTG IgA e IgG anti-tTG foram obtidas nestes pacientes. Endoscopia gastrointestinal foi recomendada para pacientes que tiveram sorologia positiva. Resultados - Dos 402 pacientes com anemia por deficiência de ferro, 42 (10,4%) tiveram sorologia positiva para doença celíaca. A biópsia do intestino delgado de todos os pacientes com sorologia positiva mostrou alterações patológicas (Marsh I, II e III). Não houve diferença significativa no nível de hemoglobina média entre os pacientes com deficiência de ferro com ou sem a doença celíaca. O resultado da biopsia duodenal não mostrou relação significativa entre a gravidade das alterações patológicas e níveis de IgG anti-tTG (P -valor: 0/869), mas descobriu-se relação significativa entre as alterações patológicas e níveis de anti-tTG IgA (P -valor: 0/004). Conclusão - A pesquisa de doença celíaca por dosagem de anticorpo anti-transglutaminase tissular deve ser completada como investigação de rotina em pacientes com anemia por deficiência de ferro. Os clínicos devem considerar a doença celíaca como um possível causa de anemia em todos os pacientes com anemia ferropriva.

MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis.

The age-related senescence of adult tissues is associated with the decreased level of angiogenic capability and with the development of a degenerative disease such as atherosclerosis which thereafter result in the deteriorating function of multiple systems. Findings indicate that tissue senescence not only diminishes repair processes but also promotes atherogenesis, serving as a double-edged sword in the development and prognosis of ischaemia-associated diseases. Evidence evokes microRNAs (miRNAs) as molecular switchers that underlie cellular events in different tissues. Here, miRNAs would promote new potential targets for optimizing therapeutic methods in blood flow recovery to the ischaemic area. Effectively beginning an ischaemia therapy, a more characteristic of miRNA changes in adult tissues is prerequisite and in the forefront. It may also be a preliminary phase in treatment strategies by stem cell-based therapy.

The master switchers in the aging of cardiovascular system, reverse senescence by microRNA signatures; as highly conserved molecules.

The incidence of CVD increases with aging, because of long-term exposure to risk factors/stressors. Aging is a complex biological process resulting in progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The main hallmarks of aging are cellular senescence, stem cell exhaustion, and altered intracellular communication. The major hallmarks of senescence are mitochondrial dysfunction, genomic instability, telomere attrition and epigenetic alterations, all of which contributing to cellular aging. Such events are controls by a family of small, non-coding RNAs (miRNAs) that interact with component of cellular senescence pathway; mitochondrial biogenesis/removal, DNA damage response machinery and IGF-1 signaling pathway. Here, we review recent in vivo/in vitro reports that miRNAs are key modulators of heart senescence, and act as master switchers to influence reprogramming pathway. We discuss evidence that abrupt deregulation of some mit-miRNAs governing senescence programs underlies age-associated CVD. In particular, due to the highly conserved nature and well-recognized target sites, miRNAs have been defined as master switchers in controlling heart progenitor cell biology. Modulation of mit-miRNA expression holds the great promise in switching off/on cellular senescence/reprogramming to rejuvenate stem cells to aid regenerative process.

THE PREVALENCE OF CELIAC DISEASE IN PATIENTS WITH IRON-DEFICIENCY ANEMIA IN CENTER AND SOUTH AREA OF IRAN.

BACKGROUND: Celiac disease is an immune-mediated enteropathy due to a permanent sensitivity to gluten in genetically susceptible people. Iron-deficiency anemia is the most widely experienced anemia in humans. Iron-deficiency anemia additionally is a common extra intestinal manifestation of celiac disease. OBJECTIVE: To investigate correlation between tTg levels and histological alterations and then to determine the prevalence of celiac disease in Center and South area patients of Iran with iron deficiency anemia. METHODS: A total of 402 patients aged 12-78 years who presented with iron-deficiency anemia were included in this study. Hemoglobin, mean corpuscular volume and serum ferritin were determined. Venous blood samples for anti-tissue transglutaminase antibody immunoglobuline A and G were obtained from these patients. Upper gastrointestinal endoscopy was recommended to patients who had positive serology. RESULTS: Of 402 patients with iron-deficiency anemia, 42 (10.4%) had positive serology for celiac disease. The small intestine biopsy of all patients with positive serology showed pathological changes (Marsh I, II & III). There was not significant difference in the mean hemoglobin level between iron-deficiency anemia patients with celiac disease and without celiac disease, duodenal biopsy results did not show significant relationship between the severity of pathological changes and levels of anti-tTG IgG (P -value: 0/869) but significant relationship was discovered between pathological changes and levels of anti-tTG IgA (P -value: 0/004). CONCLUSION: Screening of celiac disease by anti-tissue transglutaminase antibody should be completed as a routine investigation in patients with iron-deficiency anemia. Also physicians must consider celiac disease as a possible reason of anemia in all patients with iron deficiency anemia.