The Role of the JAK-STAT Signaling Pathway in the Protective Effects of Hepatic Ischemia Post-conditioning Against the Injury Induced by Ischemia/Reperfusion in the Rat Liver.

Purpose: Hepatic ischemic post-conditioning (IPOC) is shown to protect the liver from injury induced by ischemia/reperfusion (IR). However, the mechanism underlying this protection has remained elusive. The present study aimed to investigate the role of the interleukin 6-Janus kinase-signal transducers and activators of transcription (IL-6-JAK-STAT) pathway in the protective effect of hepatic IPOC against the IR-induced injury in the liver. Methods: Twenty-five rats were randomly divided into 5 groups of (1) sham-operated, (2) IR, (3) IR+hepatic IPOC, (4) IR+tofacitinib (TOFA), and (5) IR+TOFA+hepatic IPOC. The changes induced by IR and the effects of different treatments were assessed by enzyme release, histopathological observations, the serum level of IL-6, and the occurrence of apoptosis detected via the expression of the Bax/Bcl-2 ratio. Results: The hepatic IPOC improved the liver injury induced by IR as shown by histological changes, reduction of IL-6 level, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) compared to the IR group (P<0.001, P<0.05, P<0.05, respectively). There was also downregulation of the Bax/Bcl2 ratio in the rats exposed to IR+hepatic IPOC compared with those in the IR group (P<0.05). However, TOFA, an inhibitor of JAK-STAT activity, inhibited the protective effect of hepatic IPOC. Conclusion: It suggests that the protective effect of hepatic IPOC against IR-induced injury may be mediated by activating the IL-6-JAK-STAT pathway.

Alcohol: Epigenome alteration and inter/transgenerational effect.

While DNA serves as the fundamental genetic blueprint for an organism, it is not a static entity. Gene expression, the process by which genetic information is utilized to create functional products like proteins, can be modulated by a diverse range of environmental factors. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNAs, play a pivotal role in mediating the intricate interplay between the environment and gene expression. Intriguingly, alterations in the epigenome have the potential to be inherited across generations. Alcohol use disorder (AUD) poses significant health issues worldwide. Alcohol has the capability to induce changes in the epigenome, which can be inherited by offspring, thus impacting them even in the absence of direct alcohol exposure. This review delves into the impact of alcohol on the epigenome, examining how its effects vary based on factors such as the age of exposure (adolescence or adulthood), the duration of exposure (chronic or acute), and the specific sample collected (brain, blood, or sperm). The literature underscores that alcohol exposure can elicit diverse effects on the epigenome during different life stages. Furthermore, compelling evidence from human and animal studies demonstrates that alcohol induces alterations in epigenome content, affecting both the brain and blood. Notably, rodent studies suggest that these epigenetic changes can result in lasting phenotype alterations that extend across at least two generations. In conclusion, the comprehensive literature analysis supports the notion that alcohol exposure induces lasting epigenetic alterations, influencing the behavior and health of future generations. This knowledge emphasizes the significance of addressing the potential transgenerational effects of alcohol and highlights the importance of preventive measures to minimize the adverse impact on offspring.

Sericin alleviates motor dysfunction by modulating inflammation and TrkB/BDNF signaling pathway in the rotenone-induced Parkinson's disease model.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the degeneration of nigrostriatal dopaminergic neurons and movement impairment. Based on theories, neuroinflammatory processes may be vital in the etiology of PD and other neurodegenerative diseases. Reports show that rotenone has neurotoxic, inflammatory, and motor impairment effects in PD. Sericin is a natural polymer with effective properties, such as neuroprotective and anti-inflammatory. Therefore, this study aimed to examine the effects of sericin administration on motor dysfunction by modulating inflammation and tyrosine kinase B/brain-derived neurotrophic factor (TrkB/BDNF) pathway in the rotenone-induced PD model. METHODS: Wistar male rats (3-months-old) were treated with rotenone (2 mg/kg every 48 h for 30 days) to induce a rotenone-induced PD model. Also, sericin was administered orally at dose of 200 mg/kg every 48 h for 30 days. Rotarod and bar tests were performed for motor dysfunction. The protein levels of BDNF, c-fos, TrkB, tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6) and catalase activity were evaluated in the striatum area. RESULTS: Results showed that sericin increased latent time in the rotarod test and decreased the time staying on the pole in the bar test compared to the PD group (P < 0.001 for both tests). Moreover, sericin treatments decreased TNF-α (P < 0.001) and IL-6 (P < 0.001) concentration levels and enhanced the levels of BDNF (P < 0.001), c-fos (P < 0.001), TrkB (P < 0.001) proteins and catalase activity (P < 0.05) in the striatum area compared to the PD group. CONCLUSION: These results support a protective benefit of sericin therapy in a rotenone-induced PD paradigm by reducing motor impairment, inflammatory response, and disruption of the TrkB/BDNF signaling pathway.

Restoring the firing activity of ventral tegmental area neurons by lateral hypothalamic deep brain stimulation following morphine administration in rats.

We have previously shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) compromises morphine-induced addiction-like behavior in rats. The exact mechanism underlying this effect is not known. Here, we investigated the assumption that DBS in the LH influences the firing activity of neurons in the ventral tegmental area (VTA). To that end, male Wistar rats received morphine (5 mg/kg; s.c.) for three days and underwent extracellular single unit recording under general anesthesia one day later. During the recording, the rats received an intraoperative injection of morphine (5 mg/kg; s.c.) plus DBS in the LH (130 Hz pulse frequency, 150 µA amplitude, and 100 µs pulse width). One group of animals also received preoperative DBS after each morphine injection before the recording. The spiking frequency of VTA neurons was measured at three successive phases: (1) baseline (5-15 min); (2) DBS-on (morphine + DBS for 30 min); and (3) After-DBS (over 30 min after termination of DBS). Results showed that morphine suppressed the firing activity of a large population of non-DA neurons, whereas it activated most DA neurons. Intraoperative DBS reversed morphine suppression of non-DA firing, but did not alter the excitatory effect of morphine on DA neurons firing. With repeated preoperative application of DBS, non-DA neurons returned to the morphine-induced suppressive state, but DA neurons released from the excitatory effect of morphine. It is concluded that the development of morphine reward is associated with a hypoactivity of VTA non-DA neurons and a hyperactivity of DA neurons, and that DBS modulation of the spiking activity may contribute to the blockade of morphine addiction-like behavior.

Point-of-care salivary oxidative and renal functional markers to assess kidney function in reperfusion-induced acute kidney injury in male rats.

OBJECTIVES: Saliva is one of the most promising body fluids in the research of new biomarker for various diseases diagnosis. However, serial sampling in this condition is very dangerous and pose iatrogenic anemia with blood loss. This study was done to evaluate the cost-effectiveness of point-of-care salivary tests and identify the validity of salivary markers. METHODS: Rats were randomly assigned to four experimental groups: (1) control (2) IR-3 h (3) IR-6 h (4) IR-24 h. Both renal pedicles were occluded for 55 min and then were declamped to allow reperfusion for 3, 6 and 24 h in IR groups. After reperfusion, all rats received pilocarpine 1 mg/kg to collect saliva. Plasma samples were also collected. Renal parameters including Cr, uric acid, and urea, malondialdehyde (MDA) levels, Bax/Bcl2 ratio, nitrite/nitrate ratio, corticosterone levels and oxidant/antioxidant ratio were measured in both plasma and salivary samples. RESULTS: There were significant increased level of renal function parameters, MDA levels, Bax/Bcl2 ratio, nitrite/nitrate ratio and corticosterone in both saliva and plasma. The comparison of above parameters in both saliva and plasma showed significant correlation. CONCLUSIONS: This study demonstrated that concentrations of indices specifically renal functional parameters increase in saliva in the IR-induced kidney injury in male rats and result indicate the potential of saliva as a tool to monitoring AKI. Measurement of salivary parameters may can become reliable diagnostic tests for patients with AKI.

Beneficial effects of tannic acid on comorbid anxiety in cecal ligation and puncture-induced sepsis in rats and potential underlying mechanisms.

Sepsis-associated encephalopathy (SAE), a neurological dysfunction caused by sepsis, is the most common complication among septic ICU patients. Given the major role of inflammation in the pathophysiology of sepsis-induced anxiety, an extreme and early manifestation of SAE, the present study examined whether tannic acid, as an anti-inflammatory agent, has anxiolytic effects in cecal ligation and puncture (CLP)-induced sepsis. Forty male Wistar rats were assigned to four groups: (1) sham; (2) sham + tannic acid; (3) sepsis and (4) sepsis + tannic acid. Sepsis was induced by cecal ligation and puncture model. Animals in the sham + tannic acid and sepsis + tannic acid groups received tannic acid (20 mg/kg, i.p.), 6, 12, and 18 h after the sepsis induction. Twenty-four hours after the sepsis induction, systolic blood pressure and sepsis score were assessed. Anxiety-related behaviors were evaluated using elevated plus-maze and dark-light transition tests. Moreover, inflammatory markers (TNF-α and IL-6) and oxidative stress parameters (MDA and SOD) were measured in the brain tissue while protein levels (GABAA receptors and IL-1ß) were assessed in the hippocampus. Administration of tannic acid significantly improved sepsis score and hypotension induced by sepsis. Anxiety-related behaviors showed a significant decrease in the sepsis + tannic acid group compared to the sepsis group. Tannic acid caused a significant decrease in the brain inflammatory markers and a remarkable improvement in the brain oxidative status compared to the septic rats. Tannic acid prevented animals from decreasing GABAA receptors and increasing IL-1ß protein levels in the hippocampus compared to the sepsis group. This study indicated that tannic acid mitigated anxiety-related behaviors through decreasing inflammation and oxidative stress and positively modifying IL-1ß/GABAA receptor pathway. Therefore, tannic acid shows promise as an efficacious treatment for comorbid anxiety in septic patients.

Deep brain stimulation of the lateral hypothalamus to block morphine reward: Does the intensity of stimulation matter?

It has been shown that high-frequency deep brain stimulation (DBS) of the lateral hypothalamus (LH) prevents morphine-induced conditioned place preference (CPP) in rats. However, our previous study demonstrated that the application of DBS at 150 µA did not block morphine CPP in all rats. Here, we investigated the possibility to completely block morphine CPP by increasing the intensity of LH DBS. Morphine reward was assessed by the CPP paradigm in male Wistar rats. DBS was applied in the LH during the conditioning trials with morphine (5 mg/kg, S.C.) at 130 Hz pulse frequency, 100 µs pulse duration, and either 150 µA or 200 µA pulse amplitude. Results showed that repeated morphine injections produced a robust CPP that was blocked partially by DBS at 150 µA and completely by DBS at 200 µA. Response rate was 47% with 150-µA and 100% with 200-µA stimulation. DBS treatment was not associated with changes in motor activity. In conclusion, the development of morphine reward was modulated by LH DBS in an intensity-dependent manner.

Aerobic Training with Naringin Supplementation Improved Spatial Cognition via H2S Signaling Pathway in Alzheimer's Disease Model Rats.

OBJECTIVES: This study examined the effects of one-month naringin administration and exercise training on cognitive impairment and H2S signaling pathway in an Amyloid ß (Aß)-injected rat. METHODS: Rats were divided into four groups: control group; rats underwent Aß microinjection surgery, exercise group; rats underwent Aß microinjection surgery and trained by treadmill for four weeks, naringin group; rats underwent Aß microinjection surgery, and rats orally administrated 80 mg.kg-1 naringin for four weeks, naringin+exercise group; rats underwent Aß microinjection surgery and were trained by treadmill for four weeks, and also, rats orally administrated 80 mg.kg-1 naringin for four weeks. After one month of treatment, spatial learning and memory were measured, and then hippocampi were sampled. S-adenosylmethionine (SAM), cystathionine-ß-synthase (CBS), hydrogen sulfide (H2S) levels, and neuronal death were detected in the hippocampi of rats. RESULTS: Naringin and exercise improved spatial learning (latency time, P < .001) and memory (P < .001) in the Morris Water Maze test in Aß-injected rats compared with the control group. SAM (P < .01), CBS (P < .001), and H2S (P < .01) levels are increased in the naringin+exercise group compared with the control group. CONCLUSION: The result of this study supports the effect of exercise and/or naringin to improve cognitive dysfunction and cell death through the production of H2S.

Inter/Transgenerational Effects of Drugs of Abuse: A Scoping Review.

Drug addiction is a chronic relapsing disorder that makes it a global problem. Genetics and environmental factors are the two most important factors that make someone vulnerable to drug addiction. Investigations in the past decade highlighted the role of epigenetics in the inter/transgenerational inheritance of drug addiction. A growing body of evidence showed that parental (paternal, maternal, and biparental) drug exposure before conception changes the phenotype of the offspring, which is correlated with neurochemical and neurostructural changes in the brain. The current paper reviews the effects of parental (maternal, paternal, and biparental) exposure to drugs of abuse (opioids, cocaine, nicotine, alcohol, and cannabis) before gestation in animal models.

Protective effects of nanocurcumin against stress-induced deterioration in the intestine.

The therapeutic activities of curcumin have long been investigated in some chronic and inflammatory diseases. This study was designed to investigate the protective effects of nanocurcumin on intestinal barrier function, apoptosis, and oxidative stress in rats exposed to traffic noise. Forty rats were divided into four groups: two traffic noise-exposed groups of animals that received either vehicle (NOISE) or nanocurcumin (NCUR + NOISE) and two control groups that either remained intact (CON) or received nanocurcumin (NCUR). Nanocurcumin injection (15 mg/Kg/ip) and traffic noise exposure were administered daily for two weeks. The relative protein expression of intestinal tight junctions, occludin, and ZO-1 and Bax/Bcl-2 ratio was measured to evaluate barrier integrity and apoptosis in intestinal samples, respectively. Plasma D-lactate concentration was examined as a criterion of intestinal permeability. Corticosterone, superoxide dismutase (SOD) activity, glutathione (GSH), total antioxidant capacity (TAC), and nitrite were measured in serum. The noise exposure increased Bax/Bcl-2 ratio, corticosterone, and oxidative stress in the NOISE animals. Nanocurcumin treatment improved the Bax/Bcl-2 ratio and reduced corticosterone and oxidative stress in the NCUR + NOISE animals. The expression of tight junction proteins was decreased while the concentration of D-lactate was increased in the NOISE animals. Nanocurcumin did not efficiently impact the expression of tight junction proteins and the D-lactate level in the NCUR + NOISE group. Nanocurcumin administration displayed antioxidant and anti-apoptotic roles in the noise-exposed rats, however, it did not affect the intestinal barrier integrity. We concluded that reduced apoptosis in the intestine might be related to the antioxidant activity of nanocurcumin and its modulatory effects on the HPA axis in the nanocurcumin-treated animals.

Mesenchymal stem cells and their conditioned medium as potential therapeutic strategies in managing comorbid anxiety in rat sepsis induced by cecal ligation and puncture.

Objectives: Sepsis-associated encephalopathy (SAE) is a common brain dysfunction following sepsis. Due to the beneficial effects of mesenchymal stem cells (MSCs) therapy on anxiety, an extreme and early manifestation of SAE, we hypothesized that MSCs-derived conditioned medium (CM) may be able to attenuate anxiety in cecal ligation and puncture (CLP)-induced sepsis. Materials and Methods: Rats were assigned into 4 groups: sham, CLP, MSC, and CM. All animals, except in the sham group, underwent the CLP procedure to induce sepsis. Two hours after sepsis induction, the rats in MSC and CM groups, received 1×106 MSCs and CM derived from the same number of cells, respectively. 48 hr after the treatments, anxiety-related behaviors were assessed, and brain and right hippocampal tissues were collected. Results: MSCs and CM enhanced the percentages of open arm entries and time spent in the open arms of the elevated plus-maze and the time spent in the light side of the light-dark box. MSCs and CM decreased the Evans blue content and decreased the IL-6 and TNF-α levels in the brain tissue samples. Reductions in the expression of 5-HT2A receptors and phosphorylation of ERK1/2 and an increase in the expression of 5-HT1A receptors in the hippocampal tissue samples were observed in the MSC and CM groups. Conclusion: MSCs and MSCs-derived CM attenuated anxiety-related behaviors to an equal extent by reducing inflammation, modifying 5-HT receptor expression changes, and inhibiting the ERK pathway. Therefore, MSCs-derived CM may be considered a promising therapy for comorbid anxiety in septic patients.

Adipose-derived mesenchymal stem cells reduced transient cerebral ischemia injury by modulation of inflammatory factors and AMPK signaling.

Stem cell-based treatments have been recommended as a feasible therapy for stroke victims due to their potential for angiogenesis, neurogenesis, and synaptic plasticity. The intracellular mechanisms of stem cells against cerebral hypoperfusion are not well recognized. In this study, by releasing the clips, the reperfusion period was extended to 96 h, and two hours after cerebral ischemia, animals received adipose-derived MSCs. MSCs were isolated from the inguinal fat pads of rats and injected into two-vessel occlusion (2VO) rats 1 h after ischemia induction. Ninety-six hours after 2VO induction, behavioral and molecular tests were assessed. Adipose-derived MSCs treatment improves neurological scores, passive avoidance memory, and novel object recognition tests in the 2VO model compared to 2VO rats (P < 0.001). MSCs treatment decreased TNF-α (P < 0.01) and IL-6 (P < 0.01) and apoptotic factors (Bax/Bcl-2 ratio and caspase-3 level (P < 0.01)) compared with ischemic rats. MSCs treatment of ischemic rats could enhance Klotho-α and AMPK-α compared with ischemic rats (P < 0.001). The study disclosed that adipose-derived MSCs could improve neurological damage and memory deficits by reducing neuronal death in cerebral ischemia. Data proposed that adipose-derived MSCs inhibit pro-inflammatory factors such as IL-6 and TNF-α, consequently decreasing apoptosis in the hippocampus of CCAO rats. Besides, the Klotho-α and AMPK-α measurements found that MSCs might induce intracellular neuroprotective pathways via activation of Klotho-α/AMPK-α signaling.

The neuroprotective effects of transcranial direct current stimulation on global cerebral ischemia and reperfusion via modulating apoptotic pathways.

BACKGROUND: Cerebral ischemia-reperfusion, subsequent hyperthermia, and hyperglycemia lead to neural damage. This study aimed to investigate the effects of using cathodal and/or anodal transcranial direct current stimulation (tDCS) in different stages of ischemia-reperfusion on apoptosis and controlling hyperthermia and hyperglycemia. MATERIALS AND METHODS: A total of 78 male Wistar rats were randomly assigned into six groups (n = 13), including sham, ischemia/reperfusion (I/R), anodal-tDCS (a-tDCS), cathodal-tDCS (c-tDCS), anodal/cathodal-tDCS (a/c-tDCS), and cathodal/anodal-tDCS (c/a-tDCS) groups. Global cerebral I/R was induced in all of the groups except for sham group. In a-tDCS and c-tDCS groups, the rats received anodal and cathodal currents in both I/R stages, respectively. In a/c-tDCS group, the rats received anodal current during the ischemia and cathodal current during the reperfusion. The c/a-tDCS group received the currents in the reverse order. The current intensity of 400 µA was applied in ischemia phase (15 min) and reperfusion phase (30 min, twice a day). Body temperature and plasma blood sugar were measured daily. Rats were also tested for novel object recognition and passive avoidance memory. The apoptosis of hippocampal tissue was evaluated by measuring Bax, Bcl-2, Caspase-3, and TUNEL staining. RESULTS: All tDCS significantly reduced hyperthermia and hyperglycemia, as well as Bax and Caspase-3 levels, it also increased Bcl-2 expression. The preliminary results from c/a-tDCS mode could improve the expression of apoptotic markers, memory function, hyperthermia, and hyperglycemia control and reduce DNA fragmentation compared to other stimulatory therapies. CONCLUSION: All tDCS modes could save neurons by suppressing apoptotic and enhancing anti-apoptotic pathways, especially in the c/a tDCS mode.

Using dual polarities of transcranial direct current stimulation in global cerebral ischemia and its following reperfusion period attenuates neuronal injury.

Multiple neuronal injury pathways are activated during cerebral ischemia and reperfusion (I/R). This study was designed to decrease potential neuronal injuries by using both transcranial direct current stimulation (tDCS) polarities in cerebral ischemia and its following reperfusion period. Ninety rats were randomly divided into six groups. In the sham group, rats were intact. In the I/R group, global cerebral I/R was only induced. In the I/R + c-tDCS and I/R + a-tDCS groups, cathodal and anodal currents were applied, respectively. In the I/R + c/a-tDCS, cathodal current was used in the cerebral ischemia and anodal in the reperfusion. In the I/R + a/c-tDCS group, cathodal and anodal currents were applied in the I/R, respectively. Hippocampal tissue was used to determine the levels of IL-1ß, TNF-α, NOS, SOD, MDA, and NMDAR. Hot plate and open field tests evaluated sensory and locomotor performances. The cerebral edema was also measured. Histological assessment was assessed by H/E and Nissl staining of the hippocampal CA1 region. All tDCS modes significantly decreased IL-1ß and TNF-α levels, especially in the c/a-tDCS. All tDCS caused a significant decrease in MDA and NOS levels while increasing SOD activity compared to the I/R group, especially in the c/a-tDCS mode. In the c-tDCS and a/c-tDCS groups, the NMDAR level was significantly decreased. The c/a-tDCS group improved sensory and locomotor performances more than other groups receiving tDCS. Furthermore, the least neuronal death was observed in the c/a-tDCS mode. Using two different polarities of tDCS could induce more neuroprotective versus pathophysiological pathways in cerebral I/R, especially in c/a-tDCS mode. HIGHLIGHTS: Multiple pathways of neuronal injury are activated in cerebral ischemia and reperfusion (I/R). Using tDCS could modulate neuroinflammation and oxidative stress pathways in global cerebral I/R. Using c/a-tDCS mode during cerebral I/R causes more neuroprotective effects against neuronal injuries of cerebral I/R.

Effects of nano-curcumin on noise stress-induced hippocampus-dependent memory impairment: behavioral and electrophysiological aspects.

BACKGROUND: Noise pollution is one of the fundamental factors in the etiology of many disorders. Noise stress adversely affects cognitive behaviors and long-term potentiation (LTP), the candidate mechanism of learning and memory. In the present study, we examined the neuroprotective effects of nano-curcumin on behavioral and electrophysiological aspects of hippocampus-dependent memory in noise-exposed animals. METHODS: The stressed animals received either vehicle (ST) or nano-curcumin (NANO + ST) for 2 weeks. The control groups remained either intact (CON) or received nano-curcumin (NANO + CON). The ST and NANO + ST groups were exposed to daily noise for 2 weeks. The spatial memory was assessed in the Morris water maze. The LTP was investigated through field potential recording in the CA3-CA1 pathway of the hippocampus. Serum corticosterone level was measured at the end of the experiments. RESULTS: The ST group showed a lower cognitive function and suppressed LTP compared to the CON group. The nano-curcumin treatment improved the maze navigation and LTP induction compared to the ST group. While the stress exposure elevated the serum level of corticosterone in the ST animals, nano-curcumin treatment reduced it. CONCLUSIONS: The nano-curcumin treatment restores impaired behavioral and electrophysiological aspects of learning and memory in the noise-exposed animals. The plasma corticosterone levels may be associated with changes in cognitive behavior and synaptic plasticity.

A Single Immediate Use of the Cathodal Transcranial Direct Current Stimulation Induces Neuroprotection of Hippocampal Region Against Global Cerebral Ischemia.

OBJECTIVES: Global cerebral ischemia (CI) causes severe neuronal injury, mainly in the hippocampal CA1 region. This study aimed to investigate an immediate using transcranial direct current stimulation (tDCS) in reducing neuronal injury induced by CI. MATERIALS AND METHODS: The 32 Wistar male rats were randomly divided into four groups (n=8 per group). In the ischemia group (I), CI was induced via the 4-vessel occlusion model. In the sham group (Sh), rats did not receive any intervention. In the ischemia+cathodal group (I+c/tDCS), the cathodal current was applied during CI. In the ischemia+anodal group (I+a/tDCS), the anodal current was applied. The current intensity of 400 µA was applied for 15-min during the ischemia. Hippocampal tissue was used to assess levels of NMDAR, IL-1ß, TNF-α, MDA, SOD, NOS, and apoptosis markers. Histological assessment and TUNEL staining were performed in CA1 hippocampal region. RESULTS: The c/tDCS significantly decreased the levels of IL-1ß and TNF-α than the I and a/tDCS groups. The c/tDCS significantly reduced MDA and NOS levels, while increasing the level of SOD than the I and a/tDCS. The c/tDCS caused a significant decrease in NMDAR level than the a/tDCS. Using c/tDCS significantly reduced the Bax and Caspase-3 expressions, while increasing the Bcl-2 expression than the I group. In the c/tDCS group, DNA fragmentation and neuronal death were significantly lower than the I and a/tDCS groups. CONCLUSION: Using cathodal a direct current could attenuate primary pathophysiological pathways induced by CI, and it eventually reduced neurons death and apoptosis in the CA1 hippocampal region.

Dimethyl fumarate protects the aged brain following chronic cerebral hypoperfusion-related ischemia in rats in Nrf2-dependent manner.

It has been stated that chronic cerebral hypoperfusion (CCH) markedly prompts neuronal damage and affects cognition. Dimethyl fumarate (DMF), a nuclear erythroid 2-related factor 2 (Nrf2) activator, represents a class of molecules exhibiting neuroprotection. We explored the effect of DMF on CCH using a model of permanent left common carotid occlusion. The left common carotid artery was occluded and then DMF (100mg.kg-1) was orally administrated three times per week for four consecutive weeks. Behavioral rests, PET imaging and Hematoxylin and Eosin staining, were examined and also, the hippocampal level of inflammatory, Nrf2 antioxidant, neuronal plasticity and apoptotic factors were determined using Western blot analysis and related ELISA kits. The neurological deficit scores were significantly reduced in the treatment group compared with the CCH group (P<0.001). DMF decreased the novel object recognition index (NOR) compared with the CCH group, while CCH + DMF increased the NOR compared with the CCH group (P<0.001). CCH + DMF reduces the ratio of Bax/Bcl2 and capase-3 activity in comparison to the CCH group (P<0.001). Treatment with DMF increased Nrf2, NAD(P)H dehydrogenase-1 and Heme oxygenase-1 and decreased Tumor necrosis factor α and Nuclear factor-κB density compared with the CCH group (P<0.001). A significant increase in brain-derived neurotrophic factor and c-fos was found in DMF-treated rats compared with the CCH group (P<0.001). Also, retinoic acid inhibits Nrf2 activation via DMF and increases inflammatory factors in hypoperfused rats' hippocampus compared with the CCH group (P<0.001). Long-term DMF treatment induces the Nrf2 pathway and has beneficial effects on memory and motility in CCH.

Lactobacillus rhamnosus R0011 Treatment Enhanced Efficacy of Capecitabine against Colon Cancer in Male Balb/c Mice.

The microbiome of the intestinal system is well-known as a modulatory factor. Having a balanced status of microbiota could help to prevent diseases, especially cancers related to the gastrointestinal system. We investigated the effects of Lactobacillus rhamnosus (Lr) and capecitabine on tumor size and physiologic features, such as bodyweight, liver enzymes, and blood profile, in a subcutaneously induced cancer model using CT-26 murine colon carcinoma cells. We divided 48 male Balb/c inbred mice into six groups. Lr had been orally pre-inoculated to the mice for 14 day consecutively. CT-26 cells were implanted subcutaneously into the mice's flank. Following the injection of cancer cells, Lr was inoculated to the mice three times per week for four weeks. Capecitabine was inoculated in the third week after the induction of cancer. The tumor size was significantly decreased in treated groups in comparison to the cancer group (1174.5 ± 63.8, 1119.2 ± 86.3, and 985.6 ± 48 mm3 vs. 1674.2 ± 66 mm3, P < 0.0001). Data showed that Lr and capecitabine enhanced Bax/Bcl-2 ratio and caspase-3 level compared to cancer group (p < 0.0001). White blood cells (WBCs) were significantly decreased in the capecitabine group compared to probiotic group (P < 0.05). Measurement of bodyweight, liver enzymes, and interleukin-6 (IL-6) level showed that Lr, in addition to preventive and therapeutic effects, might have protective effects against chemotherapy side effects. Preventing WBCs' reduction, protecting mice from losing weight, induction of apoptosis, and enhancing the serum level of IL-6 indicated that Lr might be associated with better management of colorectal cancer and chemotherapy side effects.

Beneficial effects of combination therapy with testosterone and hydrogen sulfide by reducing oxidative stress and apoptosis: Rat experimental varicocele model.

Background: Despite the effectiveness of testosterone therapy in conditions associated with testosterone deficiency, including varicocele, several dose-dependent side effects limit the clinical use of testosterone therapy. Hydrogen sulfide, a toxic gas in high concentrations but a beneficial molecule in low concentrations, acts as both a major effector and an important inducer of testosterone. Objective: This study investigated whether a subeffective dose of testosterone combined with a subeffective dose of hydrogen sulfide donor sodium hydrosulfide (NaHS) can be effective in an experimental varicocele model through a possible additive effect. Materials and Methods: Thirty Wistar rats weighing 200-250 gr were divided into 5 groups as (n = 6/each): sham, varicocele, testosterone (200 µg/kg, 5 times per wk for 4 consecutive weeks), NaHS (15 µmol/L, daily for 4 consecutive wk) and testosterone + NaHS (200 µg/kg, 5 times per wk + 15 µmol/L, daily, both for 4 consecutive wk). All animals, except in the sham group, underwent varicocele induction. Results: The coadministration of testosterone and NaHS significantly increased serum testosterone (10.23 ± 0.95, p = 0.01), testicular H2S levels (608.94 ± 21.09, p < 0.001), and testicular superoxide dismutase activity (66.14 ± 1.56, p < 0.001), decreased malondialdehyde levels (0.77 ± 0.52, p < 0.001), and B-cell lymphoma 2-associated X protein to B-cell lymphoma 2 (0.16 ± 0.01, p < 0.001) protein expression ratio in the testicular tissues and improved sperm parameters and testicular histopathology compared to the varicocele group. Conclusion: The combination therapy of subeffective doses of testosterone and NaHS can attenuate the varicocele-induced damages by reducing testicular oxidative stress and apoptosis and thus can be considered an effective approach with fewer side effects.