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.

Astaxanthin improves fatty acid dysregulation in diabetes by controlling the AMPK-SIRT1 pathway.

Due to the rising prevalence of metabolic disorders, including type 2 diabetes (T2DM), new prevention and treatment strategies are needed. The aim was to examine the effect of astaxanthin (AST) on the major regulatory metabolism pathway SIRT-MAPK and fatty acid (FA) profile of plasma in patients with T2DM. This clinical trial included 68 T2DM patients randomly assigned to receive 10 mg/day of oral AST (n = 34) or placebo (n = 33) for 12 weeks. The expression level of SIRT1, AMPK activity, and the level of fatty acids in the serum were examined. The results showed that AST could modify the serum levels of saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA), particularly that of Arachidonic acid, from 11.31±0.35 to 8.52±0.72 %. Also, AST increased the expression and activity levels of SIRT1 and AMPK, respectively. Pearson analysis also revealed a significant association between AMPK activity and Linoleic acid serum (LA) levels (~ -0.604, p~0.013). AST can modify the FA profile of plasma by inducing metabolizing cells to uptake them. Also, it can activate the SIRT-AMPK pathway related to metabolism regulation. See also Figure 1(Fig. 1).

The impact of a blend of Pistacia atlantica seed and canola oil compared with a blend of corn-canola oil with synthetic antioxidant and corn-canola oil without synthetic antioxidant on oxidative stress markers in patients with metabolic syndrome: protocol for a triple-blind, randomized, three-way cross-over clinical trial.

BACKGROUND: Metabolic syndrome (MetS) is regarded as a complex metabolic disorder. Recently, the role of dietary antioxidants in the underlying pathogenesis and complications of MetS has come into focus. Pistacia atlantica oil is known as a high antioxidant oil which might improve the antioxidant status of dietary oils and also oxidative stress markers. On the other hand, tert-Butylhydroquinone (TBHQ) is an approved food-grade synthetic antioxidant that acts both as an inducer and inhibitor of carcinogenesis. The current trial will explore the possible effect of a blend of Pistacia atlantica seed-canola oils, corn-canola oils with TBHQ, and corn-canola oil without TBHQ on oxidative stress markers in patients with MetS. METHODS: We will conduct a single-center, triple-blind, three-way randomized cross-over clinical trial (RCT) among 72 patients with MetS. After a 1-month run-in period, eligible participants will consume the intervention oils as their regularly consumed oils in a random order. Each intervention period will last 8 weeks separated by 4-week washout periods. Anthropometric indices, body composition, physical activity, blood pressure, and 24-h dietary food recall measurements will be assessed at the beginning and the end of each intervention period. The primary outcome will be oxidative stress markers including serum total antioxidant capacity, total oxidant status, malondialdehyde, nitric oxide, and the enzyme activity of myeloperoxidase, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase. The secondary outcomes will be changes in MetS components including blood pressure, fasting blood glucose, triglyceride, high-density lipoprotein cholesterol, and anthropometric measurements. DISCUSSION: Pistacia atlantica seed oil is high in antioxidants. An intervention with this oil could offer an option for oxidative stress prevention among patients with metabolic syndrome. The present clinical trial will be the first one assessing the impact of Pistacia atlantica oil on human oxidative stress markers. TRIAL REGISTRATION: Iranian Registry of Clinical trials IRCT20130223012571N8 . Registered on 4 March 2022.

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.

New synthetic derivatives of isoindoline-dione: synthesis, neuroprotection assay and impact on the expression level of oxidative stress-related genes in neuronal-like cell line.

PURPOSE: Oxidative stress can damage cells and cause age-related illnesses such as Alzheimer's, Parkinson's, and Huntington's. This study looked at newly synthesized isoindole derivatives and their effects on SH-SY5Y as a neuroblastoma cell under oxidative stress through the NRF2 signaling pathway. NRF2 transcription factor plays a vital role in the oxidative stress response and cellular homeostasis. METHOD: Three isoindoline-dione derivatives were synthesized by reacting phthalic anhydrides with 4-(2-aminoethyl)-1-benzyl piperidine. Their structures were confirmed through FT-IR, NMR, and Mass spectroscopy. The derivatives were then tested on human SH-SY5Y cells under an oxidative stress model induced by hydrogen peroxide (H2O2). The cell viability, ROS levels, protein carbonyl content, and gene expression of NRF2 and phase II antioxidative enzymes were measured after 24 h. RESULTS: Three isoindoline derivatives (3a-3c) were observed to increase the viability of SH-SY5Y cells by protective against oxidative stress, reducing intracellular reactive oxygen species and carbonylated proteins, and increasing gene expression levels of NRF2 and associated genes such as NQO-1, and GSTK1. CONCLUSION: Isoindoline derivatives demonstrated a neuroprotective effect on SH-SY5Y cells through various neuroprotective mechanisms, although more studies are needed.

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.

Evaluating the Effects of Separate and Concomitant Use of MK-2206 and Salinomycin on Prostate Cancer Cell Line.

Background: Prostate cancer is known as one of the most prevalent health disorders in the male population globally. The aim of the current study was to evaluate the effects of separate and concomitant use of MK-2206 and salinomycin on prostate cancer cell line. Methods: The antitumor potential of separate and concomitant use of MK-2206 and salinomycin was evaluated in a panel of prostate cancer cell line (PC-3). To get insights into the underlying mechanism of action, different assays including the rate of apoptosis, cell viability, and gene expression were performed in treated prostate cancer cells. Results: A significant reduction was detected in the viability percentage of prostate cancer cells (p< 0.001) and the rate of Akt expression (p< 0.001) in all salinomycin, MK-2206, and salinomycin+MK-2206 groups compared to the negative control group. Furthermore, in comparison with the negative control group, there was a notable increase in both the rate of Bad expression (p< 0.001) and prostate cancer cells apoptosis after salinomycin, MK-2206, and salinomycin+MK-2206 treatments. Moreover, the concomitant use of salinomycin+MK-2206 revealed synergistic improvements regarding the viability of prostate cancer cells and the rate of the Akt and Bad expressions compared to the separate administration of salinomycin and MK-2206 (all p< 0.05). Conclusion: The findings of the present study may contribute to improving the efficacy of the therapies regarding the management of prostate cancer and providing a beneficial strategy in clinical trials.

Targeting the glycans: A paradigm for host-targeted and COVID-19 drug design.

There is always a need for new approaches for the control of virus burdens caused by seasonal outbreaks, the emergence of novel viruses with pandemic potential and the development of resistance to current antiviral drugs. The outbreak of the 2019 novel coronavirus-disease COVID-19 represented a pandemic threat and declared a public health emergency of international concern. Herein, the role of glycans for the development of new drugs or vaccines, as a host-targeted approach, is discussed where may provide a front-line prophylactic or threats to protect against the current and any future respiratory-infecting virus and possibly against other respiratory pathogens. As a prototype, the role of glycans in the coronavirus infection, as well as, galectins (Gal) as the glycan-recognition agents (GRAs) in drug design are here summarized. Galectins, in particular, Gal-1 and Gal-3 are ubiquitous and important to biological systems, whose interactions with viral glycans modulate host immunity and homeostatic balance.

Transposable elements, contributors in the evolution of organisms (from an arms race to a source of raw materials).

There is a concept proposing that the primitive lineages of prokaryotes, eukaryotes, and viruses emerged from the primordial pool of primitive genetic elements. In this genetic pool, transposable elements (TEs) became a source of raw material for primitive genomes, tools of genetic innovation, and ancestors of modern genes (e.g. ncRNAs, tRNAs, and rRNAs). TEs contributed directly to the genome evolution of three forms of life on the earth. TEs now appear as tools that were used to giving rise to sexual dimorphism and sex determination, lineage-specific expression of genes and tissue differentiation and finally genome stability and lifespan determination.

Ginger Extract Increases GLUT-4 Expression Preferentially Through AMPK Than PI3K Signalling Pathways in C2C12 Muscle Cells.

PURPOSE: There are two signal transduction pathways related to glucose metabolism in C2C12 mouse myoblast cells; one through AMP-activated protein kinase (AMPK), and the other through phosphoinositide 3-kinase (PI3K). Ginger is reported to have hypoglycemic effects. The aim of this study was to determine the exact mechanism of action of ginger in those pathways. METHODS: C2C12 cells were seeded to four separate experimental groups; Control: treated with 50 µg/mL DMSO in the absence of any inhibitor; Treatment 1: treated with 50 µg/mL ethyl acetate ginger extract without any inhibitor; Treatment 2: treated with 50 µg/mL extract in the presence of 20 µM AMPK inhibitor; Treatment 3: treated with 50 µg/mL extract in the presence of 25 µM PI3K inhibitor. The amount of GLUT-4 protein (an important glucose transporter) was determined in cytosolic and membrane fractions using sodium dodecyl sulfate polyacrylamide gel electrophoresis and Western blotting. RESULTS: GLUT-4 concentration was significantly higher in the membrane fraction of cells treated with ethyl acetate ginger extract in the absence of any inhibitor in comparison with cells treated with this extract in the presence of each of the inhibitors (P-value < 0.05). GLUT-4 quantity in the membrane fractions in all groups was more than cytosolic fractions. The amount of GLUT-4 in membrane fraction of treated cells in the presence of PI3K inhibitor was higher than in the cells treated with this extract in the presence of AMPK inhibitor (P-value < 0.05). CONCLUSION: Ethyl acetate ginger extract affects the amount of GLUT-4 protein in membrane and cytosolic fractions of C2C12 myoblast cells mostly through AMPK pathway but less via PI3K.

Metformin downregulates miR223 expression in insulin-resistant 3T3L1 cells and human diabetic adipose tissue.

AIMS AND DESIGNS: Metformin, an anti-diabetic drug, is the first line medication for the treatment of type 2 diabetes mellitus and some studies show its relationship with micro-RNAs. This study set up to determine the effect of metformin on miR223 expression and content of AKT/GLUT4 proteins in insulin resistant signaling in 3T3L1 cells and adipocyte of human diabetic patients. MATERIALS AND METHODS: Subcutaneous adipose tissues were taken from newly diagnosed diabetic patients (HOMA-IR > 1.8), before and after three months treatment with 500 mg of metformin twice a day. Cellular homogenate was prepared and miR223 expression and AKT/GLUT4 protein expression were determined by quantitative real-time PCR and western blotting. The results were compared to insulin resistant 3T3L1 adipocytes that were treated with 10 mM Metformin. RESULTS: MiR223 expression was significantly overexpressed both in insulin-resistant 3T3L1 adipocytes compared to non-insulin resistant adipocytes and in human diabetic adipose tissue, compared to non-diabetics (P value < 0.01). Metformin treatment downregulated miR223 expression in both adipocytes and human diabetic adipose tissue. In contrast the IRS/PI3-K/AKT pathway signaling components, Akt and GLUT4 increased in insulin-resistant 3T3L1 adipocytes and human diabetic adipose tissue after three months of metformin treatment. CONCLUSIONS: Metformin reduced insulin resistance in adipocytes by reduction of miR223 expression and improving of IRS/Akt/GLUT4 signaling pathways. Plasma miR223 expression of human diabetic patients was reduced by metformin treatment. These results point to a novel mechanism of miR223 in insulin resistance.

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.

Descending Expression of miR320 in Insulin-Resistant Adipocytes Treated with Ascending Concentrations of Metformin.

Some miRNAs are supposed to play a role in insulin resistance and metabolic disorders. Such miRNAs can be differentially expressed in response to a pharmacologic intervention for insulin resistance as a biomarker/risk factor for insulin resistance. This study aimed at determining the effect of Metformin on miR320 expression in insulin-resistant (IR) adipocytes. The 3T3L1 cells were expanded in DMEM, differentiated into adipocytes by differentiating medium, became resistant to insulin, and then were treated with ascending concentrations of Metformin. Quantitative real-time PCR was performed to profile the miR320 expression in 3T3L1 adipocytes, IR adipocytes, and Metformin-treated IR adipocytes. Compared to the normal adipocytes, IR adipocytes exhibited a significantly higher level of miR320 expression, however, in response to Metformin graded concentrations, IR adipocytes down-regulated miR320 and were almost at normal level. The maximum effect of Metformin was at 10 mM. In IR adipocytes, miR320 expression is over-expressed which can be down-regulated by Metformin treatment. The findings provide some information on a potentially new marker to determine insulin resistance and to predict response to insulin resistance therapy.

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.

Development of An Artificial Male Germ Cell Niche Using Electrospun Poly Vinyl Alcohol/Human Serum Albumin/Gelatin Fibers.

OBJECTIVE: Recent achievements in stem cell biotechnology, nanotechnology and tissue engineering have led to development of novel approaches in regenerative medicine. Azoospermia is one of the challenging disorders of the reproductive system. Several efforts were made for isolation and culture of testis-derived stem cells to treat male infertility. However, tissue engineering is the best approach to mimic the three dimensional microenvironment of the testis in vitro. We investigated whether human testis-derived cells (hTCs) obtained by testicular sperm extraction (TESE) can be cultured on a homemade scaffold composed of electrospun nanofibers of homogeneous poly (vinyl alcohol)/human serum albumin/gelatin (PVA/HSA/gelatin). MATERIALS AND METHODS: In this experimental lab study, human TCs underwent two steps of enzymatic cell isolation and five culture passages. Nanofibrous scaffolds were characterized by scanning electron microscopy (SEM) and Fouriertransform infrared spectroscopy (FTIR). Attachment of cells onto the scaffold was shown by hematoxylin and eosin (H and E) staining and SEM. Cell viability study using MTT [3-(4, 5-dimethyl-2-thiazolyl) -2, 5-diphenyl -2H- tetrazolium bromide] assay was performed on days 7 and 14. RESULTS: Visualization by H and E staining and SEM indicated that hTCs were seeded on the scaffold. MTT test showed that the PVA/HSA/gelatin scaffold is not toxic for hTCs. CONCLUSION: It seems that this PVA/HSA/gelatin scaffold is supportive for growth of hTCs.

Ectopic microRNAs used to preserve human mesenchymal stem cell potency and epigenetics.

Human mesenchymal stem cells (hMSCs) have remarkable potential for use in regenerative medicine. However, one of the great challenges is preserving their potency for long time. This study investigated the effect of miRNA ectopic expression on their proliferation and also on the expression level of Parp1 as an epigenetic switch preserving pluripotency in hMSCs. A cationic liposome was prepared as an efficient carrier for miRNA delivery. The miRNA loading efficiency and physical stability of vesicles were measured, and their scanning electron microscopic shapes determined. hMSCs were transfected with miR-302a and miR-34a followed by assessment of their proliferation potency with MTT assay and measurement of the expression of Parp1 by quantitative polymerase chain reaction (QPCR). Cell transfection with miR-302a and miR-34a efficiently and differentially affects the proliferation potency of hMSCs and the expression level of Parp1 as the key epigenetic factor involved in pluripotency. While miR-302a increases Parp1 expression, miR-34a suppresses it significantly, showing differential effects. Our results demonstrated that miRNA-based treatments represent efficient therapeutic systems and hold a great promise for future use in regenerative medicine through modification of hMSC pluripotency and epigenome.

Effects of a Peganum harmala (Zygophyllaceae) preparation for root canal disinfection.

The aim of this study was to determine the antimicrobial capacity, minimum inhibitory concentration (MIC), and cytotoxic effects of a Peganum harmala seed extract in comparison to 5.25% sodium hypochlorite (NaOCl). The oral pathogen Enterococcus faecalis was used to evaluate the antimicrobial capacity, and the MIC values were determined through serial dilution. Inhibition zones were measured in millimeter, and the data were analyzed statistically by analysis of variance and the Tukey HSD test. For cytotoxicity testing, P. harmala seed extract and 5.25% NaOCl solution were incubated with L929 fibroblast cells. After 1, 24, and 72 hr of incubation, cells were stained and the optical density determined with an enzyme-linked immunosorbent assay (ELISA) reader. Data were analyzed with Chi-Square statistical test. The significance level was set at p < .05. There was no significant difference between the antimicrobial capacity of 5.25% NaOCl and the P. harmala extract (p > .05; MIC 4 µg/ml). The Microculture Tetrazolium (MTT) assay test showed that the cytotoxic effects of the P. harmala extract were significantly lower than 5.25% NaOCl (p < .05). The results show that 5.25% NaOCl and P. harmala seed extract have similar antimicrobial activity against Enterococcus faecalis; but P. harmala, which shows reduced cytotoxicity, should be considered for further investigation as a safe, phytotherapeutic, intracanal irrigant.

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.