Effects of nicotine on microRNA-124 expression in bile duct ligation-induced liver fibrosis in rats.

BACKGROUND: Nicotine, the main compound of smoking may exert its effects by changing the expression of microRNAs (miRNAs). This study was conducted to further investigate the molecular mechanisms of miRNA-dependent effects of nicotine in an animal model of liver fibrosis. METHODS: The bile duct ligation (BDL) approach was used to create a model of liver fibrosis. Twenty-four male Wistar rats were used in the study. The effects of nicotine administration on miRNA-124 expression, as well as alpha-smooth muscle actin (liver fibrosis marker) and chemokine ligand 2 (an inflammatory chemokine), were investigated using RT-qPCR. In addition, the mRNA and protein expression of signal transducer and activator of transcription 3 (STAT-3; as a potential target for miRNA-124) were investigated by RT-qPCR and immunofluorescence, respectively. Liver enzyme activity levels were measured using a colorimetric assay. In addition, the effects of nicotine on the process of liver fibrosis were investigated with histological studies. RESULTS: The development of liver fibrosis in BDL rats and nicotine administration led to a decrease in miRNA-124 expression. The decrease in the expression is accompanied by the increase in the expression of fibrotic and proinflammatory genes. Also, an increase in STAT-3 mRNA and protein expression was observed in the fibrotic rats that received nicotine. In addition, the significant increase in bilirubin and liver enzymes in fibrotic rats worsens with nicotine administration. The results of histological studies also confirm these results. CONCLUSION: Considering that miRNA-124 is an anti-inflammatory miRNA, it can be concluded that the decrease in its expression due to nicotine exposure leads to an increase in inflammatory processes and subsequently to an increase in liver fibrosis.

Aging and age-related diseases with a focus on therapeutic potentials of young blood/plasma.

Aging is accompanied by alterations in the body with time-related to decline of physiological integrity and functionality process, responsible for increasing diseases and vulnerability to death. Several ages associated with biomarkers were observed in red blood cells, and consequently plasma proteins have a critical rejuvenating role in the aging process and age-related disorders. Advanced age is a risk factor for a broad spectrum of diseases and disorders such as cardiovascular diseases, musculoskeletal disorders and liver, chronic kidney disease, neurodegenerative diseases, and cancer because of loss of regenerative capacity, correlated to reduced systemic factors and raise of pro-inflammatory cytokines. Most studies have shown that systemic factors in young blood/plasma can strongly protect against age-related diseases in various tissues by restoring autophagy, increasing neurogenesis, and reducing oxidative stress, inflammation, and apoptosis. Here, we focus on the current advances in using young plasma or blood to combat aging and age-related diseases and summarize the experimental and clinical evidence supporting this approach. Based on reports, young plasma or blood is new a therapeutic approach to aging and age-associated diseases.

Human Mesenchymal Stem Cell Transplantation Improved Functional Outcomes Following Spinal Cord Injury Concomitantly with Neuroblast Regeneration.

Purpose: Spinal cord injury (SCI) is damage to the spinal cord that resulted in irreversible neuronal loss, glial scar formation and axonal injury. Herein, we used the human amniotic fluid mesenchymal stem cells (hAF-MSCs) and their conditioned medium (CM), to investigate their ability in neuroblast and astrocyte production as well as functional recovery following SCI. Methods: Fifty-four adult rats were randomly divided into nine groups (n=6), included: Control, SCI, (SCI + DMEM), (SCI + CM), (SCI + MSCs), (SCI + Astrocyte), (SCI + Astrocyte + DMEM), (SCI + Astrocyte + CM) and (SCI + Astrocyte + MSCs). Following laminectomy and SCI induction, DMEM, CM, MSCs, and astrocytes were injected. Western blot was performed to explore the levels of the Sox2 protein in the MSCs-CM. The immunofluorescence staining against doublecortin (DCX) and glial fibrillary acidic protein (GFAP) was done. Finally, Basso-Beattie-Brenham (BBB) locomotor test was conducted to assess the neurological outcomes. Results: Our results showed that the MSCs increased the number of endogenous DCX-positive cells and decreased the number of GFAP-positive cells by mediating juxtacrine and paracrine mechanisms (P<0.001). Transplanted human astrocytes were converted to neuroblasts rather than astrocytes under influence of MSCs and CM in the SCI. Moreover, functional recovery indexes were promoted in those groups that received MSCs and CM. Conclusion: Taken together, our data indicate the MSCs via juxtacrine and paracrine pathways could direct the spinal cord endogenous neural stem cells (NSCs) to the neuroblasts lineage which indicates the capability of the MSCs in the increasing of the number of DCX-positive cells and astrocytes decline.

Chronic Sustained Hypoxia Leads to Brainstem Tauopathy and Declines the Power of Rhythms in the Ventrolateral Medulla: Shedding Light on a Possible Mechanism.

Hypoxia, especially the chronic type, leads to disruptive results in the brain that may contribute to the pathogenesis of some neurodegenerative diseases such as Alzheimer's disease (AD). The ventrolateral medulla (VLM) contains clusters of interneurons, such as the pre-Bötzinger complex (preBötC), that generate the main respiratory rhythm drive. We hypothesized that exposing animals to chronic sustained hypoxia (CSH) might develop tauopathy in the brainstem, consequently changing the rhythmic manifestations of respiratory neurons. In this study, old (20-22 months) and young (2-3 months) male rats were subjected to CSH (10 ± 0.5% O2) for ten consecutive days. Western blotting and immunofluorescence (IF) staining were used to evaluate phosphorylated tau. Mitochondrial membrane potential (MMP or ∆ψm) and reactive oxygen species (ROS) production were measured to assess mitochondrial function. In vivo diaphragm's electromyography (dEMG) and local field potential (LFP) recordings from preBötC were employed to assess the respiratory factors and rhythmic representation of preBötC, respectively. Findings showed that ROS production increased significantly in hypoxic groups, associated with a significant decline in ∆ψm. In addition, tau phosphorylation elevated in the brainstem of hypoxic groups. On the other hand, the power of rhythms declined significantly in the preBötC of hypoxic rats, parallel with changes in the respiratory rate, total respiration time, and expiration time. Moreover, there was a positive and statistically significant correlation between LFP rhythm's power and inspiration time. Our data showed that besides CSH, aging also contributed to mitochondrial dysfunction, tau hyperphosphorylation, LFP rhythms' power decline, and changes in respiratory factors.

The Impact of Cerebral Ischemia on Antioxidant Enzymes Activity and Neuronal Damage in the Hippocampus.

Cerebral ischemia and subsequent reperfusion, leading to reduced blood supply to specific brain areas, remain significant contributors to neurological damage, disability, and mortality. Among the vulnerable regions, the subcortical areas, including the hippocampus, are particularly susceptible to ischemia-induced injuries, with the extent of damage influenced by the different stages of ischemia. Neural tissue undergoes various changes and damage due to intricate biochemical reactions involving free radicals, oxidative stress, inflammatory responses, and glutamate toxicity. The consequences of these processes can result in irreversible harm. Notably, free radicals play a pivotal role in the neuropathological mechanisms following ischemia, contributing to oxidative stress. Therefore, the function of antioxidant enzymes after ischemia becomes crucial in preventing hippocampal damage caused by oxidative stress. This study explores hippocampal neuronal damage and enzymatic antioxidant activity during ischemia and reperfusion's early and late stages.

Cancer immunotherapy focusing on the role of interleukins: A comprehensive and updated study.

Cytokines bind to specific receptors on target cells to activate intracellular signaling pathways that control diverse cellular functions, such as proliferation, differentiation, migration, and death. They are essential for the growth, activation, and operation of immune cells and the control of immunological reactions to pathogens, cancer cells, and other dangers. Based on their structural and functional properties, cytokines can be roughly categorized into different families, such as the tumor necrosis factor (TNF) family, interleukins, interferons, and chemokines. Leukocytes produce interleukins, a class of cytokines that have essential functions in coordinating and communicating with immune cells. Cancer, inflammation, and autoimmunity are immune-related disorders brought on by dysregulation of cytokine production or signaling. Understanding cytokines' biology to create novel diagnostic, prognostic, and therapeutic methods for various immune-related illnesses is crucial. Different immune cells, including T cells, B cells, macrophages, and dendritic cells, and other cells in the body, including epithelial cells and fibroblasts, generate and secrete interleukins. The present study's main aim is to fully understand interleukins' roles in cancer development and identify new therapeutic targets and strategies for cancer treatment.

Tau Protein Biosensors in the Diagnosis of Neurodegenerative Diseases.

Tau protein plays a crucial role in diagnosing neurodegenerative diseases. However, performing an assay to detect tau protein on a nanoscale is a great challenge for early diagnosis of diseases. Enzyme-linked immunosorbent assay (ELISA), western-blotting, and molecular-based methods, e.g., PCR and real-time PCR, are the most widely used methods for detecting tau protein. These methods are subject to certain limitations: the need for advanced equipment, low sensitivity, and specificity, to name a few. With the above said, it is necessary to discover advanced and novel methods for monitoring tau protein. Counted among remarkable approaches adopted by researchers, biosensors can largely eliminate the difficulties and limitations associated with conventional methods. The main objective of the present study is to review the latest biosensors developed to detect the tau protein. Furthermore, the problems and limitations of conventional diagnosis methods were discussed in detail.

New immunotherapeutic approaches for cancer treatment.

Neoplasms are a worldwide recognized non-contagious disease which has the most mortality rate after cardiovascular diseases. For decades, there has been a vast amount of study on treatment methods of cancer which has led to conventional therapies such as chemotherapy, radiation therapy, surgery and so on. Clinicians and researchers believed that there is an urgent need, considering the high rate of incidence and prevalence, for an alternative treatment option which is more efficacious and has less adverse effects than the above-mentioned treatments. Immunotherapy has emerged as a potential treatment alternative in a few years and became one of the fastest developing therapeutic approaches. Different kinds of immunotherapies are FDA approved and available for treatment of various cancer types. In this review, we have summarized the major immunotherapy methods including checkpoint inhibitors, CAR T cell therapies and cancer vaccines. Furthermore, application of combination therapy, precision medicine, biomarker discovery, overcoming resistance and reduction of adverse effects are discussed in this study.

Theranostic chimeric antigen receptor (CAR)-T cells: Insight into recent trends and challenges in solid tumors.

Cell therapy has reached significant milestones in various life-threatening diseases, including cancer. Cell therapy using fluorescent and radiolabeled chimeric antigen receptor (CAR)-T cell is a successful strategy for diagnosing or treating malignancies. Since cell therapy approaches have different results in cancers, the success of hematological cancers has yet to transfer to solid tumor therapy, leading to more casualties. Therefore, there are many areas for improvement in the cell therapy platform. Understanding the therapeutic barriers associated with solid cancers through cell tracking and molecular imaging may provide a platform for effectively delivering CAR-T cells into solid tumors. This review describes CAR-T cells' role in treating solid and non-solid tumors and recent advances. Furthermore, we discuss the main obstacles, mechanism of action, novel strategies and solutions to overcome the challenges from molecular imaging and cell tracking perspectives.

Pattern-recognition receptors (PRRs) in SARS-CoV-2.

Pattern recognition receptors (PRRs) are specific sensors that directly recognize various molecules derived from viral or bacterial pathogens, senescent cells, damaged cells, and apoptotic cells. These sensors act as a bridge between nonspecific and specific immunity in humans. PRRs in human innate immunity were classified into six types: toll-like receptors (TLR), C-type lectin receptors (CLRs), nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs), absent in melanoma 2 (AIM2)-like receptors (ALRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and cyclic GMP-AMP (cGAMP) synthase (cGAS). Numerous types of PRRs are responsible for recognizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is immensely effective in prompting interferon responses. Detection of SARS-CoV-2 infection by PRRs causes the initiation of an intracellular signaling cascade and subsequently the activation of various transcription factors that stimulate the production of cytokines, chemokines, and other immune-related factors. Therefore, it seems that PRRs are a promising potential therapeutic approach for combating SARS-CoV-2 infection and other microbial infections. In this review, we have introduced the current knowledge of various PRRs and related signaling pathways in response to SARS-CoV-2.

An updated review of a novel method for examining P53 mutations in different forms of cancer.

In the past fifteen years, it has been clear that tumor-associated p53 mutations can cause behaviors distinct from those brought on by a simple loss of p53's tumor-suppressive function in its wild-type form. Many of these mutant p53 proteins develop oncogenic characteristics that allow them to encourage cell survival, invasion, and metastasis. But it is now understood that the immune response is also significantly influenced by the cancer cell's p53 status. The recruitment and activity of myeloid and T cells can be impacted by p53 loss or mutation in malignancies, allowing immune evasion and accelerating cancer growth. Additionally, p53 can work in immune cells, which can have various effects that either hinder or assist the growth of tumors. In this review article, we examined different mutations of P53 in some significant cancers, such as liver, colorectal, and prostate, and reviewed some new therapeutic approaches.

The role of microRNAs in nicotine signaling.

Cigarette smoking is a harmful habit that is widespread around the world. It is among the well-known lifestyle-related risk factors for many diseases. Nicotine, as its principal constituent, has various detrimental, and beneficial functions. Nicotinic acetylcholine receptors (nAChRs), which are present in nearly all body cells, are how nicotine works. Numerous investigations have demonstrated that nicotine causes abnormal microRNA expression (miRNAs). These short sequences of RNAs are known to regulate gene expression post-transcriptionally. A wide range of miRNAs are modulated by nicotine, and nicotine-induced miRNA changes could subsequently mediate nicotine's effect on gene expression regulation. We will focus on the reciprocal interaction between nAChRs and miRNAs and describe the essential targets of these dysregulated miRNAs after nicotine exposure and activation of nAChRs. It appears that crucial subcellular mechanisms implicated in nicotine's effects are miRNA-related pathways. It is crucial to investigate the molecular mechanism underlying the effects of nicotine as well as the dysregulation of miRNA following nAChR activation. The finding about epigenetic mechanisms of nicotine-induced effects may shed light on the establishment of new treatment strategies to prevent the harmful effects of nicotine and perhaps may augment the beneficial effects in diverse smoking-related diseases.

Spinal cord injury leads to more neurodegeneration in the hippocampus of aged male rats compared to young rats.

Although the disruptive effects of spinal cord injury (SCI) on the hippocampus have been confirmed in some animal studies, no study has investigated its retrograde manifestations in the hippocampus of aged subjects. Herein, we compared the aged rats with young ones 3 weeks after the induction of SCI (Groups: Sham.Young, SCI.Young, Sham.Aged, SCI.Aged). The locomotion, hippocampal apoptosis, hippocampal rhythms (Delta, Theta, Beta, Gamma) max frequency (Max.rf) and power, hippocampal neurogenesis, and hippocampal receptors (NMDA, GABA A, Muscarinic1/M1), which are important in the generation of rhythms and neurogenesis, were compared in aged rats in contrast to young rats. At the end of the third week, the number of apoptotic (Tunel+) cells in the hippocampus (CA1, DG) of SCI animals was significantly higher compared to the sham animals, and also, it was significantly higher in the SCI.Aged group compared to SCI.Young group. Moreover, the rate of neurogenesis (DCX+, BrdU+ cells) and expression of M1 and NMDA receptors were significantly lower in the SCI.Aged group compared to SCI.Young group. The power and Max.fr of all rhythms were significantly lower in SCI groups compared to sham groups. Despite the decrease in the power of rhythms in the SCI.Aged group compared to SCI.Young group, there was no significant difference between them, and in terms of Max.fr index, only the Max.fr of theta and beta rhythms were significantly lower in the SCI.Aged group compared to SCI.Young group. This study showed that SCI could cause more neurodegeneration in the hippocampus of aged animals compared to young animals.

Dysregulation of P53 in breast cancer: Causative factors and treatment strategies.

One of the most prevalent cancers impacting women worldwide is breast cancer. Although there are several risk factors for breast cancer, the p53 gene's function has recently received much attention. The "gatekeeper" gene, or p53, is sometimes referred to as such since it is crucial in controlling cell proliferation and preventing the development of malignant cells. By identifying DNA damage and initiating cellular repair processes, p53 usually functions as a tumor-suppressor. But p53 gene alterations can result in a lack of function, allowing cells to divide out of control and perhaps triggering the onset of cancer. Various factors, such as mutation genes, signaling pathways, and hormones, can dysregulate P53 proteins and cause breast cancer. A promising strategy for individualized cancer treatment involves focusing on p53 mutations in breast cancer. While numerous techniques, including gene therapy and small compounds, have shown promise, further study is required to create safe and efficient treatments to target p53 mutations in breast cancer successfully.

Profiling inflammatory mechanisms, hyperphosphorylated tau of hippocampal tissue and spatial memory following vitamin D3 treatment in the mice model of vascular dementia.

BACKGROUND: The aim of this study was to investigate the effect of vitamin D3 (VitD3) on inflammatory mechanisms, hyperphosphorylated tau (p-tau) in the hippocampus, and cognitive impairment of the mouse model of vascular dementia (VaD). METHODS: In this study, 32 male mice were randomly assigned to the control, VaD, VitD3 (300 IU/Kg/day), and VitD3 (500 IU/Kg/day) groups. VaD and VitD3 groups were gavaged daily for 4 weeks with a gastric needle. For biochemical assessments, blood samples and the hippocampus were isolated. IL-1ß and TNF-α were analyzed by ELISA, and p-tau and other inflammatory molecules were measured by western blot. RESULTS: VitD3 supplements significantly (P < 0.05) decreased the level of inflammatory factors in the hippocampus and prevented apoptosis. However, regarding p-tau in hippocampal tissue, this decrease was not statistically significant (P > 0.05). The results of behavioral assessments showed that VitD3 significantly improved the spatial memory of treated mice. CONCLUSION: These results suggest that the neuroprotective effects of VitD3 are mainly associated with their anti-inflammatory effects.

The effects of ketogenic diet on beta-hydroxybutyrate, arachidonic acid, and oxidative stress in pediatric epilepsy.

The exact mechanism of a ketogenic diet (KD) as a suitable alternative therapeutic approach for drug-resistant epilepsy (DRE) in alleviating seizures is not yet fully understood. The present study aimed to evaluate the role of the KD in reducing oxidative stress (OS) by increasing the ketone body beta-hydroxybutyrate (BHB) and Arachidonic acid (ARA), an essential polyunsaturated fatty acid, as a possible mechanism in relieving seizure attacks in children with DRE. Forty children with refractory epilepsy were included in the present study. The serum levels of BHB, ARA, and OS markers, malondialdehyde (MDA), and 8-hydroxyl-deoxyguanosine (8-OHdG), were evaluated in children with DRE and compared before and after the three months of KD therapy. Thirty-four of 40 included children could complete the three-month KD therapy. Twenty-one (61.76%) patients had more than a 50% reduction in seizure frequency after the KD (responders). The remaining 13 children were considered non-responders to the diet. The serum levels of ARA and BHB significantly (p < 0.05) increased after the KD therapy. The serum levels of OS parameters MDA and 8-OHdG before the diet therapy were significantly (p < 0.05) higher than those after the administration. The serum levels of BHB and MDA after the KD therapy in the responders were respectively higher and lower than those in the non-responders (p < 0.001). Ketogenic diet might reduce brain OS by increasing BHB and ARA. The role of BHB in diminishing OS and seizure might be more remarkable than ARA.

Improvement of spinal cord injury symptoms by targeting the Bax/Bcl2 pathway and modulating TNF-α/IL-10 using Platelet-Rich Plasma exosomes loaded with dexamethasone.

Spinal cord injury (SCI) is a debilitating condition that results in impaired sensory and motor function due to the limited self-regenerative ability of the spinal cord. To address this issue, combination therapy has been proposed as an effective treatment strategy for SCI regeneration. In this study, Platelet-Rich Plasma (PRP)-derived exosomes loaded with dexamethasone were utilized in a mouse model of SCI compression. PRP-derived exosomes loaded with dexamethasone (Dex) were prepared using ultracentrifugation and sonication methods and were administered to the mice via intravenous injection. Following a four-week duration, behavioral assessments were administered to assess functional recuperation, and diverse metrics encompassing the expression of genes associated with apoptosis and antiapoptosis, serum cytokine concentrations and tissue sampling were subjected to thorough examination. The results of this study demonstrated that mice treated with PRP-derived exosomes loaded with Dex (ExoDex) exhibited altered levels of TNF-α and IL-10, along with decreased Bax and increased Bcl2 expression in comparison to the model group. Furthermore, intravenously injected ExoDex reduced the size of the lesion site, lymphocyte infiltration, vacuolation, cavity size and tissue disorganization while also improving locomotor recovery. We propose that the utilization of exosome-loaded Dex therapy holds potential as a promising and clinically relevant approach for injured spinal cord repair. However, further extensive research is warranted in this domain to validate and substantiate the outcomes presented in this study.

Intersection of hippocampus and spinal cord: a focus on the hippocampal alpha-synuclein accumulation, dopaminergic receptors, neurogenesis, and cognitive function following spinal cord injury in male rats.

BACKGROUND: Following Spinal Cord Injury (SCI), innumerable inflammatory and degenerative fluctuations appear in the injured site, and even remotely in manifold areas of the brain. Howbeit, inflammatory, degenerative, and oscillatory changes of motor cortices have been demonstrated to be due to SCI, according to recent studies confirming the involvement of cognitive areas of the brain, such as hippocampus and prefrontal cortex. Therefore, addressing SCI induced cognitive complications via different sights can be contributory in the treatment approaches. RESULTS: Herein, we used 16 male Wistar rats (Sham = 8, SCI = 8). Immunohistochemical results revealed that spinal cord contusion significantly increases the accumulation of alpha-synuclein and decreases the expression of Doublecortin (DCX) in the hippocampal regions like Cornu Ammonis1 (CA1) and Dentate Gyrus (DG). Theses degenerative manifestations were parallel with a low expression of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), SRY (sex determining region Y)-box 2 (SOX2), and dopaminergic receptors (D1 and D5). Additionally, based on the TUNEL assay analysis, SCI significantly increased the number of apoptotic cells in the CA1 and DG regions. Cognitive function of the animals was assessed, using the O-X maze and Novel Object Recognition (NORT); the obtained findings indicted that after SCI, hippocampal neurodegeneration significantly coincides with the impairment of learning, memory and recognition capability of the injured animals. CONCLUSIONS: Based on the obtained findings, herein SCI reduces neurogenesis, decreases the expression of D1 and D5, and increases apoptosis in the hippocampus, which are all associated with cognitive function deficits.

Spinal Cord Injury Causes Prominent Tau Pathology Associated with Brain Post-Injury Sequela.

Spinal cord injury (SCI) can result in significant neurological impairment and functional and cognitive deficits. It is well established that SCI results in focal neurodegeneration that gradually spreads to other cord areas. On the other hand, traumatic brain injury (TBI) is strongly associated with tau protein pathology and neurodegeneration that can spread in areas throughout the brain. Tau is a microtubule-associated protein abundant in neurons and whose abnormalities result in neuronal cell death. While SCI and TBI have been extensively studied, there is limited research on the relationship between SCI and brain tau pathology. As a result, in this study, we examined tau pathology in spinal cord and brain samples obtained from severe SCI mouse models at various time points. The effects of severe SCI on locomotor function, spatial memory, anxiety/risk-taking behavior were investigated. Immunostaining and immunoblotting confirmed a progressive increase in tau pathology in the spinal cord and brain areas. Moreover, we used electron microscopy to examine brain samples and observed disrupted mitochondria and microtubule structure following SCI. SCI resulted in motor dysfunction, memory impairment, and abnormal risk-taking behavior. Notably, eliminating pathogenic cis P-tau via systemic administration of appropriate monoclonal antibodies restored SCI's pathological and functional consequences. Thus, our findings suggest that SCI causes severe tauopathy that spreads to brain areas, indicating brain dysfunction. Additionally, tau immunotherapy with an anti-cis P-tau antibody could suppress pathogenic outcomes in SCI mouse models, with significant clinical implications for SCI patients. SCI induces profound pathogenic cis p-tau, which diffuses into the brain through CSF, resulting in brain neurodegeneration and cognitive decline.