The effects of CORM3 or NaHS on the oxidative stress caused by chronic kidney disease in rats: potential interaction between CO and H2S signaling pathway.

Neurotoxicity is implicated as a severe complication of chronic kidney disease (CKD). Accumulation of urea and other toxic compounds leads to oxidative stress, inflammation and destruction of the blood-brain barrier. Carbon monoxide (CO) and hydrogen sulfide (H2S) have been shown to have anti-inflammatory, anti-apoptotic, and anti-proliferative properties. The aims of the present study were evaluated the protective effects of CO-releasing molecule (CORM3) and H2S donor (NaHS) on oxidative stress and neuronal death induced by CKD in the hippocampus and prefrontal cortex by considering interaction between CO and H2S on CBS expression. CORM3 or NaHS significantly compensated deficits in the antioxidant defense mechanisms, suppressed lipid peroxidation and reduced neuronal death in hippocampus and prefrontal cortex and improvement the markers of renal injury that induced by CKD. In addition, CORM3 or NaHS significantly improved CBS expression which were reduced by CKD. However, improving effects of CORM3 on antioxidant defense mechanisms, lipid peroxidation, neuronal death, renal injury and CBS expression were prevented by amino-oxy acetic acid (AOAA) (CBS inhibitor) and reciprocally improving effects of NaHS on all above indices were prevented by zinc protoporphyrin IX (Znpp) (HO-1 inhibitor). In conclusion, this study demonstrated that formation of CO and H2S were interdependently improved CKD-induced oxidative stress and neuronal death, which is may be through increased expression of CBS.

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.

The effects of vitamin C on respiratory, allergic and immunological diseases: an experimental and clinical-based review.

Vitamin C is used in modern medicine supplements for treatment of various disorders associated with oxidative stress, inflammation and immune dysregulation. In this review article, experimental and clinical results regarding the effects of vitamin C on respiratory immunologic, and allergic diseases are reviewed. Various databases and appropriate keywords are used to search the effect of vitamin C on respiratory diseases until the end of May 2022. Books, theses and articles were included. These studies assessed the effects of vitamin C on respiratory disorders including asthma, chronic obstructive pulmonary disease (COPD), lung infection and lung cancer. Vitamin C showed relaxant effect on tracheal smooth muscle via various mechanisms. The preventive effects of vitamin C were mediated by antioxidant, immunomodulatory and anti-inflammatory mechanisms in the experimental animal models of different respiratory diseases. Some clinical studies also indicated the effect of vitamin C on lung cancer and lung infections. Therefore, vitamin C could be used a preventive and/or relieving therapy in respiratory diseases.

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.

Therapeutic effects of CORM3 and NaHS in chronic kidney disease induced cognitive impairment via the interaction between carbon monoxide and hydrogen sulfide on Nrf2/HO-1 signaling pathway in rats.

Cognitive impairment is one of the major complications of chronic kidney disease (CKD). The present study aims to evaluate the protective effects of carbon monoxide (CO) and hydrogen sulfide (H2S) and their interactions on CKD-induced cognitive deficits by considering the Nrf2/HO-1 signaling pathway. Sixty rats were divided into six experimental groups: sham, five-sixth (5/6) nephrectomy (CKD), CKD + H2S donor (NaHS), CKD + CO-releasing molecule (CORM3), CKD + NaHS and zinc protoporphyrin IX (Znpp), CKD + CORM3 and amino-oxy acetic acid (AOAA). Eleven weeks after 5/6Nx, behavioral tests (Novel object recognition test, Passive avoidance test and Barnes maze test) were performed to evaluate the cognitive level. At the end of the twelfth week, blood urea nitrogen (BUN) and serum creatinine (sCr) levels, as well as the expression levels of nuclear factor-erythroid factor 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and neuronal loss in the hippocampus and prefrontal cortex were evaluated. CKD caused enhancement of BUN and sCr, reduction of Nrf2 and HO-1 proteins and enhancement of neuronal loss in the hippocampus and prefrontal cortex. In addition, CKD led to cognitive disturbances and memory impairment. CORM3 and NaHS returned all above indices to the levels measured in the control group. However, improving effects of CORM3 on cognitive impairment and Nrf2/HO-1 signaling pathway were prevented by AOAA and decreased H2S level as well as reciprocally improving effects of NaHS on cognitive disturbances and Nrf2/HO-1 signaling pathway were prevented by Znpp and decreased CO level. In conclusion, this study demonstrated that formation of CO and H2S were interdependently improved CKD-induced cognitive dysfunctions, through interaction with Nrf2/HO-1 signaling pathway.

A Mouse Model of Orotracheal Intubation and Ventilated Lung Ischemia Reperfusion Surgery.

Ischemia reperfusion (IR) injury frequently results from processes that involve a transient period of interrupted blood flow. In the lung, isolated IR permits the experimental study of this specific process with continued alveolar ventilation, thereby avoiding the compounding injurious processes of hypoxia and atelectasis. In the clinical context, lung ischemia reperfusion injury (also known as lung IRI or LIRI) is caused by numerous processes, including but not limited to pulmonary embolism, resuscitated hemorrhagic trauma, and lung transplantation. There are currently limited effective treatment options for LIRI. Here, we present a reversible surgical model of lung IR involving first orotracheal intubation followed by unilateral left lung ischemia and reperfusion with preserved alveolar ventilation or gas exchange. Mice undergo a left thoracotomy, through which the left pulmonary artery is exposed, visualized, isolated, and compressed using a reversible slipknot. The surgical incision is then closed during the ischemic period, and the animal is awakened and extubated. With the mouse spontaneously breathing, reperfusion is established by releasing the slipknot around the pulmonary artery. This clinically relevant survival model permits the evaluation of lung IR injury, the resolution phase, downstream effects on lung function, as well as two-hit models involving experimental pneumonia. While technically challenging, this model can be mastered over the course of a few weeks to months with an eventual survival or success rate of 80%-90%.

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.

Nephroprotection through Modifying the Apoptotic TNF-α/ERK1/2/Bax Signaling Pathway and Oxidative Stress by Long-term Sodium Hydrosulfide Administration in Ovalbumin-induced Chronic Asthma.

Asthma is one of the most common respiratory diseases in the world. Nevertheless, it is reported that inflammation induced by asthma is not only restricted to the lung and may cause damaging effects on remote organs. Therefore, this study was designed to investigate the beneficial effects of long-term sodium hydrosulfide (NaHS) administration on lung inflammation and oxidative stress markers to protect the kidney during chronic asthma. BALB/c mice were divided into three groups (n = 5-7): control, asthma and NaHS. Except the control group, sensitization and challenge were performed with ovalbumin. The NaHS group intraperitoneally received 14 µmol/kg NaHS 30 min before each challenge. 24 h after the last challenge, samples of bronchoalveolar lavage fluid (BALF), plasma, lung and kidney tissues were collected. NaHS administration significantly decreased total white blood cell count, percentages of eosinophils, neutrophils and macrophages and increased percentage of lymphocytes. Administration of NaHS considerably decreased the levels of BALF interleukin-13, plasma tumor necrosis factor-alpha (TNF-α), lung malondialdehyde (MDA) and lung phosphorylated nuclear factor-kappa B (p-NF-κB) expression and scores of peribronchial inflammatory cell infiltration, goblet cell hyperplasia and subepithelial fibrosis and increased the activity of lung superoxide dismutase (SOD). The MDA levels and expressions of p-ERK1/2 and Bax were decreased and SOD activity and expressions of Bcl-2 and p-Akt were significantly increased in kidney tissues by NaHS administration. Administration of NaHS decreased renal oxidative stress indices and reduced apoptosis by the inhibition of TNF-α/ERK1/2/Bax. Therefore, H2S may have an essential role in renal protection during asthma.

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.

Pharmacological Properties of Allium cepa, Preclinical and Clinical Evidences; A Review.

Onion or Allium cepa (A. cepa) is one of the most important condiment plants grown and consumed all over the world. This plant has various therapeutic effects attributed to its constituents, such as quercetin, thiosulphinates and phenolic acids. In the present article, various pharmacological and therapeutic effects of A. cepa were reviewed. Different online databases using keywords such as onion, A. cepa, therapeutic effects, and pharmacological effects until the end of December 2019 were searched for this purpose. Onion has been suggested to be effective in treating a broad range of disorders, including asthma, inflammatory disorders, dysentery, wounds, scars, keloids and pain. In addition, different studies have demonstrated that onion possesses numerous pharmacological properties, including anti-cancer, anti-diabetic and anti-platelet properties as well as the effect on bone, cardiovascular, gastrointestinal, nervous, respiratory, and urogenital systems effects such as anti-osteoporosis, anti-hypertensive, antispasmodic, anti-diarrheal, neuro-protective, anti-asthmatic and diuretic effects. The present review provides detailed the various pharmacological properties of onion and its constituents and possible underlying mechanisms. The results of multiple studies suggested the therapeutic effect of onion on a wide range of disorders.

Effects of Allium cepa and Its Constituents on Respiratory and Allergic Disorders: A Comprehensive Review of Experimental and Clinical Evidence.

The health benefits of Allium cepa (A. cepa) have been proclaimed for centuries. Various pharmacological and therapeutic effects on respiratory, allergic, and immunologic disorders are shown by A. cepa and its constituents. Flavonoids such as quercetin and kaempferol, alk(en)yl cysteine sulfoxides including S-methyl cysteine sulfoxide and S-propyl cysteine sulfoxide, cycloalliin, thiosulfinates, and sulfides are the main compounds of the plant. A. cepa displays broad-spectrum pharmacological activities including antioxidant, anti-inflammatory, antihypertensive, and antidiabetic effects. Our objective in this review is to present the effects of A. cepa and its constituents on respiratory, allergic, and immunologic disorders. Different online databases were searched to find articles related to the effect of A. cepa extracts and its constituents on respiratory, allergic, and immunologic disorders until the end of December 2020 using keywords such as onion, A. cepa, constituents of A. cepa, therapeutic effects and pharmacological effects, and respiratory, allergic, and immunologic disorders. Extracts and constituents of A. cepa showed tracheal smooth muscle relaxant effects, indicating possible bronchodilator activities or relieving effects on obstructive respiratory diseases. In experimental animal models of different respiratory diseases, the preventive effect of various extracts and constituents of A. cepa was induced by their antioxidant, immunomodulatory, and anti-inflammatory effects. The preventive effects of the plant and its components on lung disorders induced by exposure to noxious agents as well as lung cancer, lung infection, and allergic and immunologic disorders were also indicated in the experimental and clinical studies. Therefore, this review may be considered a scientific basis for development of therapies using this plant, to improve respiratory, allergic, and immunologic disorders.

A review of anti-inflammatory, antioxidant, and immunomodulatory effects of Allium cepa and its main constituents.

CONTEXT: Allium cepa L. (Liliaceae), known as onion, is consumed throughout the world. Onion and its derivatives including saponins, aglycones, quercetin, cepaenes, flavonoids, organosulfurs, and phenolic compounds, showed various pharmacological properties and therapeutic effects. OBJECTIVE: Anti-inflammatory, antioxidant, and immunomodulatory effects of A. cepa and its main constituents, along with the underlying molecular mechanisms are presented. METHODS: Databases including, Web of Knowledge, Medline/PubMed, Scopus, and Google Scholar were checked for articles published between 1996 and the end of July 2020, using the key-words Allium cepa, quercetin, anti-inflammatory, antioxidant and immunomodulatory. RESULTS: A. cepa and its constituents mainly quercetin showed anti-inflammatory effects mediated via reduction of total and differential WBC counts, inhibition of chemotaxis of polymorphonuclear leukocytes, COX, and LOX pathways and prevented formation of leukotrienes and thromboxanes, prostaglandin E2 (PGE2) as onVCAM-1, NF-κB, MARK,d STAT-1, JNK, p38 and osteoclastogenesis. A. cepa and its derivatives showed antioxidant effect by decreasing lipid peroxidation, NAD(P)H, MDA, NO, LPO and eNOS but enhancing antioxidants such as SOD, CAT, GSH, GPx, GSPO, TrxR, SDH, GST and GR activities and thiol level. Immunomodulatory effects of the plant and quercetin was also shown by reduction of Th2 cytokines, IL-4, IL-5, and IL-13 as well as IL-6, IL-8, IL-10, IL-1ß and TNF-α and IgE levels, but increased CD4 cells, IFN-γ level and IFN-γ/IL4 ratio (Th1/Th2 balance). CONCLUSIONS: The effect of onion and its constituents on oxidative stress, inflammatory and immune system were shown indicating their therapeutic value in treatment of various diseases associated with oxidative stress, inflammation, and immune-dysregulation.

Sperm and testicular dysfunction during cecal ligation and puncture-induced sepsis in male rats and effects of tannic acid through reducing testicular oxidative stress and inflammation.

Objectives: One of the problems caused by infectious diseases is the decrease in sperm count and motility. Tannic acid is known as an anti-oxidant and anti-inflammatory agent. In this study, Cecal Ligation and Puncture (CLP) sepsis model was induced to investigate the effect of tannic acid on oxidative stress and inflammation in testicular and sperm structure and function. Materials and Methods: Twenty-four male Wistar rats (250-300 g) were randomly divided into 3 groups of 8: 1) sham, 2) sepsis, and 3) sepsis + tannic acid (20 mg/kg at 6, 12, and 24 hr after sepsis induction). Thirty hours after induction of sepsis, testicular samples were collected to measure SOD activity and MDA, IL-6, and TNF-α levels. Another part of the testis was fixed in 10% formalin for histological examinations. Results: In the sepsis group, testicular MDA, TNF-α, and IL-6 levels increased and SOD activity decreased compared with the sham group. In addition, the percentage of motile sperm and the survival rate of sperm decreased significantly in the sepsis group. Administration of tannic acid significantly decreased inflammatory markers (TNF-α and IL-6) and MDA levels and increased SOD activity. Furthermore tannic acid significantly improved sperm parameters and increased sperm and animal survival rates. Conclusion: The results of this study showed that the reproductive system may be strongly affected by the conditions created during sepsis. Tannic acid improved reproductive dysfunction in sepsis by reducing oxidative stress and inflammation.

The Trend of Interpersonal Violence Mortality at National and Provincial Levels in Iran From 1990 to 2015.

Interpersonal violence (IPV) is a major public health concern with a significant impact on physical and mental health. This study was designed to evaluate age-sex-specific IPV mortality trends and the assault mechanisms (firearm, sharp objects, and other means), at national and provincial levels, in Iran. We used the Iranian Death Registration System (DRS) and the population and housing censuses in this analysis. Spatio-temporal and Gaussian Process Regression methods were used to adjust for inconsistencies at the provincial level and to integrate data from various sources. After assessing their validity, all records were reclassified according to the International Classification of Diseases, 10th Revision (ICD-10). All ICD-10 codes were then mapped to Global Burden of Disease (GBD) 2013 coding. More than 700 individuals died due to IPV in 1990 and more than twice this number in 2015. The IPV mortality age-standardized rate, per 100,000, increased from 1.62 (95% Uncertainty Interval [UI] = [0.96, 2.75]) in 1990 to 1.81 [1.15, 2.89] in 2015. Among females, the age-standardized mortality rate at national level per 100,000 due to IPV was 1.27 [0.66, 2.43] in 1990 and decreased to 1.08 [0.60, 1.96] in 2015. Among males, the age-standardized mortality rate was 1.96 [1.25, 3.09] in 1990 rising to 2.54 [1.70, 3.82] in 2015. Data from provinces revealed that during the period of our study, Hormozgan province had the largest increase of IPV among females, and Fars province had the largest increase of IPV among males. Conversely, the largest decrease was detected in West Azarbaijan and Qom provinces in females and males, respectively. This study showed a wide variation in the incidence and trends of IPV in Iran by age, sex, and location. The study has provided valuable information to reduce the burden of IPV in Iran and a means to monitor future progress through repeated analyses of the trends.

An overview of high-mobility group box 1, a potent pro-inflammatory cytokine in asthma.

High-mobility group box 1 (HMGB1), also called amphoterin, HMG1 and p30, is a highly conserved protein between different species that has various functions in nucleus such as stabilization of nucleosome formation, facilitation of deoxyribonucleic acid (DNA) bending and increasing the DNA transcription, replication and repair. It has also been indicated that HMGB1 acts as a potent pro-inflammatory cytokine with increasing concentrations in acute and chronic inflammatory diseases. Asthma is a common chronic respiratory disease associated with high morbidity and mortality rates. One central characteristic in its pathogenesis is airway inflammation. Considering the inflammatory role of HMGB1 and importance of inflammation in asthma pathogenesis, a better understanding of this protein is vital. This review describes the structure, cell surface receptors, signaling pathways and intracellular and extracellular functions of HMGB1, but also focuses on its inflammatory role in asthma. Moreover, this manuscript reviews experimental and clinical studies that investigated the pathologic role of HMGB1.

Adipose-Derived Mesenchymal Stem Cells and Conditioned Medium Attenuate the Memory Retrieval Impairment During Sepsis in Rats.

In this study, we hypothesized that sepsis induction impairs memory retrieval in rats while transplanted mesenchymal stem cells (MSCs) and MSC-conditioned medium (MSC-CM) application are capable of attenuating those complications. MSCs were obtained from adipose tissue of rats and at the second culture passage; MSCs and MSC-CM were collected. Rats were randomly divided into four experimental groups: sham, CLP, MSC, and MSC-CM. Sepsis was induced by cecal ligation and puncture (CLP) model in the CLP, MSC, and MSC-CM groups. The MSC group received 1 × 106 MSCs/rat (i.p., 2 h after CLP surgery); the MSC-CM rats received the conditioned medium (CM) from 1 × 106 MSCs intraperitoneally 2 h after sepsis induction. Novel object recognition test, sepsis score, and blood pressure measurement were performed 24 h after the treatments. The right hippocampus was taken for western blot analysis. CLP rats showed a significantly higher sepsis score and systolic blood pressure. They also had a significant increase in the phosphorylated form of CAMKII-α, cleaved caspase 3 and Bax/Bcl2 ratio, and a reduction in c-fos protein in the hippocampus tissue samples compared with the sham group. MSC transplantation and MSC-CM administration significantly decreased the mean sepsis score and prevented sepsis-induced attenuation of blood pressure compared with the CLP rats. Animals in the MSC and MSC-CM groups showed a better memory retrieval, attenuation in phosphorylated form of CAMKII-α, cleaved caspase 3 and Bax/Bcl2 ratio, and an increase in c-fos protein expression compared with the CLP group. It seems that CAMKII and c-fos are inversely involved in regulating memory processes in hippocampus. Phosphorylated form of CaMKII-α overexpression may impair the ability of object recognition. Our findings confirmed that MSC-CM application has more advantages compared with transplanted MSCs and may be offered as a promising therapy for inflammatory diseases such as severe sepsis.

Administration of sodium hydrosulfide reduces remote organ injury by an anti-oxidant mechanism in a rat model of varicocele.

OBJECTIVES: Infertility in varicocele may have an adverse outcome on the future life of an infertile male. This study was designed to investigate whether varicocele affects remote organs, including the kidney, liver, and brain. We have also evaluated the protective effects of NaHS administration on the structure and function of these organs. MATERIALS AND METHODS: Thirty-six rats were randomly assigned to 3 experimental groups: 1) Sham, 2) Varicocele, and 3) Varicocele + sodium hydrosulfide. Varicocele was induced via partial ligation of the left renal veins. Animals in the Varicocele + sodium hydrogen sulfide group received 30 µmol/l NaHS in drinking water for 56 days. On the 57th day of the treatment, blood samples, as well as kidney, liver, and brain tissues, were collected to assess kidney and liver functions, measurement of oxidative stress markers, and histological changes. For evaluation of sperm parameters caudal epididymis was used. The behavioral tests were performed to evaluate the animal's anxiety-related behaviors. RESULTS: Varicocele caused significant decrease in sperm parameters (motility and viability) and superoxide dismutase activity in the kidney, liver, and brain tissue. Anxiety-related parameters decreased in varicocele. Moreover, varicocele resulted in a significant increase in malondialdehyde levels in the kidney, liver and brain tissue, and liver function enzymes. Varicocele did not alter kidney function parameters. The administration of NaHS improves the above parameters. CONCLUSION: This study showed that notice to remote organs such as the liver and brain beside reproductive organs in varicocele is important. The administration of NaHS improved remote organ injury in varicocele via its anti-oxidant mechanism.

Protective effects of ascorbic acid and calcitriol combination on airway remodelling in ovalbumin-induced chronic asthma.

Context: Airway remodelling is one of the most refractory problems in asthma. According to the critical roles of oxidative stress and inflammation in airway remodelling, it is supposed that ascorbic acid and calcitriol have beneficial effects. However, a combination of antioxidants may be more effective for asthma therapy.Objective: This study investigated the protective effects of ascorbic acid in combination with calcitriol on airway remodelling in ovalbumin (OVA)-induced chronic asthma.Materials and methods: BALB/c mice were assigned into seven groups: (1) Control; (2) Asthma; (3) Ineffective C (orally 39 mg/kg ascorbic acid); (4) Ineffective D (intraperitoneally 1.5 µg/kg calcitriol); (5) Effective C (orally 130 mg/kg ascorbic acid); (6) Effective D (intraperitoneally 5 µg/kg calcitriol); (7) Combination (orally 39 mg/kg ascorbic acid + intraperitoneally 1.5 µg/kg calcitriol). All animals were sensitized and challenged with OVA except in the control group (normal saline). In all treatment groups, mice were administrated vitamins 30 min before each challenge (three times per week for 8 consecutive weeks).Results: In comparison with the asthma group, co-administration of ineffective doses of ascorbic acid and calcitriol led to the decreased levels of IL-13 (50.5 ± 1.85 vs. 42.13 ± 0.37 pg/mL, p = 0.02) and IgE (58.74 ± 0.43 vs. 45.78 ± 2.05 ng/mL, p = 0.003) as well as the reduction of goblet hyperplasia and subepithelial fibrosis (5 vs. 1 score, p = 0.001 and 5 vs. 2 score, p = 0.001, respectively).Discussion and conclusions: Combination of ascorbic acid with calcitriol in ineffective doses improves airway remodelling due to additive effects possibly through reduction of oxidative stress and inflammation. This study provides a scientific basis for further research and clinical applications of ascorbic acid and calcitriol and can be generalized to the broader pharmacological studies.

Long-term NaHS administration reduces oxidative stress and apoptosis in a rat model of left-side varicocele.

The main aim of this study was to assay the testicular H2 S levels in the varicocele rat model and then to investigate the protective effects of NaHS on morphometric changes, sperm parameters, oxidative stress and apoptosis markers in rat's testis. D,L-propargylglycine (PAG) was administrated to show the effects of cystathionine γ-lyase enzyme (CSE) inhibition in the varicocele. Rats were assigned to four groups: (a) Sham, (b) varicocele, (c) varicocele + PAG and (d) varicocele + NaHS. Animals in varicocele + NaHS group received 30 µmol/L NaHS in drinking water for 56 days. In the varicocele + PAG group, animals received PAG 19 mg/kg twice a week. Morphometric assessment, oxidative stress markers, testicular H2 S levels, sperm parameters, TUNEL assay and expression of Bax/Bcl2 were evaluated at the end of experiment. Testicular H2 S levels were significantly decreased in varicocele group. NaHS significantly improved sperm parameters, morphometric characteristics and oxidative stress compared to varicocele group. Oxidative stress status deteriorated in the PAG group compared to the varicocele group. This study showed that a low testicular H2 S level might play a critical role in male infertility. Thus, NaHS administration may be a promising treatment strategy for male infertility in varicocele. In addition, CSE may not be the only important enzyme in testicular H2 S production.

Combination of ascorbic acid and calcitriol attenuates chronic asthma disease by reductions in oxidative stress and inflammation.

Airway inflammation and oxidative stress are the two major characteristics of asthma pathogenesis. Therefore, this study evaluated the protective effects of ascorbic acid in combination with calcitriol on the oxidative damages and inflammation in asthma model. All animals, except in the control group, were sensitized and challenged with ovalbumin. One day after the last challenge, samples of bronchoalveolar lavage fluid was collected for the assessment of total white blood cell counts and differential count of white blood cell and plasma was used for the measurement of pro-oxidant/antioxidant balance level. Lung tissue samples were also stored for examining peribronchial inflammatory cell infiltration, phosphorylated nuclear factor-kappa B expression and measurement of malondialdehyde level. Induction of asthma caused significant increases in total white blood cell counts, percentage of neutrophils and eosinophils and a decrease in the percentage of lymphocytes. Moreover, asthma resulted in significant increases of peribronchial inflammatory cell infiltration, phosphorylated nuclear factor-kappa B expression and malondialdehyde level. However, no significant changes were observed in pro-oxidant/antioxidant balance level with the induction of asthma. Co-administration of low doses of ascorbic acid and calcitriol returned all to the levels measured before sensitization and challenge. Combination of low doses of ascorbic acid with calcitriol improves mouse asthma model by a possible additive effects through the decrease of oxidative stress and inflammation.