Which neuroimaging and fluid biomarkers method is better in theranostic of Alzheimer's disease? An umbrella review.

Biomarkers are measured to evaluate physiological and pathological processes as well as responses to a therapeutic intervention. Biomarkers can be classified as diagnostic, prognostic, predictor, clinical, and therapeutic. In Alzheimer's disease (AD), multiple biomarkers have been reported so far. Nevertheless, finding a specific biomarker in AD remains a major challenge. Three databases, including PubMed, Web of Science, and Scopus were selected with the keywords of Alzheimer's disease, neuroimaging, biomarker, and blood. The results were finalized with 49 potential CSF/blood and 35 neuroimaging biomarkers. To distinguish normal from AD patients, amyloid-beta42 (Aß42), plasma glial fibrillary acidic protein (GFAP), and neurofilament light (NFL) as potential biomarkers in cerebrospinal fluid (CSF) as well as the serum could be detected. Nevertheless, most of the biomarkers fairly change in the CSF during AD, listed as kallikrein 6, virus-like particles (VLP-1), galectin-3 (Gal-3), and synaptotagmin-1 (Syt-1). From the neuroimaging aspect, atrophy is an accepted biomarker for the neuropathologic progression of AD. In addition, Magnetic resonance spectroscopy (MRS), diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), tractography (DTT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI), can be used to detect AD. Using neuroimaging and CSF/blood biomarkers, in combination with artificial intelligence, it is possible to obtain information on prognosis and follow-up on the different stages of AD. Hence physicians could select the suitable therapy to attenuate disease symptoms and follow up on the efficiency of the prescribed drug.

Caffeine attenuates spermatogenic disorders in mice with induced chronic scrotal hyperthermia.

OBJECTIVE: Chronic scrotal hyperthermia (SHT) can lead to serious disorders of the male reproductive system, with oxidative stress playing a key role in the onset of these dysfunctions. Thus, we evaluated the impact of caffeine, a potent antioxidant, on cellular and tissue disorders in mice with chronic SHT. METHODS: In this experimental study, 56 adult male NMRI mice were allocated into seven equal groups. Apart from the non-treated control group, all were exposed to heat stress. Two groups, termed "preventive" and "curative," were orally administered caffeine. The preventive mice began receiving caffeine immediately prior to heat exposure, while for the curative group, a caffeine regimen was initiated 15 consecutive days following cessation of heat exposure. Each treated group was subdivided based on pairing with a positive control (Pre/curative [Cur]+PC) or a vehicle (Pre/Cur+vehicle). Upon conclusion of the study, we assessed sperm characteristics, testosterone levels, stereological parameters, apoptosis, antioxidant and oxidant levels, and molecular markers. RESULTS: Sperm parameters, testosterone levels, stereological parameters, biochemical factors (excluding malondialdehyde [MDA]), and c-kit gene expression were significantly elevated in the preventive and curative groups, especially the former, relative to the other groups. Conversely, expression levels of the heat shock protein 72 (HSP72) and nuclear factor kappa beta (NF-κß) genes, MDA levels, and apoptotic cell density were markedly lower in both caffeine-treated groups relative to the other groups, with more pronounced differences observed in the preventive group. CONCLUSION: Overall, caffeine attenuated cellular and molecular abnormalities induced by heat stress in the testis, particularly in the mice treated under the preventive condition.

Cerebrospinal fluid and blood exosomes as biomarkers for amyotrophic lateral sclerosis; a systematic review.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Due to the limited knowledge about potential biomarkers that help in early diagnosis and monitoring disease progression, today's diagnoses are based on ruling out other diseases, neurography, and electromyography examination, which takes a time-consuming procedure. METHODS: PubMed, ScienceDirect, and Web of Science were explored to extract articles published from January 2015 to June 2023. In the searching strategy following keywords were included; amyotrophic lateral sclerosis, biomarkers, cerebrospinal fluid, serum, and plama. RESULTS: A total number of 6 studies describing fluid-based exosomal biomarkers were included in this study. Aggregated proteins including SOD1, TDP-43, pTDP-43, and FUS could be detected in the microvesicles (MVs). Moreover, TDP-43 and NFL extracted from plasma exosomes could be used as prognostic biomarkers. Also, downregulated miR-27a-3p detected through exoEasy Maxi and exoQuick Kit in the plasma could be measured as a diagnostic biomarker. Eventually, the upregulated level of CORO1A could be used to monitor disease progression. CONCLUSION: Based on the results, each biomarker alone is insufficient to evaluate ALS. CNS-derived exosomes contain multiple ALS-related biomarkers (SOD1, TDP-43, pTDP-43, FUS, and miRNAs) that are detectable in cerebrospinal fluid and blood is a proper alternation. Exosome detecting kits listed as exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus, and Exo-Flow, are helpful to reach this purpose.

All-trans retinoic acid and fibroblast growth factor-2 enhance the fertility rate and embryo development in polycystic ovary syndrome mouse model.

Objectives: Polycystic ovary syndrome (PCOS) causes a developmental arrest of antral follicles and disrupts oocyte maturation. Retinoic acid (RA) and Fibroblast Growth Factor-2 (FGF2) are effective in follicle growth, thus their effects on histopathology and in vitro fertility of oocytes were investigated in PCOS-induced mice. Materials and Methods: Eighty female NMRI mice were randomly divided into 8 groups including 1-Normal mice, 2-PCOS mice without any treatment, 3-Normal mice treated with RA, 4-Normal mice treated with FGF2, 5-PCOS mice treated with RA, 6- PCOS mice treated with FGF2, 7- PCOS mice treated with RA and FGF2, and 8- Normal mice treated with RA and FGF2. Following PCOS induction, the mice were treated with intraperitoneal RA and FGF2 as a treatment. Then ovarian stimulation, for preparing the oocyte and embryo microscopic examinations was performed. After oocyte morphometry, through in vitro fertilization, the embryo formation was assessed. Data was analyzed by one-way ANOVA and Tukey tests. Results: The results showed simultaneous injection of RA and FGF2 into PCOS-induced mice increases antral follicles and corpus luteum, but decreases cystic follicles. Simultaneous injection of these two substances into healthy mice increases the pre-antral follicles and corpus luteum. Simultaneous injection of RA and FGF2 increases the number of embryos in both control and intervention groups. Conclusion: It can be concluded that RA and FGF2 increase the maturity of ovarian follicles, the number of two-celled embryos, and the number of grade-A embryos in mice with PCOS, which is more effective when these two substances are injected simultaneously.

Intranasal delivery of sunitinib: A new therapeutic approach for targeting angiogenesis of glioblastoma.

Glioblastoma multiforme (GBM) is one of the most vascular among solid tumors, and despite the use of multimodal therapies, the survival of these patients is poor. In order to target angiogenesis in GBM as a promising strategy, an antiangiogenic drug is required. This study was designed to evaluate the effects of sunitinib, a multityrosine kinase inhibitor with tumor proliferation and angiogenesis inhibitory properties, on GBM-bearing rats. Given the ineffective drug delivery to the brain due to the presence of the blood-brain barrier (BBB), intra-nasal (IN) drug delivery has recently been considered as a non-invasive method to bypass BBB. Therefore, in the current study, IN was used as an ideal method for the delivery of sunitinib to the brain, and the effects of this method were also compared to the OR administration of the sunitinib. GBM was induced in the brain of male Wistar rats, and they were randomly divided into 4 groups; IN-STB (sunitinib intranasal delivery), IN-sham (placebo intranasal delivery), OR-STB (sunitinib oral delivery) and OR-sham (placebo oral delivery). After the end of the treatment period, an MRI of animals' brains showed a reduction in tumor growth in the treatment groups. Immunohistochemistry revealed that sunitinib inhibits angiogenesis in GBM in both OR and IN delivery methods. Analysis of liver tissue and enzymes showed that IN delivery of sunitinib had less hepatotoxicity than the OR method. Overall, it was found that IN sunitinib delivery could be used as a potential non-hepatotoxic alternative for the treatment of GBM.

Protective effects of epigallocatechin gallate in the mice induced by chronic scrotal hyperthermia.

One of the most common complications of chronic scrotal hyperthermia (SHT) is a serious disorder in the male reproductive system. The most important factor in the occurrence of these disorders is oxidative stress. Currently, we investigated the effects of epigallocatechin gallate (EGCG), as a highly potent antioxidant, against cells and tissue disorders in mice affected by chronic SHT. Fifty-six male adult NMRI mice were allocated into seven equal groups. Except the non-treated (Control) group, six other groups were exposed to heat stress. Two treated groups including Preventive and Curative received oral administration of EGCG (50 mg/kg/day) starting immediately before heat exposure and fifteen consecutive days after the end of the heat exposure, respectively. For each treated group, two subgroups including positive control (Pre/Cur + PC groups) and vehicle (Pre/Cur + vehicle groups) were considered. At the end of the study, sperm characteristics, testosterone levels, stereological parameters, apoptosis, oxidant state, and molecular assessments were performed. We found that the sperm parameters, testosterone levels, the numerical density of spermatogonia, primary spermatocytes, spermatids, sertoli, leydig cells, and seminiferous tubules, biochemical factors (except MDA), and expression of c-kit gene were significantly higher in the Preventive and Curative groups, especially in Preventive ones, compared to other groups (P < 0.05). This is while expression of HSP72 and NF-κß genes, MDA levels, as well as density of apoptotic cells considerably decreased in both EGCG-treated groups compared to other groups and it was more pronounced in Preventive ones (P < 0.05). Generally, EGCG attenuated cellular and molecular disorders induced by heat stress in the testis and it was more pronounced in Preventive status.

In Silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer's Disease: Prospects for Designing New Therapeutics Compound.

Memory impairment is a result of multiple factors including amyloid-beta (Aß) accumulation. Several receptors are mediated for Aß transport and signaling. Moreover, blood lipids are involved in Aß signaling pathway through these receptors. Mediated blood lipid level by statins aims to regulate Aß signaling cascade. First, the structure of receptors was taken from the RCSB PDB database and prepared with MGLTools and AutoDock tool 4. Second, the ligand was prepared for docking through AutoDock Vina. The binding affinity was calculated, and the binding sites were determined through LigPlot+ software. Besides, pharmacokinetic properties were calculated through multiple software. Finally, a molecular dynamics (MD) simulation was conducted to evaluate ligands stability along with clustering analysis to evaluate proteins connection. Our molecular docking and dynamic analyses revealed silymarin as a potential inhibitor of acetylcholinesterase (AChE), P-glycoprotein, and angiotensin-converting enzyme 2 (ACE2) with 0.704, 0.85, and 0.83 Å for RMSD along with -114.27, -107.44, and -122.51 kcal/mol for free binding energy, respectively. Moreover, rosuvastatin and quercetin have more stability compared to silymarin and donepezil in complex with P-glycoprotein and ACE2, respectively. Eventually, based on clustering and pharmacokinetics analysis, silymarin, rosuvastatin, and quercetin are suggested to be involved in peripheral clearance of Aß. The bioactivity effects of mentioned statins and antioxidants are predicted to be helpful in treating memory impairment in Alzheimer's disease (AD). Nevertheless, mentioned drug effect could be improved by nanoparticles to facilitate penetration of the blood-brain barrier (BBB).

In-vivo and in vitro assessments of the radioprotective potential natural and chemical compounds: a review.

PURPOSE: The study of the radioactive role of natural and chemical substances on human and animal studies has been the subject of research by some researchers. Therefore, the review of some of the past and current studies conducted in this field, can provide helpful information to elucidate of the importance of radioprotective components in reducing radiation exposure side effects. METHODS: The authors search for keywords including In vitro, In vivo, Radioprotective, Ionizing radiation, and Vitamin in ScienceDirect, Scopus, Pubmed, and Google Scholar databases to access previously published articles and search for more reference articles on the role of radioprotective materials from natural and chemical compounds. RESULTS: Radiation exposure can produce reactive oxygen species (ROS) in the body, however most of which are eliminated by the body's natural mechanisms, but when the body's antioxidant systems do not have enough ability to neutralize free radicals, oxidative stress occurs, which causes damage to DNA and body tissues. Therefore, it is necessary use of alternative substances that reduce and inhibit free radicals. CONCLUSION: In general, recommended that antioxidant component(s) can be protect tissue damages in humans or animals, due to the their ability to scavenge free radicals generated by ionizing radiation.

Promotion of cutaneous diabetic wound healing by subcutaneous administration of Wharton's jelly mesenchymal stem cells derived from umbilical cord.

Wound healing is a major problem in diabetic patients, and current treatments have been confronted with limited success. The present study examined the benefit of Wharton's jelly mesenchymal stem cells (WJ-MSCs) derived from the human umbilical cord (UC) in wound healing in diabetic rats. Thirty days after inducing diabetes, a circular excision was created in the skin of rats, and the treatments were performed for 21 days. Two groups were studied, which included the Control group and WJ-MSCs group. The studied groups were sampled on the 7th, 14th, and 21st days after wounding. Histological ultrasound imaging of dermis and epidermis in the wound area for thickness and density measurement and skin elasticity were evaluated. Our results on post-wounding days 7, 14, and 21 showed that the wound closure, thickness, and density of new epidermis and dermis, as well as skin elasticity in the healed wound, were significantly higher in the WJ-MSCs group compared to the Control group. Subcutaneous administration of WJ-MSCs in diabetic wounds can effectively accelerate healing. Based on this, these cells can be used along with other treatment methods in the healing of different types of chronic wounds.

Neurochemical Ameliorating of the Hippocampus in Dyslipidemic Alzheimer Patients Following Silymarin; a Double-Blind Placebo-Controlled Randomized Clinical Trial.

Background: Amyloid-beta (Aß) production is a normal physiological process, and an imbalance in Aß production/excretion rate is the basis of the plaque load increase in AD. LRP1 is involved in both central clearance of Aß from the CNS and transport of Aß toward peripheral organs. In this study, the effect of silymarin combination compared to rosuvastatin and placebo on neuro-metabolites and serum levels of LRP1 and Aß1-42 proteins and oxidative stress enzymes and lipid and cognitive tests of Iranian AD patients. Methods: In this double-blind placebo-controlled study, thirty-six mild AD patients were divided into groups (n=12) of silymarin 140mg, placebo, and rosuvastatin 10mg. Medications were administered 3 times a day for 6 months. Clinical tests, lipid profile (TG, HDL, TC, and LDL), Aß1-42, and LRP1 markers were measured at the beginning and end of the intervention. Magnetic resonance spectroscopy (MRS) was used to measure metabolites. Using SPSS software a one-way ANOVA test was used to compare the means of the quantitative variables and Pearson and Spearman's correlations to measure the correlation. GraphPad Prism software was used for drawing graphs. P < 0.05 was considered a significant. Results: The levels of LRP1 and Aß1-42 in the silymarin group were significantly increased compared to the other groups (P < 0.05). NAA/mI in the silymarin group had a significant increase compared to both placebo and rosuvastatin groups (P < 0.05). Right and left hippocampal mI/Cr directly correlated with TG (r = 0.603, P = 0.003 and r = 0.595, P = 0.004, respectively). NAA/Cr of the right and left hippocampus was inversely related to TG (r = -0.511, P = 0.0033, and r = -0.532, P = 0.0021, respectively). NAA/Cr and NAA/mI of bilateral hippocampi directly correlated with HDL (P < 0.05). An inverse correlation was observed between the Aß1-42 and mI/Cr of the right and left hippocampus (r = -0.661, P = 0.000 and r = -0.638, P = 0.000, respectively). Conclusion: Donepezil and silymarin improved lipid profile associated with increased NAA/Cr, and decreased mI/Cr, in AD patients. Biomarker NAA/mI can be clinically significant in examining AD pathology. Measurement of the lipid factors and neurometabolites can be a suitable method for monitoring this disease.

Stem cell therapy for cuprizone model of multiple sclerosis focusing on the effectiveness of different injection methods and cell labeling.

Multiple Sclerosis (MS) is a chronic and autoimmune disease of the central nervous system that causes inflammation in the brain and spinal cord, progressive degeneration of central nervous system tissue, damage to neuronal axons, and loss of function of central nervous system neurons. Experimental encephalomyelitis is an alternative animal model of MS that can simulate the symptoms of this disease. Cuprizone is one of the factors creating this model. Various researchers are testing the use of different cells to reduce the symptoms of cuprizone-demyelinated mice. The different injection methods explained in this article include intracerebral, intraperitoneal, intravenous, and intranasal. The intracerebral method, in contrast to the intranasal method, was widely employed by researchers. In each technique, the researchers try to inject a specific type of stem cell (SC) and monitor their efficiency. For monitoring SCs various labeling procedures are available, however, there is an upward trend in using magnetic resonance imaging (MRI). Two main barriers to using this method are high cost and complexity. In the current review, we try to make review cell therapy in the cuprizone model of MS.

Neuroprotective effects of lovastatin against traumatic spinal cord injury in rats.

BACKGROUND: Lovastatin, as a drug of statins subgroup, has been conceptualized to have anti-inflammatory, antioxidant, and anti-apoptotic properties. Accordingly, the present study aimed to investigate the neuroprotective ramification of lovastatin on spinal cord injury (SCI). MATERIAL AND METHODS: Seventy-five female adult Wistar rats were divided into five groups (n = 15). In addition to non-treated (Control group) and laminectomy alone (Sham group), SCI animals were randomly assigned to non-treated spinal cord injury (SCI group), treated with 2 mg/kg of lovastatin (Lova 2 group), and treated with 5 mg/kg of lovastatin (Lova 5 group). At the end of the study, to evaluate the treatments, MDA, CAT, SOD, and GSH factors were evaluated biochemically, apoptosis and gliosis were assessed by immunohistochemical while measuring caspase-3 and GFAP antibodies, and inflammation was estimated by examining the expression of IL-10, TNF-α, and IL-1ß genes. The stereological method was used to appraise the total volume of the spinal cord at the site of injury, the volume of the central cavity created, and the density of neurons and glial cells in the traumatic area. In addition, Basso-Beattie-Bresnehan (BBB) and narrow beam test (NBT) were utilized to rate neurological functions. RESULTS: Our results exposed the fact that biochemical factors (except MDA), stereological parameters, and neurological functions were significantly ameliorated in both lovastatin-treated groups, especially in Lova 5 ones, compared to the SCI group. The expression of the IL-10 gene was significantly upregulated in both lovastatin-treated groups compared to the SCI group and was considerably heighten in Lova 5 group. Expression of TNF-α and IL-1ß, as well as the rate of apoptosis and GFAP positive cells significantly decreased in both lovastatin treated groups compared to the SCI group, and it was more pronounced in the Lova 5 ones. CONCLUSION: Overall, using lovastatin, especially at a dose of 5 mg/kg, has a dramatic neuroprotective impact on SCI treatment.

Silk fibroin and Nettle extract promote wound healing in a rat model: A histological and morphometrical study.

INTRODUCTION: Considering the anti-inflammatory, antimicrobial ability, and antioxidant effects besides stimulating ability of silk fibroin (SF) in cell migration and proliferation of Nettle, the current study aimed to investigate the effect of Nettle leaf extract (NLE) and SF on histology, morphometrical parameters and apoptosis on the wound in the rat model. MATERIALS AND METHODS: Wistar rats are divided into 5 groups, including 1-control (rats with healthy skin and no treatment); 2-wound (without any treatment); 3-SF (administration of silk fibroin solution for 14 consecutive days); 4- Nettle (administration of Nettle ointment for 14 consecutive days), and 5- Eucerin group (administration of Eucerin substance for 14 consecutive days) and then assessed wound area by photography, angiogenesis, inflammation, and thickness of epidermis using hematoxylin and eosin (H&E) staining, collagen deposition, and structure of dermis layers evaluated by Masson's trichrome staining and the apoptosis index determined by tunnel assay on days 7, 14 and 21. RESULTS: photographic illustrations showed that the wound surface environment on the seventh day in group 4 was significantly different from group 2 (p < 0.002). The rate of wound healing on the fourteenth day was higher in groups 3 and 4 than in group 2 (p < 0.001). Also, at this time, group 4 was significantly different from group 3 and group 5 (p = 0.003 and p = 0.000, respectively). There was a significant difference in epidermal thickness between the wound group and other experimental groups (p < 0.05). The number of apoptotic cells at the wound edges on the seventh day in both group 3 and group 4 had a significant decrease compared to other groups of wounds (p = 0.000), but there was a significant increase on the fourteenth day. Also, on the 21st day, a significant decrease in apoptotic cells was observed in both group 3 and group 4 compared to other wound groups (p = 0.000). DISCUSSION AND CONCLUSION: Nettle and SF maintain cell homeostasis and accelerate wound closure by reducing cell apoptosis and enhancing cell proliferation on the seventh day, but by increasing the apoptosis of fibroblast cells on the fourteenth day, they lead to remodeling and keratinocytes migration to epidermis formation. Increased apoptosis also seems to be one of the pathophysiological mechanisms to prevent the formation of keloid and hypertrophic scar tissue. SF and Nettle extract, by increasing cell proliferation and migration of different cell types to the site of injury, control the remodeling process by inducing and regulating apoptosis in the first two weeks of wound healing and accelerating the process of collagen deposition and epithelialization.

Caffeine modulates apoptosis, oxidative stress, and inflammation damage induced by tramadol in cerebellum of male rats.

Tramadol, an opioid used as analgesic, can induce neurotoxic effects associated to cognitive dysfunction. Moreover, caffeine has been reported to have neuroprotective effects. In this regard, we hypothesized that administration of caffeine can modulate tramadol-induced damages in cerebellum. For this study, forty male Wistar rats were divided into four groups: the control group, the tramadol group (50 mg/kg), the caffeine group (37.5 mg/kg), and the tramadol+caffeine group (50 mg/kg tramadol+37.5 mg/kg caffeine). At the end of study (day 21), after performing rotarod behavioral test, cerebellum tissue samples were removed and prepared for further evaluations including biochemical profile markers (MDA, GPx, and SOD), immunohistochemistry for Caspase-3, as well as the expression of genes involved in cellular processes such as inflammation markers (IL-1ß, HMGB1, IL-6, and TNF), apoptosis markers (Caspase-3, Caspase-8, Bax, and P21), and autophagy markers (LAMP2, ATG5, BECN1, and ATG12). Stereological evaluations were performed to determine the total volume of granular and molecular layers and white matter of cerebellum tissue and numerical density of the Purkinje cells. Our results showed that the stereological parameters, biochemical profiles (except MDA) and behavioral function were significantly higher in the tramadol+caffeine group compared to the tramadol group. Autophagy-related genes were significantly upregulated in tramadol+caffeine group compared to the tramadol group. While the expression of inflammatory and apoptosis genes, MDA level, as well as density of apoptosis cells were significantly lower in the tramadol+caffeine group compared to the tramadol group. Briefly, it can be concluded that administration of caffeine has neuroprotective effects in cerebellar damages induced by tramadol.

Topical spray of Wharton's jelly mesenchymal stem cells derived from umbilical cord accelerates diabetic wound healing.

BACKGROUND AND AIM: Cell-based therapy utilizing mesenchymal stem cells (MSCs) is currently being investigated as a therapeutic agent for chronic wounds. There is no evidence regarding effectiveness of the spray and local transfer of this cellular product in diabetic wound healing. Accordingly, the present study, using clinical, pathological and biometric parameters, investigated the effectiveness of the spray of these cells in the healing of diabetic wounds in rats. METHODS: Three days after the induction of diabetes (50 mg/kg single dose of streptozotocin) a circular excision was created on the back of rats. Diabetic rats were divided into two groups (n = 21): Control and WJ-MSCs group. Sampling of the studied groups was performed on Days 7, 14, and 21 after wounding. Histological, ultrasound imaging of dermis and epidermis in the wound area for thickness and density measurement and skin elasticity were evaluated. RESULTS: Our results on Days 7, 14, and 21 after wounding showed that the wound closure, thickness, and density of new epidermis and dermis, as well as skin elasticity in healed wound were significantly higher in WJ-MSCs group compared with the Control group. CONCLUSION: Application of WJ-MSCs suspension spray on the wound area can accelerate healing in diabetic wounds. Our findings may potentially provide a helpful therapeutic strategy for patients with a diabetic wound.