Partial Reprogramming as a Method for Regenerating Neural Tissues in Aged Organisms.

Aging causes numerous age-related diseases, leading the human species to death. Nevertheless, rejuvenating strategies based on cell epigenetic modifications are a possible approach to counteract disease progression while getting old. Cell reprogramming of adult somatic cells toward pluripotency ought to be a promising tool for age-related diseases. However, researchers do not have control over this process as cells lose their fate, and cause potential cancerous cells or unexpected cell phenotypes. Direct and partial reprogramming were introduced in recent years with distinctive applications. Although direct reprogramming makes cells lose their identity, it has various applications in regeneration medicine. Temporary and regulated in vivo overexpression of Yamanaka factors has been shown in several experimental contexts to be achievable and is used to rejuvenate mice models. This regeneration can be accomplished by altering the epigenetic adult cell signature to the signature of a younger cell. The greatest advantage of partial reprogramming is that this method does not allow cells to lose their identity when they are resetting their epigenetic clock. It is a regimen of short-term Oct3/4, Sox2, Klf4, and c-Myc expression in vivo that prevents full reprogramming to the pluripotent state and avoids both tumorigenesis and the presence of unwanted undifferentiated cells. We know that many neurological age-related diseases, such as Alzheimer's disease, stroke, dementia, and Parkinson's disease, are the main cause of death in the last decades of life. Therefore, scientists have a special tendency regarding neuroregeneration methods to increase human life expectancy.

PyComp: A Versatile Tool for Efficient Data Extraction, Conversion, and Management in High-throughput Virtual Drug Screening.

BACKGROUND: Virtual screening (VS) is essential for analyzing potential drug candidates in drug discovery. Often, this involves the conversion of large volumes of compound data into specific formats suitable for computational analysis. Managing and processing this wealth of information, especially when dealing with vast numbers of compounds in various forms, such as names, identifiers, or SMILES strings, can present significant logistical and technical challenges. METHODS: To streamline this process, we developed PyComp, a software tool using Python's PyQt5 library, and compiled it into an executable with Pyinstaller. PyComp provides a systematic way for users to retrieve and convert a list of compound names, IDs (even in a range), or SMILES strings into the desired 3D format. RESULTS: PyComp greatly enhances the efficiency of data extraction, conversion, and storage processes involved in VS. It searches for similar compounds coupled with its ability to handle misidentified compounds and offers users an easy-to-use, customizable tool for managing largescale compound data. By streamlining these operations, PyComp allows researchers to save significant time and effort, thus accelerating the pace of drug discovery research. CONCLUSION: PyComp effectively addresses some of the most pressing challenges in highthroughput VS: efficient management and conversion of large volumes of compound data. As a user-friendly, customizable software tool, PyComp is pivotal in improving the efficiency and success of large-scale drug screening efforts, paving the way for faster discovery of potential therapeutic compounds.

Extremely Low Frequency-Electromagnetic Fields (ELF-EMF) Can Decrease Spermatocyte Count and Motility and Change Testicular Tissue.

Background: Substantial evidence indicates that exposure to extremely low frequency-electromagnetic fields (ELF-EMFs) affects male reproductive system. Objective: The goal of this study was to evaluate the effects of long-term irradiation with ELF-EMF on sperm quality and quantity and testicular structure. Material and Methods: In this case-control study, sixty male Sprague-Dawley rats were randomly divided into six groups. Experimental groups were exposed to ELF-EMF (50 Hz EMF, 100 µT) for either 1 h/day for 52 days (Group 1), 4 h/day for 52 days (Group 3), 1 h/day for 5 days (Group 5), 4 h/day for 52 days (Group 7). Groups 2, 4, 6 and 8 were only sham exposed at durations equal to Groups 1, 3, 5 and 7, respectively. Results: Both count and motility of sperms were significantly decreased in animals exposed to ELF-EMF (1 h/day for 52 days, 4 h/day for 52 day, and 4 h/day for 5 days) compared to the sham-exposed groups (P<0.05). Serum testosterone levels showed a significant decrease in the animals exposed to ELF-EMF (4 h/day for 5 days) compared to the control groups (P<0.05). A significant decrease was observed in the volume of the seminiferous tubules, seminiferous tubules epithelium and interstitial tissue in the animals exposed to ELF-EMF for 4 h/day for 5 days. Tubules length was also reduced by 18% in animals exposed to ELF-EMF (4 h/day for 5 days). Conclusion: Our results show that ELF-EMF can reduce spermatocyte count and motility and is able to induce structural changes in testicular tissue.

PyProtModel: An easy to use GUI for comparative protein modeling.

A deep insight into the 3D structures of the proteins is essential to understand their functions and will be helpful in drug design and making decisions for the treatment of diseases. The 3D structure for less than one-thousandth of the protein sequences has been determined so far due to the slow structure elucidation procedures with experimental methods, such as X-ray. For this reason, different computational methods were used to determine the structure of the proteins, including template-based and de novo approaches. Much software has been developed to facilitate the computational approaches in protein modeling, some of which need user expertise and extensive knowledge in bioinformatics. The present study attempted to provide a user-friendly environment to motivate the researchers in computational biology, a Python-based interface based on MODELLER software. PyProtModel can be used as a toolbox in structural bioinformatics for protein modeling from sequence to the prediction of 3D structure. In addition, the users can take benefits of PyProtModel in order to prepare and evaluate protein PDB files prior to other in silico experiments. PyProtModel allows the user to apply different MODELLER options, automates, and speeds up time-consuming homology modeling steps. Different aspects of PyProtModel and a comprehensive view of the application will be discussed in this paper. The application is available for download and use at: https://github.com/msisakht/pyprotmodel.git.

Adrenomedullin increases cAMP accumulation and BDNF expression in rat DRG and spinal motor neurons.

OBJECTIVES: Adrenomedullin (AM) has high expression in the spinal cord. In this study, we investigated the expression of AM and its receptor components, including calcitonin receptor-like receptor (CLR) and receptor activity modifying proteins (RAMPs) in dorsal root ganglion (DRG) and spinal motor (SM) neurons. Furthermore, the effects of AM on cAMP/cAMP response element-binding protein (CREB), AKT/glycogen synthase kinase-3 beta (GSK-3ß) signaling pathways, and expressions of brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were evaluated. MATERIALS AND METHODS: Rat embryonic DRG and SM neurons were isolated, purified, and cultured. Real-time PCR was used to assess expressions of AM, CLR, and RAMPs. cAMP levels, p-CREB, BDNF, and NT-3 were determined using an enzyme-linked immunosorbent assay. p-AKT and p-GSK-3ß levels were determined by western blotting. Real-time PCR showed expressions of AM, CLR, RAMP2, and RAMP3 in both DRG and SM neurons. RESULTS: AM increased cAMP accumulation and p-CREB levels in DRG and SM neurons. AM increased p-AKT and p-GSK-3ß in DRG, but not SM neurons. AM significantly increased BDNF expression in both DRG and SM neurons. There was also an increase in NT-3 level in both DRG and SM neurons, which is statistically significant in SM neurons. CONCLUSION: These results showed both DRG and SM neurons are targets of AM actions in the spinal cord. An increase in BDNF expression by AM in both DRG and SM neurons suggests the possible beneficial role of AM in protecting, survival, and regeneration of sensory and motor neurons.

Potential inhibitors of the main protease of SARS-CoV-2 and modulators of arachidonic acid pathway: Non-steroidal anti-inflammatory drugs against COVID-19.

The main protease of SARS-CoV-2 is one of the key targets to develop and design antiviral drugs. There is no general agreement on the use of non-steroidal anti-inflammatory drugs (NSAIDs) in COVID-19. In this study, we investigated NSAIDs as potential inhibitors for chymotrypsin-like protease (3CLpro) and the main protease of the SARS-CoV-2 to find out the best candidates, which can act as potent inhibitors against the main protease. We also predicted the effect of NSAIDs on the arachidonic pathway and evaluated the hepatotoxicity of the compounds using systems biology techniques. Molecular docking was conducted via AutoDock Vina to estimate the interactions and binding affinities between selected NSAIDs and the main protease. Molecular docking results showed the presence of 10 NSAIDs based on lower binding energy (kcal/mol) toward the 3CLpro inhibition site compared to the co-crystal native ligand Inhibitor N3 (-6.6 kcal/mol). To validate the docking results, molecular dynamic (MD) simulations on the top inhibitor, Talniflumate, were performed. To obtain differentially-expressed genes under the 27 NSAIDs perturbations, we utilized the L1000 final Z-scores from the NCBI GEO repository (GSE92742). The obtained dataset included gene expression profiling signatures for 27 NSAIDs. The hepatotoxicity of NSAIDs was studied by systems biology modeling of Disturbed Metabolic Pathways. This study highlights the new application of NSAIDs as anti-viral drugs used against COVID-19. NSAIDs may also attenuate the cytokine storm through the downregulation of inflammatory mediators in the arachidonic acid pathway.

Plant-derived chemicals as potential inhibitors of SARS-CoV-2 main protease (6LU7), a virtual screening study.

SARS-CoV-2 has caused millions of infections and more than 700,000 deaths. Taking the urgent need to find new therapeutics for coronavirus disease 2019 (COVID-19), a dataset of plant-based natural compounds was selected for the screening of antiviral activity. The viral 3-chymotrypsin-like cysteine protease (Mpro, 3CLpro) was selected as the target. Molecular docking was performed on 2,845 phytochemicals to estimate the spatial affinity for the active sites of the enzyme. The ADMET screening was used for the pharmacological and physicochemical properties of the hit compounds. Nelfinavir and Lopinavir were used as control for binding energy comparison. The top 10 hits, based on the binding energy (Kcal/mol), were Ginkgolide M (-11.2), Mezerein (-11), Tubocurarine (-10.9), Gnidicin (-10.4), Glycobismine A (-10.4), Sciadopitysin Z-10.2), Gnididin (-9.2), Glycobismine A (-10.4), Sciadopitysin (-10.2), Gnididin (-9.20, Emetine (-8.7), Vitexin (-8.3), Calophyllolide (-8.3), and 6-(3,3-Dimethylallyl)galangin (-7.9). The binding energy for nelfinavir and lopinavir were - 9.1 and - 8.4, respectively. Interestingly, some of these natural products were previously shown to possess antiviral properties against various viruses, such as HIV, Zika, and Ebola viruses. Herein, we suggest several phytochemicals as the inhibitors of the main protease of SARS-CoV-2 that could be used in the fight against COVID-19.

The effectiveness of pistachio on glycemic control and insulin sensitivity in patients with type 2 diabetes, prediabetes and metabolic syndrome: A systematic review and meta-analysis.

BACKGROUND AND AIMS: Pistachio nuts have been considered to improve dysglycemia. However, there are controversial results. This systematic review and meta-analysis carried out to evaluate the effects of pistachio nuts on glycemic control and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM), prediabetes, and metabolic syndrome. METHODS: Medline/PubMed, ProQuest, Web of Knowledge, Scopus, Cochrane library, and ScienceDirect were systematically searched to find randomized controlled trials (RCTs). Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) checklist was used to conduct the study. RESULTS: Six RCTs were included in the review. Treatment with pistachio nuts exerted a significant reduction in fasting blood glucose (FBG) level (OR = 1.7, 95% CI; 1.2-2.4, P = 0.002, I2 = 0.0%, P = 0.731) and homeostasis model assessment of insulin resistance (HOMA-IR) index (OR = 1.5, 95% CI; 1.0-2.4, P = 0.043, I2 = 0.0%, P = 0.617), but no significant improvement was observed in regard to hemoglobin A1c (HbA1c) level (OR = 1.4, 95% CI; 0.9-2.1 P = 0.089, I2 = 0.0%, P = 0.957) and fasting plasma insulin (FPI) level (OR = 1.3, 95% CI; 0.9-1.9, P = 0.133, I2 = 0.0%, P = 0.776). CONCLUSIONS: Pistachio nuts might cause a significant reduction in FBG and HOMA-IR, although HbA1c and FPI might not significantly improve in patients suffering from or at risk of T2DM.

Adrenomedullin protects rat dorsal root ganglion neurons against doxorubicin-induced toxicity by ameliorating oxidative stress.

OBJECTIVES: Despite effective anticancer effects, the use of doxorubicin (DOX) is hindered due to its cardio and neurotoxicity. The neuroprotective effect of adrenomedullin (AM) was shown in several studies. The present study aimed to evaluate the possible protective effects of AM against DOX-induced toxicity in dorsal root ganglia (DRGs) neurons. MATERIALS AND METHODS: Rat embryonic DRG neurons were isolated and cultured. The effect of various concentrations of DOX (0.0 to 100 µM) in the absence or presence of AM (3.125 -100 nM) on cell death, apoptosis, oxidative stress, expression of tumor necrosis-α (TNF-α), interleukin1- ß (IL-1ß), inducible nitric oxide synthase (iNOS), matrix metalloproteinase (MMP) 3 and 13, and SRY-related protein 9 (SOX9) were examined. RESULTS: Based on MTT assay data, DOX decreased the viability of DRG neurons in a dose and time-dependent manner (IC50=6.88 µm) while dose-dependently, AM protected DRG neurons against DOX-induced cell death. Furthermore, results of annexin V apoptosis assay revealed the protective effects of AM (25 nm) against DOX (6.88 µM)-induced apoptosis and necrosis of DRG neurons. Also, AM significantly ameliorated DOX-induced oxidative stress in DRG neurons. Real-time PCR results showed a significant increase in the expression of TNF-α, IL-1ß, iNOS, MMP 3, and MMP 13, and a decrease in the expression of SOX9 following treatment with DOX. Treatment with AM (25 nM) significantly reversed the effects of DOX on the above-mentioned genes expression. CONCLUSION: Our findings suggest that AM can be considered a novel ameliorating drug against DOX-induced neurotoxicity.

The role of radiation induced oxidative stress as a regulator of radio-adaptive responses.

Purpose: Various sources of radiation including radiofrequency, electromagnetic radiation (EMR), low- dose X-radiation, low-level microwave radiation and ionizing radiation (IR) are indispensable parts of modern life. In the current review, we discussed the adaptive responses of biological systems to radiation with a focus on the impacts of radiation-induced oxidative stress (RIOS) and its molecular downstream signaling pathways.Materials and methods: A comprehensive search was conducted in Web of Sciences, PubMed, Scopus, Google Scholar, Embase, and Cochrane Library. Keywords included Mesh terms of "radiation," "electromagnetic radiation," "adaptive immunity," "oxidative stress," and "immune checkpoints." Manuscripts published up until December 2019 were included.Results: RIOS induces various molecular adaptors connected with adaptive responses in radiation exposed cells. One of these adaptors includes p53 which promotes various cellular signaling pathways. RIOS also activates the intrinsic apoptotic pathway by depolarization of the mitochondrial membrane potential and activating the caspase apoptotic cascade. RIOS is also involved in radiation-induced proliferative responses through interaction with mitogen-activated protein kinases (MAPks) including p38 MAPK, ERK, and c-Jun N-terminal kinase (JNK). Protein kinase B (Akt)/phosphoinositide 3-kinase (PI3K) signaling pathway has also been reported to be involved in RIOS-induced proliferative responses. Furthermore, RIOS promotes genetic instability by introducing DNA structural and epigenetic alterations, as well as attenuating DNA repair mechanisms. Inflammatory transcription factors including macrophage migration inhibitory factor (MIF), nuclear factor κB (NF-κB), and signal transducer and activator of transcription-3 (STAT-3) paly major role in RIOS-induced inflammation.Conclusion: In conclusion, RIOS considerably contributes to radiation induced adaptive responses. Other possible molecular adaptors modulating RIOS-induced responses are yet to be divulged in future studies.

Bee venom induces apoptosis and suppresses matrix metaloprotease-2 expression in human glioblastoma cells

Abstract Glioblastoma is the most common malignant brain tumor representing with poor prognosis, therapy resistance and high metastasis rate. Increased expression and activity of matrix metalloproteinase-2, a member of matrix metalloproteinase family proteins, has been reported in many cancers including glioblastoma. Inhibition of matrix metalloproteinase-2 expression has resulted in reduced aggression of glioblastoma tumors in several reports. In the present study, we evaluated effect of bee venom on expression and activity of matrix metalloproteinase-2 as well as potential toxicity and apoptogenic properties of bee venom on glioblastoma cells. Human A172 glioblastoma cells were treated with increasing concentrations of bee venom. Then, cell viability, apoptosis, matrix metalloproteinase-2 expression, and matrix metalloproteinase-2 activity were measured using MMT assay, propidium iodide staining, real time-PCR, and zymography, respectively. The IC50 value of bee venom was 28.5 µg/ml in which it leads to decrease of cell viability and induction of apoptosis. Incubation with bee venom also decreased the expression of matrix metalloproteinase-2 in this cell line (p < 0.05). In zymography, there was a reverse correlation between bee venom concentration and total matrix metalloproteinase-2 activity. Induction of apoptosis as well as inhibition of matrix metalloproteinase-2 activity and expression can be suggested as molecular mechanisms involved in cytotoxic and antimetastatic effects of bee venom against glioblastoma cells.