Advances in stimuli-responsive gold nanorods for drug-delivery and targeted therapy systems.

In recent years, the use of gold nanorods (AuNRs) has garnered considerable attention in biomedical applications due to their unique optical and physicochemical properties. They have been considered as potential tools for the advanced treatment of diseases by various stimuli such as magnetic fields, pH, temperature and light in the fields of targeted therapy, imaging and drug delivery. Their biocompatibility and tunable plasmonic properties make them a versatile platform for a range of biomedical applications. While endogenous stimuli have limited cargo delivery control at specific sites, exogenous stimuli are a more favored approach despite their circumscribed penetration depth for releasing the cargo at the specific target. Dual/multi-stimuli responsive AuNTs can be triggered by multiple stimuli for enhanced control and specificity in biomedical applications. This review provides to provide a summary of the biomedical applications of stimuli-responsive AuNRs, including their endogenous and exogenous properties, as well as their dual/multi-functionality and potential for clinical delivery. This review provides a comprehensive review on the improvement of therapeutic efficacy and the effective control of drug release with AuNRs, highlights AuNRs design strategies in recent years, discusses the advantages or challenges so far in the field of AuNRs. Finally, we have addressed the clinical translation bio-integrated nanoassemblies (CTBNs) in this field.

Changes in D4 and GABAA subunit α3 receptors in the thalamic reticular nucleus caused by unilateral lesion of the globus pallidus.

The thalamic reticular nucleus controls information processing in thalamocortical neurons. GABAergic neurons present in this nucleus express the α3 subunit of post­synaptic GABAA receptors, which bind GABA from globus pallidus neurons. Pallidal neurons, in turn, have dopaminergic D4 receptors in their axon terminals. The thalamic reticular nucleus connects reciprocally with the thalamus, and it receives afferents from the brain cortex, as well as from other brain structures that have an important role in the modulation of the thalamic network. Based on the above, the purpose of this study was to assess the electrophysiological and molecular effects of unilateral lesion of the globus pallidus on the electric activity of the thalamic reticular nucleus. Two­month­old male rats were used. The right globus pallidus was lesioned with quinolinic acid. Seven days after the lesion, ipsilateral turning was registered, confirming the lesion. Afterward, electrophysiological evaluation of the right thalamic reticular nucleus' electrical activity was performed. Subsequently, mRNA expression for D4 receptors and subunit α3, as well as protein content were assessed in the right reticular nucleus. Pallidum lesion caused an increase in firing frequency and decreased firing bursts of reticular neurons. In addition, dopaminergic D4 mRNA, as well as protein increased. In contrast, GABAergic GABAA subunit α3 expression was suppressed, but protein content increased. These results show that the globus pallidus regulates firing in reticular neurons through D4 receptors and subunit α3 of GABAA receptor in the reticular nucleus of the thalamus.

Protective effects of silymarin on preventing vancomycin nephrotoxicity in infectious patients: a randomized, double-blinded, placebo-controlled, pilot clinical trial.

Nephrotoxicity is one of the most common complications of vancomycin use in clinical practice. Silymarin has potential to be a renoprotective agent for nephrotoxic drugs due to its antioxidant, anti-inflammatory, and anti-apoptotic effects. The aim of this clinical study is evaluating the potential effects of silymarin on preventing vancomycin nephrotoxicity. A multicenter, randomized, double-blinded, placebo-controlled, clinical trial was conducted on patients with the indication of systemic vancomycin for at least 7 days. Patients were screened daily and those who met the inclusion criteria were selected and randomly assigned into either silymarin or placebo groups. Accordingly, 140 mg silymarin tablet (Livergol®) or placebo was given orally three times daily. Silymarin or placebo were provided in conjunction with vancomycin for at least 7 days. If vancomycin therapy was extended beyond 7 days, the administration of silymarin or placebo was continued until the end of vancomycin treatment. Malondialdehyde, glutathione, and total antioxidant capacity were measured in the serum on days 0 and 7. A trough level of vancomycin was assessed 30 min before the fifth dose of vancomycin. Acute kidney injury (AKI) was monitored in each patient daily during the course of vancomycin treatment. The causality assessment of all identified cases of vancomycin associated AKI was performed by the Naranjo scale. The primary endpoint was vancomycin nephrotoxicity. It was defined based on the KDIGO 2012 criteria for AKI as either an increase of 0.3 units or more in serum creatinine level during 48 h or 50% (1.5-fold) or more during 7 days compared to baseline values. During the study period, 34 patients in the silymarin group and 32 patients in the placebo group completed the clinical trial. Demographic, baseline clinical, and laboratory characteristics were comparable between placebo and silymarin groups. The number of patients with AKI on days 5, 6, 7, 11,12, 13, and 14 in the placebo group was significantly higher than that in the silymarin group (p-value < 0.05). The incidence of acute tubular injury on the day  5 and 7 of vancomycin treatment was significantly lower in the silymarin group (p-value = 0.005 and p-value = 0.032, respectively). Antioxidant indexes including serum total antioxidant capacity and glutathione significantly increased in the silymarin group (p-value < 0.001 for both indexes). In contrast, serum malondialdehyde as an end product of lipid peroxidation pathway significantly decreased in the silymarin group during 7 days (p-value < 0.001). The results of the present pilot, clinical trial suggested that silymarin co-administration may prevent vancomycin nephrotoxicity.

Safety and potential effects of intrathecal injection of allogeneic human umbilical cord mesenchymal stem cell-derived exosomes in complete subacute spinal cord injury: a first-in-human, single-arm, open-label, phase I clinical trial.

OBJECTIVE: Neurological and functional impairments are commonly observed in individuals with spinal cord injury (SCI) due to insufficient regeneration of damaged axons. Exosomes play a crucial role in the paracrine effects of mesenchymal stem cells (MSCs) and have emerged as a promising therapeutic approach for SCI. Thus, this study aimed to evaluate the safety and potential effects of intrathecal administration of allogeneic exosomes derived from human umbilical cord MSCs (HUC-MSCs) in patients with complete subacute SCI. METHODS: This study was a single-arm, open-label, phase I clinical trial with a 12-month follow-up period. HUC-MSCs were extracted from human umbilical cord tissue, and exosomes were isolated via ultracentrifugation. After intrathecal injection, each participant a underwent complete evaluation, including neurological assessment using the American Spinal Injury Association (ASIA) scale, functional assessment using the Spinal Cord Independence Measure (SCIM-III), neurogenic bowel dysfunction (NBD) assessment using the NBD score, modified Ashworth scale (MAS), and lower urinary tract function questionnaire. RESULTS: Nine patients with complete subacute SCI were recruited. The intrathecal injection of allogeneic HUC-MSCs-exosomes was safe and well tolerated. No early or late adverse event (AE) attributable to the study intervention was observed. Significant improvements in ASIA pinprick (P-value = 0.039) and light touch (P-value = 0.038) scores, SCIM III total score (P-value = 0.027), and NBD score (P-value = 0.042) were also observed at 12-month after the injection compared with baseline. CONCLUSIONS: This study demonstrated that intrathecal administration of allogeneic HUC-MSCs-exosomes is safe in patients with subacute SCI. Moreover, it seems that this therapy might be associated with potential clinical and functional improvements in these patients. In this regard, future larger phase II/III clinical trials with adequate power are highly required. TRIAL REGISTRATION: Iranian Registry of Clinical Trials, IRCT20200502047277N1. Registered 2 October 2020, https://en.irct.ir/trial/48765 .

A thermoresponsive chitosan-based in situ gel formulation incorporated with 5-FU loaded nanoerythrosomes for fibrosarcoma local chemotherapy.

Local administration of drugs at tumor sites over an extended period of time shows potential as a promising approach for cancer treatment. In the present study, the temperature-induced phase transition of chitosan and poloxamer 407 is used to construct an injectable hydrogel encapsulating 5-FU-loaded nanoerythrosome (5-FU-NER-gel). The 5-FU-NERs were found to be spherical, measuring approximately 115 ± 20 nm in diameter and having a surface potential of -7.06 ± 0.4. The drug loading efficiency was approximately 40 %. In situ gel formation took place within 15 s when the gel was exposed to body temperature or subcutaneous injection. A sustained release profile was observed at pH 7.4 and 6.8, with a total 5-FU release of 76.57 ± 4.4 and 98.07 ± 6.31 in 24 h, respectively. MTT, Live/dead, and migration assays confirmed the cytocompatibility of the drug carrier and its effectiveness as a chemotherapeutic formulation. After in vivo antitumor assessment in a subcutaneous autograft model, it was demonstrated that tumor growth inhibition in 14 days was 90 %. Therefore, the obtained injectable chitosan-based hydrogel containing 5-FU-loaded nanoerythrosomes illustrated promising potential as a candidate for local and enhanced delivery of chemotherapeutics at the tumor site.

Trinitroglycerin-loaded chitosan nanogels accelerate angiogenesis in wound healing process.

Trinitroglycerin (TNG) with remarkable angiogenic, antibacterial, and antioxidative activity is a promising candidate to govern wound healing capacity. However, its clinical administration is limited due to associated complications and NO short half-life. In the current study, TNG-loaded chitosan nanogels (TNG-Ngs) were examined in-vitro and in-vivo to gain insight into their clinical application. We prepared TNG-Ngs and characterized their physiochemical properties. The potential of TNG-Ngs was assessed using biocompatibility, scratch assay, and a full-thickness skin wounds model, followed by histopathological and immunohistochemistry examinations. TNG-Ngs particle size 96 ± 18 and definite size distribution histogram. The loading capacity (LC) and encapsulation efficiency (EE) of prepared TNG-Ngs were 70.2 % and 2.1 %, respectively. The TNG-Ngs samples showed enhanced migration of HUVECs with no apparent cytotoxicity. The topical use of TNG-Ngs200 on the wounds revealed a complete wound closure ratio, skin component formation, less scar width, remarkable granulation tissue, promoted collagen deposition, and enhanced the relative mean density of α-SMA and CD31. TNG-Ngs accelerated wound healing by promoting collagen deposition and angiogenic activity, as well as reducing inflammation. The findings indicated that TNG-Ngs is expected to be well vascularized in the wound area and to be more effective in topical therapy.

In Vitro and In Vivo Evaluation of Electrospun PVA Nanofiber Containing ZnO/Curcumin for Wound Healing Application.

The development of biocompatible wound dressings containing therapeutic agents to accelerate wound healing is an interesting field of study in biomedical sciences. Polyvinyl alcohol (PVA) nanofibers were loaded with zinc oxide nanoparticles (ZnO NPs) and curcumin (Cur) through electrospinning. The dressings were characterized by SEM and XRD and FTIR. The antioxidant, antibacterial, and cytotoxic activities Cur/ZnO/PVA nano dressing were evaluated using DPPH radical scavenging assay, disc diffusion method, and MTT assay, respectively. Cur/ZnO/PVA nano dressing showed sustained Cur release about 19.7% and 61.1% after 8h and 168h, respectively. Cur/ZnO NPs/PVA mixture had higher antioxidant potential than PVA, ZnO NPs, and Cur. The dressing showed a good antibacterial effect. The in vivo wound healing effect of different types of prepared dressings, including PVA, Cur/PVA, Cur/ZnO/PVA, and ZnO/ PVA nanofibers, was also investigated. PVA dressing containing Cur/ZnO NPs resulted in the highest increase of wound contraction in rats. The assembly of Cur and ZnO NPs on PVA nanofibers could propose as an effective delivery method to improve the wound healing process. The investigated wound dressing could be commercialized and used on a large scale after proper further studies, including clinical trials.

Differential methylation of DNA promoter sequences in peripheral blood mononuclear cells as promising diagnostic biomarkers for colorectal cancer.

OBJECTIVES: Previous reports have indicated that the methylation profile in peripheral blood mononuclear cells (PBMCs) in different genes and loci is altered in colorectal cancer (CRC). Regarding the high mortality rate and silent nature of CRC, screening and early detection can meaningfully reduce disease-related deaths. Therefore, for the first time, we aimed to evaluate the early non-invasive diagnosis of CRC via quantitative promoter methylation analysis of RUNX3 and RASSF1A genes in PBMCs. MATERIALS AND METHODS: In the present study, we analyzed the methylation status of two important tumor suppressor genes including RUNX3 and RASSF1A in 70 CRC patients and 70 non-malignant subjects using methylation-quantification of endonuclease-resistant DNA (MethyQESD), and a bisulfite conversion-independent method. RESULTS: RUNX3 was significantly hypermethylated in PBMCs of CRC patients compared to healthy controls (P < 0.001). By determining the efficient cutoff value, the sensitivity, and specificity of RUNX3 promoter methylation for CRC diagnosis reached 84.28% and 77.14%, respectively. The receiver operating characteristic (ROC) curve analyses demonstrated that RUNX3 promoter methylation has high accuracy (areas under the curve [AUC] = 0.840, P < 0.001) for discriminating CRC subjects from healthy individuals. Moreover, RUNX3 methylation levels in PBMCs progressively increased with the stage of the disease (P < 0.001). Although the amount of RASSF1A promoter methylation was not significantly different between CRC patients and controls as well as in different stages of the disease (P > 0.05). CONCLUSION: Our findings confirmed that PBMCs are reliable sources of methylation analysis for CRC screening, and RUNX3 promoter methylation can be used as a promising biomarker for early diagnosis of CRC.

Infectious Diarrhea Risks as a Public Health Emergency in Floods; a Systematic Review and Meta-Analysis.

Introduction: Infectious diarrhea, a significant global health challenge, is exacerbated by flooding, a consequence of climate change and environmental disruption. This comprehensive study aims to quantify the association between flooding events and the incidence of infectious diarrhea, considering diverse demographic, environmental, and pathogen-specific factors. Methods: In this systematic review and meta-analysis, adhering to PROSPERO protocol (CRD42024498899), we evaluated observational studies from January 2000 to December 2023. The analysis incorporated global data from PubMed, Scopus, Embase, Web of Science, and ProQuest, focusing on the relative risk (RR) of diarrhea post-flooding. The study encompassed diverse variables like age, sex, pathogen type, environmental context, and statistical modeling approaches. Results: The meta-analysis, involving 42 high-quality studies, revealed a substantial increase (RR = 1.40, 95% CI [1.29-1.52]) in the incidence of diarrhea following floods. Notably, bacterial and parasitic diarrheas demonstrated higher RRs (1.82 and 1.35, respectively) compared to viral etiologies (RR = 1.15). A significant sex disparity was observed, with women exhibiting a higher susceptibility (RR = 1.55) than men (RR = 1.35). Adults (over 15 years) faced a greater risk than younger individuals, highlighting age-dependent vulnerability. Conclusion: This extensive analysis confirms a significant correlation between flood events and increased infectious diarrhea risk, varying across pathogens and demographic groups. The findings highlight an urgent need for tailored public health interventions in flood-prone areas, focusing on enhanced sanitation, disease surveillance, and targeted education to mitigate this elevated risk. Our study underscores the critical importance of integrating flood-related health risks into global public health planning and climate change adaptation strategies.

Advancements in small interfering RNAs therapy for acute lymphoblastic leukemia: promising results and future perspectives.

Acute lymphoblastic leukemia (ALL) is the most common type of cancer among children, presenting significant healthcare challenges for some patients, including drug resistance and the need for targeted therapies. SiRNA-based therapy is one potential solution, but problems can arise in administration and the need for a delivery system to protect siRNA during intravenous injection. Additionally, siRNA encounters instability and degradation in the reticuloendothelial system, off-target effects, and potential immune system stimulation. Despite these limitations, some promising results about siRNA therapy in ALL patients have been published in recent years, showing the potential for more effective and precise treatment, reduced side effects, and personalized approaches. While siRNA-based therapies demonstrate safety and efficacy, addressing the mentioned limitations is crucial for further optimization. Advancements in siRNA-delivery technologies and combination therapies hold promise to improve treatment effectiveness and overcome drug resistance. Ultimately, despite its challenges, siRNA therapy has the potential to revolutionize ALL treatments and improve patient outcomes.

Enhancing volumetric muscle loss (VML) recovery in a rat model using super durable hydrogels derived from bacteria.

Bacteria can be programmed to deliver natural materials with defined biological and mechanical properties for controlling cell growth and differentiation. Here, we present an elastic, resilient and bioactive polysaccharide derived from the extracellular matrix of Pantoea sp. BCCS 001. Specifically, it was methacrylated to generate a new photo crosslinkable hydrogel that we coined Pantoan Methacrylate or put simply PAMA. We have used it for the first time as a tissue engineering hydrogel to treat VML injuries in rats. The crosslinked PAMA hydrogel was super elastic with a recovery nearing 100 %, while mimicking the mechanical stiffness of native muscle. After inclusion of thiolated gelatin via a Michaelis reaction with acrylate groups on PAMA we could also guide muscle progenitor cells into fused and aligned tubes - something reminiscent of mature muscle cells. These results were complemented by sarcomeric alpha-actinin immunostaining studies. Importantly, the implanted hydrogels exhibited almost 2-fold more muscle formation and 50 % less fibrous tissue formation compared to untreated rat groups. In vivo inflammation and toxicity assays likewise gave rise to positive results confirming the biocompatibility of this new biomaterial system. Overall, our results demonstrate that programmable polysaccharides derived from bacteria can be used to further advance the field of tissue engineering. In greater detail, they could in the foreseeable future be used in practical therapies against VML.

In vivo and ex vivo gene therapy for neurodegenerative diseases: a promise for disease modification.

Neurodegenerative diseases (NDDs), including AD, PD, HD, and ALS, represent a growing public health concern linked to aging and lifestyle factors, characterized by progressive nervous system damage leading to motor and cognitive deficits. Current therapeutics offer only symptomatic management, highlighting the urgent need for disease-modifying treatments. Gene therapy has emerged as a promising approach, targeting the underlying pathology of diseases with diverse strategies including gene replacement, gene silencing, and gene editing. This innovative therapeutic approach involves introducing functional genetic material to combat disease mechanisms, potentially offering long-term efficacy and disease modification. With advancements in genomics, structural biology, and gene editing tools such as CRISPR/Cas9, gene therapy holds significant promise for addressing the root causes of NDDs. Significant progress in preclinical and clinical studies has demonstrated the potential of in vivo and ex vivo gene therapy to treat various NDDs, offering a versatile and precise approach in comparison to conventional treatments. The current review describes various gene therapy approaches employed in preclinical and clinical studies for the treatment of NDDs, including AD, PD, HD, and ALS, and addresses some of the key translational challenges in this therapeutic approach.

Pesticide-Induced Alterations in Locomotor Activity, Anxiety, and Depression-like Behavior Are Mediated through Oxidative Stress-Related Autophagy: A Persistent Developmental Study in Mice.

Chlorpyrifos (CPF), dichlorvos (DDV), and cypermethrin (CP), as commonly used pesticides, have been implicated in inducing neuropsychiatric disorders, such as anxiety, depression-like behaviors, and locomotor activity impairment. However, the exact molecular mechanisms of these adverse effects, particularly in both sexes and their next-generation effects, remain unclear. In this study, we conducted behavioral analysis, along with cellular assays (monodansylcadaverine staining) and molecular investigations (qRT-PCR and western blotting of mTOR, P62, and Beclin-1) to clear the potential role of autophagy in pesticide-induced behavioral alterations. For this purpose, 42 adult female and 21 male inbred ICR mice (F0) were distributed into seven groups. Maternal mice (F0) and 112 F1 offspring were exposed to 0.5 and 1 ppm of CPF, DDV, and CP through drinking water. F1 male and female animals were studied to assess the sex-specific effects of pesticides on brain tissue. Our findings revealed pronounced anxiogenic effects and impaired locomotor activity in mice. F1 males exposed to CPF (1 ppm) exhibited significantly elevated depression-like behaviors compared to other groups. Moreover, pesticide exposure reduced mTOR and P62 levels, while enhancing the Beclin-1 gene and protein expression. These changes in autophagy signaling pathways, coupled with oxidative and neurogenic damage in the cerebral cortex and hippocampus, potentially contribute to heightened locomotor activity, anxiety, and depression-like behaviors following pesticide exposure. This study underscores the substantial impact of pesticides on both physiological and behavioral aspects, emphasizing the necessity for comprehensive assessments and regulatory considerations for pesticide use. Additionally, the identification of sex-specific responses presents a crucial dimension for pharmaceutical sciences, highlighting the need for tailored therapeutic interventions and further research in this field.

In vivo treatment of zinc phosphide poisoning by administration of mesoporous silica nanoparticles as an effective antidote agent.

Mesoporous silica nanoparticles (MSNs) are highly advanced engineered particles with increased surface area and extreme adsorption capacity for various molecules. Herein, two types of MSNs were synthesized and applied as adsorbents for phosphine gas. One was without functional groups (MSN), and the other was post-modified with boric acid (MSN-BA). The structures of MSN and boric acid-modified MSN with high surface areas of about 1025 and 650 m2/g, respectively, were defined. MSN was found to have particles with sizes around 30 nm by transmission electron microscopy (TEM). In the present study, MSNs were used as an antidote to phosphorus poisoning, and zinc phosphide (phosphorus) powder was used as the toxic and lethal agent. In vivo analysis was carried out on rats to demonstrate the ability of MSNs to chemisorb phosphine gas. In the survival percentage assessment, Phos-poisoned animals were kept alive after treatment with MSNs, and the MSN-BA-treated group (dose of 5 mg/kg) was shown to have a 60 % survival rate. Blood serum analysis showed that MSNs have a high potential to alleviate organ blood damage, and serum biomarkers dropped sharply while phosphine-poisoned animals were treated with MSN-BA.

Trinitroglycerin-loaded chitosan nanogels: Shedding light on cytotoxicity, antioxidativity, and antibacterial activities.

AIM AND BACKGROUND: Trinitroglycerin (TNG) is a remarkable NO-releasing agent. Here, we synthesized TNG based on chitosan Nanogels (Ngs) for ameliorating complications associated with high-dose TNG administration. METHOD: TNG-Ngs fabricated through ionic-gelation technique. Fourier-transformed infrared (FT-IR), zeta-potential, dynamic light scattering (DLS), and electron microscopy techniques evaluated the physicochemical properties of TNG-Ngs. MTT was used to assess the biocompatibility of TNG-Ngs, as the antioxidative properties were determined via lactate dehydrogenase (LDH), reactive oxygen species (ROS), and lipid peroxide (LPO) assays. The antibacterial activity was evaluated against Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant Enterococci (VRE). RESULTS: Physicochemical characterization reveals that TNG-Ngs with size diameter (96.2 ± 29 nm), polydispersity index (PDI, 0.732), and negative zeta potential (-1.1 mv) were fabricated. The encapsulation efficacy (EE) and loading capacity (LC) were obtained at 71.1 % and 2.3 %, respectively, with no considerable effect on particle size and morphology. The cytotoxicity assay demonstrated that HepG2 cells exposed to TNG-Ngs showed relative cell viability (RCV) of >80 % for 70 µg/ml compared to the TNG-free drug at the same concentration (P < 0.05). TNG-Ngs showed significant differences with the TNG-free drug for LDH, LPO, and ROS formation at the same concentration (P < 0.001). The antibacterial activity of the TNG-Ngs against S. aureus, E. coli, VRE, and MRSA was higher than the TNG-free drug and Ngs (P < 0.05). CONCLUSION: TNG-Ngs with enhanced antibacterial and antioxidative activity and no obvious cytotoxicity might be afforded as novel nanoformulation for promoting NO-dependent diseases.

A photocrosslinkable and hemostatic bilayer wound dressing based on gelatin methacrylate hydrogel and polyvinyl alcohol foam for skin regeneration.

The enormous potential of multifunctional bilayer wound dressings in various medical interventions for wound healing has led to decades of exploration into this field of medicine. However, it is usually difficult to synthesize a single hydrogel with all the required capabilities simultaneously. This paper proposes a bilayer model with an outer layer intended for hydrogel wound treatment. By adding gelatin methacrylate (GelMA) and tannic acid (TA) to the hydrogel composition and using polyvinyl alcohol-carboxymethyl chitosan (PVA-CMCs) foam layer as supports, a photocrosslinkable hydrogel with an optimal formulation was created. The hydrogels were then examined using a range of analytical procedures, including mechanical testing, rheology, chemical characterization, and in vitro and in vivo tests. The resulting bilayer wound dressing has many desirable properties, namely uniform adhesion and quick crosslinking by UV light. When used against Gram-positive and Gram-negative bacterial strains, bilayer wound dressings demonstrated broad antibacterial efficacy. In bilayer wound dressings with GelMA and TA, better wound healing was observed. Those without these elements showed less effectiveness in healing wounds. Additionally, encouraging collagen production and reducing wound infection has a major therapeutic impact on wounds. The results of this study could have a significant impact on the development of better-performing wound dressings.

Carnitine in Alleviation of Complications Caused by Acute Valproic Acid Toxicity; an Exprimental Study on Mice.

Introduction: Hyperammonemia and hepatotoxicity are well-known complications of valproic acid (VPA) poisoning. The objective of this study is to evaluate the potential role of carnitine in mitigating the adverse effects of acute VPA toxicity in mice. Methods: 54 male mice (25-30 g) were randomly assigned to one of three categories, including acute, sub-acute, and chronic poisoning. Each category contained 3 groups, each consisting of 6 mice (Group 1: control, Group 2: VPA treated, and Group 3: VPA + carnitine treated). The animals were sacrificed 24 hours after the initial injection, and their blood, liver, and brain samples were compared between groups of each category regarding liver function biomarkers, oxidative stress markers, ammonia level, and liver histopathologic changes using one-way ANOVA followed by Tukey's multiple comparison test. Results: The administration of VPA increased the serum level of aspartate aminotransferase (AST) (p=0.003) and alanine aminotransferase (ALT) (p=0.001), as well as serum, and brain level of ammonia (p=0.0001 for both) in the intervention group. Elevated levels of lipid peroxidation and oxidative stress (p=0.0001 for both) in the liver tissue, decreased liver glutathione (p=0.0001) and ferric ion-reducing antioxidant power (FRAP) (p=0.0001), and histopathologic changes in the form of moderate to severe inflammation were observed. Administration of VPA + carnitine reduced AST (p=0.05) and ALT (p=0.01), increased the FRAP, reduced free oxygen radicals and liver lipid peroxidation (p=0.0001 for all), and decreased tissue damage in the form of moderate inflammation. The administration of carnitine was ineffective in reducing brain or plasma ammonia levels in acute VPA-treated animals (p = 0.0115). Conclusions: Although the administration of carnitine has been suggested as a protective remedy in cases of VPA toxicity, according to the present study, it did not have an antidotal effect and did not prevent encephalopathy or liver injury in acute VPA toxicity.

Prominent genetic variants and epigenetic changes in post-traumatic stress disorder among combat veterans.

Post-traumatic stress disorder (PTSD) is one of the most widespread and disabling psychiatric disorders among combat veterans. Substantial interindividual variability in susceptibility to PTSD suggests the presence of different risk factors for this disorder. Twin and family studies confirm genetic factors as important risk factors for PTSD. In addition to genetic factors, epigenetic factors, especially DNA methylation, can be considered as a potential mechanism in changing the risk of PTSD. So far, many genetic and epigenetic association studies have been conducted in relation to PTSD. In genetic studies, many single nucleotide polymorphisms have been identified as PTSD risk factors. Meanwhile, the variations in catecholamines-related genes, serotonin transporter and receptors, brain-derived neurotrophic factor, inflammatory factors, and apolipoprotein E are the most prominent candidates. CpG methylation in the upstream regions of many genes is also considered a PTSD risk factor. Accurate identification of genetic and epigenetic changes associated with PTSD can lead to the presentation of suitable biomarkers for susceptible individuals to this disorder. This study aimed to delineate prominent genetic variations and epigenetic changes associated with post-traumatic stress disorder in military veterans who have experienced combat, focusing on genetic and epigenetic association studies.

Comparison of the efficiency of ultrafiltration, precipitation, and ultracentrifugation methods for exosome isolation.

Extracellular vesicles (EVs) are enclosed by a lipid-bilayer membrane and secreted by all types of cells. They are classified into three groups: apoptotic bodies, microvesicles, and exosomes. Exosomes play a number of important roles in the intercellular communication and crosstalk between tissues in the body. In this study, we use three common methods based on different principles for exosome isolation, namely ultrafiltration, precipitation, and ultracentrifugation. We use field emission scanning electron microscopy (FESEM) and dynamic light scattering (DLS) analyses for characterization of exosomes. The functionality and effect of isolated exosomes on the viability of hypoxic cells was investigated by alamarBlue and Flow-cytometry. The results of the FESEM study show that the ultrafiltration method isolates vesicles with higher variability of shapes and sizes when compared to the precipitation and ultracentrifugation methods. DLS results show that mean size of exosomes isolated by ultrafiltration, precipitation, and ultracentrifugation methods are 122, 89, and 60 nm respectively. AlamarBlue analysis show that isolated exosomes increase the viability of damaged cells by 11%, 15%, and 22%, respectively. Flow-cytometry analysis of damaged cells also show that these vesicles increase the content of live cells by 9%, 15%, and 20%, respectively. This study shows that exosomes isolated by the ultracentrifugation method are characterized by smaller size and narrow size distribution. Furthermore, more homogenous particles isolated by this method show increased efficiency of the protection of hypoxic cells in comparison with the exosomes isolated by the two other methods.

Inactivation of Mst/Nrf2/Keap1 signaling flexibly mitigates MAPK/NQO-HO1 activation in the reproductive axis of experimental fluorosis.

Fluoride induced reprotoxicity through oxidative stress-mediated reproductive cell death. Hence, the current study evaluated the importance of the MST/Nrf2/MAPK/NQO-HO1 signaling pathway in fluorosis-induced reproductive toxicity. For this purpose, the reproductive toxicity of sodium fluoride (NaF) at physiological, biochemical, and intracellular levels was evaluated. In-vivo, NaF at 100 mg/L instigated physiological dysfunction, morphological, stereological, and structural injuries in the gut-gonadal axis of fluorosis mice through weakening the antioxidant signaling, Nrf2/HO-1/NQO1signaling pathway, causing the gut-gonadal barrier disintegrated via oxidative stress-induced inflammation, mitochondrial damage, apoptosis, and autophagy. Similar trends were also observed in-vitro in the isolated Leydig cells (LCs) challenging with 20 mg/L NaF. Henceforth, activating the cellular antioxidant signaling pathway, Nrf2/HO-1/NQO1, inactivating autophagy and apoptosis, or attenuating lipopolysaccharide (LPS) can be the theoretical basis and valuable therapeutic targets for coping with NaF-induced reproductive toxicity.