Cinnamic acid mitigates methotrexate-induced lung fibrosis in rats: comparative study with pirfenidone.

PURPOSE: Lung fibrosis is a heterogeneous lung condition characterized by excessive accumulation of scarred tissue, leading to lung architecture destruction and restricted ventilation. The current work was conducted to examine the probable shielding influence of cinnamic acid against lung fibrosis induced by methotrexate. METHODS: Rats were pre-treated with oral administration of cinnamic acid (50 mg/kg/day) for 14 days, whereas methotrexate (14 mg/kg) was orally given on the 5th and 12th days of the experiment. Pirfenidone (50 mg/kg/day) was used as a standard drug. At the end of the experiment, oxidative parameters (malondialdehyde, myeloperoxidase, nitric oxide, and total glutathione) and inflammatory mediators (tumor necrosis factor-α and interleukin-8), as well as transforming growth factor-ß and collagen content, as fibrosis indicators, were measured in lung tissue. RESULTS: Our results revealed that cinnamic acid, as pirfenidone, effectively prevented the methotrexate-induced overt histopathological damage. This was associated with parallel improvements in oxidative, inflammatory, and fibrotic parameters measured. The outcomes of cinnamic acid administration were more or less the same as those of pirfenidone. In conclusion, pre-treatment with cinnamic acid protects against methotrexate-induced fibrosis, making it a promising prophylactic adjuvant therapy to methotrexate and protecting against its possible induction of lung fibrosis.

Inosine attenuates rotenone-induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis.

Growing evidence points to impaired autophagy as one of the major factors implicated in the pathophysiology of Parkinson's disease (PD). Autophagy is a downstream target of adenosine monophosphate-activated protein kinase (AMPK). Inosine has already demonstrated a neuroprotective effect against neuronal loss in neurodegenerative diseases, mainly due its anti-inflammatory and antioxidant properties. We, herein, aimed at investigating the neuroprotective effects of inosine against rotenone-induced PD in rats and to focus on the activation of AMPK-mediated autophagy. Inosine successfully increased p-AMPK/AMPK ratio in PD rats and improved their motor performance and muscular co-ordination (assessed by rotarod, open field, and grip strength tests, as well as by manual gait analysis). Furthermore, inosine was able to mitigate the rotenone-induced histopathological alterations and to restore the tyrosine hydroxylase immunoreactivity in PD rats' substantia nigra. Inosine-induced AMPK activation resulted in an autophagy enhancement, as demonstrated by the increased striatal Unc-S1-like kinase1 and beclin-1 expression, and also by the increment light chain 3II to light chain 3I ratio, along with the decline in striatal mammalian target of rapamycin and p62 protein expressions. The inosine-induced stimulation of AMPK also attenuated neuronal apoptosis and promoted antioxidant activity. Unsurprisingly, these neuroprotective effects were antagonized by a preadministration of dorsomorphin (an AMPK inhibitor). In conclusion, inosine exerted neuroprotective effects against the rotenone-induced neuronal loss via an AMPK activation and through the restoration of the imbalance between autophagy and apoptosis. These findings support potential application of inosine in PD treatment.

Apigenin and Exposure to Low Dose Gamma Radiation Ameliorate Acetic Acid-Induced Ulcerative Colitis in Rats.

Ulcerative colitis (UC) is an inflammatory bowel disease involving chronic and recurring colon inflammation. Current management protocols are limited by adverse effects or short-term symptomatic relief. We aimed to investigate the possible therapeutic prospect of low dose gamma (γ) irradiation or apigenin treatment in acetic acid-induced UC in rats. Induction of UC was carried out by installation of acetic acid intra-rectally. One hour post-induction, rats received a sole dose of γ-radiation (0.5 Gray) or were treated with apigenin (3 mg/kg/day, peroral) for 7 successive days. Antioxidant and anti-inflammatory effects of both agents were assessed via determination of colon malondialdehyde (MDA), reduced glutathione (GSH), total nitrate/nitrite (NOx), mucosal addressin cell adhesion molecule-1 (MAdCAM-1), and interleukin-1beta (IL-1ß) contents as well as myeloperoxidase (MPO) activity. Body weight (BW), colon weight/length (W/L) ratio, disease activity index (DAI), and histopathological changes were evaluated. Gamma irradiation and apigenin significantly ameliorated the acetic acid-induced biochemical and histopathological changes. Both therapeutic approaches significantly restored colon contents of the investigated biomarkers. They modulated BW, colon W/L ratio and DAI. This study proposes low dose γ-irradiation as a new therapeutic candidate for the management of UC. We also concluded that apigenin exhibited therapeutic benefits in UC management.

Modulation of PTZ-induced convulsions in rats using topiramate alone or combined with low dose gamma irradiation: involving AKT/m-TOR pathway.

The current study evaluates the anticonvulsant effect low dose whole body gamma irradiation (LDR) alone or combined with topiramate against pentylenetetrazole (PTZ)-induced convulsions. Male Wister rats received either saline or PTZ (75 mg/kg i.p.). The other three groups were pretreated with single low dose radiation (0.5 Gy), topiramate (50 mg/kg, p.o., seven days) and TPM with LDR respectively before PTZ injection. Racine' score, latency, and duration of the convulsions were assessed. Glutamate and GABA were measured. AKT/m-TOR signaling pathway including AKT (protein kinase B), mammalian target of rapamycin (m-TOR), protein S6, and caspase 3 were also assessed. Measurements of markers of oxidative stress including malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) were carried out. Histological examinations of hippocampi were done. PTZ produced behavioral changes (high Racine score, short latency, and long duration). It elevated MDA and NO contents, while reduced GSH content. TPM treatment alone or combined with LDR ameliorated the PTZ-induced convulsions and caused significant improvement in behavioral changes, brain mediators, m-TOR pathway, oxidative stress, and histological pictures in hippocampal regions. Histopathological examinations of the normal group showed normal structure with intact cells, while PTZ-treated rats exhibited necrosis, pyknosis, and atrophy of pyramidal cells. The histological findings corroborated with the amendment of biochemical parameters. The positive effects of LDR could offer a possible contributor in management of convulsions due to modulation of AkT/m-TOR signaling pathway, reduction of oxidative stress and modulation of brain amino acids. LDR improved the oxidative stress side effects of topiramate.

Antisense Tissue Factor Oligodeoxynucleotides Protected Diethyl Nitrosamine/Carbon Tetrachloride-Induced Liver Fibrosis Through Toll Like Receptor4-Tissue Factor-Protease Activated Receptor1 Pathway.

Tissue factor (TF) is a blood coagulation factor that has several roles in many non-coagulant pathways involved in different pathological conditions such as angiogenesis, inflammation and fibrogenesis. Coagulation and inflammation are crosslinked with liver fibrosis where protease-activated receptor1 (PAR1) and toll-like receptor4 (TLR4) play a key role. Antisense oligodeoxynucleotides are strong modulators of gene expression. In the present study, antisense TF oligodeoxynucleotides (TFAS) was evaluated in treating liver fibrosis via suppression of TF gene expression. Liver fibrosis was induced in rats by a single administration of N-diethyl nitrosamine (DEN, 200 mg/kg; i. p.) followed by carbon tetrachloride (CCl4, 3 ml/kg; s. c.) once weekly for 6 weeks. Following fibrosis induction, liver TF expression was significantly upregulated along with liver enzymes activities and liver histopathological deterioration. Alpha smooth muscle actin (α-SMA) and transforming growth factor-1beta (TGF-1ß) expression, tumor necrosis factor-alpha (TNF-α) and hydroxyproline content and collagen deposition were significantly elevated in the liver. Blocking of TF expression by TFAS injection (2.8 mg/kg; s. c.) once weekly for 6 weeks significantly restored liver enzymes activities and improved histopathological features along with decreasing the elevated α-SMA, TGF-1ß, TNF-α, hydroxyproline and collagen. Moreover, TFAS decreased the expression of both PAR1 and TLR4 that were induced by liver fibrosis. In conclusion, we reported that blockage of TF expression by TFAS improved inflammatory and fibrotic changes associated with CCl4+DEN intoxication. In addition, we explored the potential crosslink between the TF, PAR1 and TLR4 in liver fibrogenesis. These findings offer a platform on which recovery from liver fibrosis could be mediated through targeting TF expression.

Ameliorative effect of fractionated low-dose gamma radiation in combination with ellagic acid on nicotine-induced hormonal changes and testicular toxicity in rats.

Nicotine is an active pharmacological ingredient in cigarette smoke, which may negatively influence the male reproductive system and fertility. This study aims to investigate the effect of fractionated low-dose radiation (fractionated-LDR) and/or ellagic acid (EA) on nicotine-induced hormonal changes and testicular toxicity in rats. Nicotine was administrated orally (1 mg/kg) for 30 days, afterward, rats were treated with LDR (2 × 0.25 Gy/1-week interval), EA (10 mg/kg, 14 consecutive days p.o.), or a combination of both fractionated-LDR and EA. Rats were sacrificed 24 h after the last dose of treatment, then testes were dissected for histopathology examination, along with some biochemical parameters in serum and testicular tissue were evaluated. Nicotine-induced oxidative stress was evidenced by an increase in testicular thiobarbituric acid reactive substances (TBARS) and a decrease in reduced glutathione (GSH) content. Additionally, the activities of testicular androgenic enzymes were decreased, and the activity of serum lactate dehydrogenase (LDH) was significantly increased. The hormonal changes were verified by a noticeable reduction in follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone serum levels. Histological evaluation revealed that the testicular seminiferous tubules structure was distorted. On the contrary, fractionated-LDR plus EA attenuated the negative changes caused by nicotine observed through biochemical and histological findings. Accordingly, the exposure to fractionated-LDR combined with EA may be a promising candidate for treating hormonal changes and testicular toxicity caused by nicotine.

Amelioration of adjuvant-induced arthritis by exposure to low dose gamma radiation and resveratrol administration in rats.

Purpose: Low dose radiation has been reported as an effective treatment for rheumatoid arthritis via multiple dose exposures. The present study was designed to increase the therapeutic efficacy of low dose radiation with the minimum exposure level in arthritic rats by concurrent administration of resveratrol (RSV) as an adjunctive therapy with anti-inflammatory properties.Materials and methods: Rats were rendered arthritic by sub-plantar injection of Freund's complete adjuvant (FCA) and exposed to low dose radiation at a total exposure level of 0.5 Gy (2 × 0.25). During the exposure course, RSV (50 mg/kg) was orally administered once daily for two weeks. Diclofenac (3 mg/kg) was administered as a standard anti-inflammatory drug. Paw volume was measured every 4 days. After 28 days of induction, rats were sacrificed and serum was collected for estimation of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1ß), thiobarbituric acid reactive substances (TBARS), and total nitrate/nitrite (NOx). Furthermore, paws were dissected for histopathological examinations and immuno-histochemical estimation of nuclear factor-kappa B p65 (NF-κB p65) expression.Results: Administration of RSV during the low dose radiation exposure course produced a significant decrease in the paw swelling and a potentiated inhibition in the serum levels of TNF-α, IL-1ß, TBARs, and NOx. The dual treatment strategy alleviated the histopathological damage to a greater extent than that produced by each treatment. Moreover, a pronounced suppression of NF-κB p65 expression in the synovial tissue was observed in the combination group. The combination treatment showed a nearly similar potency to that observed in the diclofenac treated group.Conclusion: Administration of RSV augmented the modulatory activity of low dose radiation with minimum exposure level on the disease progression.

New combination therapy of gliclazide and quercetin for protection against STZ-induced diabetic rats.

AIMS: The use of natural agents with anti-diabetic effect in combination therapy adds further positive clinical implications in the management of diabetes mellitus. Interestingly, quercetin is one of the most potent naturally occurring antioxidant which possesses various pharmacological actions including anti-diabetic effect. Thus, this research was conducted to assess the efficiency of a new combination from gliclazide and quercetin on glycemic control as well as pancreatic islets and beta cells in STZ-experimental model of diabetes. MAIN METHODS: Diabetes has been induced by a single intraperitoneal injection of streptozotocin (STZ; 45 mg/kg) in adult male Wistar rats. For 3 consecutive weeks, diabetic rats were given orally either gliclazide (10 mg/kg), quercetin (50 mg/kg), or their combination. At the end of the experiment, histological, immunohistochemical and morphometrical examination of pancreatic tissues was performed. Furthermore, the changes in glucose metabolism, lipid profile, oxidative and inflammatory status were evaluated. KEY FINDINGS: Treatment with gliclazide alone decreased serum glucose, total cholesterol, triglycerides, malondialdehyde, tumor necrosis factor-alpha and nuclear factor kappa-Beta while increased serum C-peptide, superoxide dismutase, reduced glutathione and adiponectin levels. Combined administration of quercetin with gliclazide markedly augmented serum superoxide dismutase and reduced glutathione more than gliclazide alone and normalized all the above-mentioned parameters. Besides, this combination therapy restored immunostaining intensity, number of pancreatic islets and beta cells along with its area and perimeter. SIGNIFICANCE: Based on the aforementioned results, this combination could be considered a promising one in diabetes mellitus management.

The potential role of B5: A stitch in time and switch in cytokine.

The wound healing process is a multifaceted sequence of activities associated with tissue restoration. Novel approaches for the perfection of wound healing have been determined as a stitch in time saves nine. Dysregulation of the immune response is a key element in the pathogenesis of rheumatic diseases and serves as a potential target for novel therapeutic strategies. Vitamin B5 (VB5), also known as pantothenate or "anti-stress vitamin," is the precursor of coenzyme A, which is essential in every micro-organism. Many pantothenic acid amides acquire persuasive antimicrobial activity. Pantothenic acid improves surgical wounds healing with moisturizing and skin barrier enhancing potential. Its deficiency leads to reduced cortisol production, increased arthritic pain, myalgia, fatigue, headache, depression, insomnia, and widespread "proinflammatory" effects on the immune-system. VB5 triggers immune cells to produce cytokines and is multifunctional. The paradoxical effect of VB5 on the switch of anti-inflammatory and proinflammatory cytokines has been revealed. This review aims to present the long research journey of B5 as it is becoming a forerunner in the healing of wounds and in enhancing the immune function, thus providing potentially important therapeutic implications. As its role in healing a wound stitch is promising, amending the immune system damage too is a hopeful target.

Targeting CDC7 sensitizes resistance melanoma cells to BRAFV600E-specific inhibitor by blocking the CDC7/MCM2-7 pathway.

Although the utilization of selective BRAFV600E inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has  emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAFV600E and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAFV600E- bearing melanoma cells. Dual targeting of CDC7 and BRAFV600E reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma.

Ambroxol attenuates cisplatin-induced hepatotoxicity and nephrotoxicity via inhibition of p-JNK/p-ERK.

Hepatotoxicity and nephrotoxicity are important drawbacks of cisplatin. The objective of this study is to evaluate the ability of ambroxol in 2 different doses (35 and 70 mg/kg, i.p.) to protect liver and kidney from damage induced by a single dose of cisplatin (10 mg/kg, i.p.) in comparison with N-acetylcysteine (250 mg/kg, i.p.). Inflammatory, oxidative stress, and apoptotic biomarkers were investigated to show the influence of ambroxol on hepatotoxicity and nephrotoxicity. Ambroxol decreased the elevated activity of liver enzymes (aspartate aminotransferase and alanine aminotransferase) and kidney function tests (blood urea nitrogen and creatinine). Ambroxol mitigated cisplatin inflammatory damage by inhibition of tumor necrosis factor-α, interleukin-1ß, and nuclear factor kappa-B and elevation of nuclear factor erythroid 2-related factor 2. Moreover, ambroxol inhibited oxidative damage indicated by reduction of malondialdehyde and replenished the store of reduced glutathione likely by upregulating glutathione reductase and superoxide dismutase. Elevation of phosphorylated c-Jun N-terminal kinases (p-JNK) and phosphorylated extracellular signal-regulated kinase (p-ERK) were attenuated by ambroxol associated with a decrease in the expression of caspase-3; these results were consistent with histopathological results. These results recommend ambroxol to be co-administered with cisplatin in cancer patients to ameliorate liver and kidney damage, and this was confirmed by MTT assay.

Modulating impacts of quercetin/sitagliptin combination on streptozotocin-induced diabetes mellitus in rats.

BACKGROUND: Since many diabetic patients require combination therapy, the use of herbal remedies with anti-diabetic activity represents a vital option in diabetes mellitus (DM) management. It has been reported that quercetin has hypoglycemic alongside anti-inflammatory and antioxidant activities. AIM: The present study aimed to investigate the effectiveness of combining quercetin with sitagliptin; a selective dipeptidyl peptidase-IV (DPP-IV) inhibitor, in the management of streptozotocin (STZ)-induced diabetic rats. METHODS: DM was induced by a single injection of STZ (45 mg/kg, i.p.) in male adult albino Wistar rats. Diabetic rats were orally treated with sitagliptin (70 mg/kg), quercetin (50 mg/kg) or their combination daily for three consecutive weeks. Serum levels of glucose, C-peptide, total cholesterol, triglycerides, malondialdehyde (MDA), superoxide dismutase, (SOD), reduced glutathione (GSH), tumor necrosis factor alpha, (TNF-α), nuclear factor kappa-B, (NF-κB) and adiponectin were estimated. In addition, histopathological, morphometrical and immunohistochemical examinations of pancreatic tissues were conducted. RESULTS: The combined administration of quercetin and sitagliptin normalized serum C-peptide, MDA, and significantly increased SOD, GSH and decreased NF-κB more than sitagliptin alone. Moreover, this combination normalized Islet number, ß-cells' number, area and perimeter alongside restoring the immunostaining intensity of ß-cells. CONCLUSION: Our results suggest the use of quercetin/sitagliptin combination for treating DM based on the observed improvements in glycemic control, metabolic profile, oxidative and inflammatory status, islet structure as well as ß-cells function compared with either treatment alone.

Effect of valproic acid alone or combined with low dose gamma irradiation in modulating PTZ-induced convulsions in rats involving AKT/m-TOR pathway.

AIM: The current study evaluates the anticonvulsant effect of valproic acid (VPA) alone or combined with low dose γ-irradiation (LDR) against pentylenetetrazol-induced convulsions in rats. MATERIAL AND METHODS: Five groups of rats were used, group I served as normal control, group II served as PTZ- control and the other three groups were pretreated with single LDR(o.5 Gy), VPA(150 mg/kg i.p.5 days) and VPA with LDR respectively before PTZ injection. Racine score, latency and duration of convulsions were assessed. Evaluation of brain neurotransmitters (glutamate and GABA) as well as AKT/m-TOR pathway (protein kinase B [AKT], mammalian target of rapamycin [m-TOR], protein S6 and caspase 3). Measurement of oxidative stress (Malondialdehyde, glutathione and nitric oxide) was carried out. Histopathological examinations of hippocampi were done. KEY FINDINGS: PTZ resulted in behavioural changes (high Racine score, long seizure duration and short latency).PTZ enhanced oxidative stress state (high MDA and NO, as well as low GSH) compared to normal control. VPA alone or combined with LDR ameliorated, the convulsions and caused significant improvement in behavioural changes and other tested parameters compared to normal control. Histopathological examination of hippocampi was carried out to adjoin the biochemical changes. Certain changes were observed after PTZ injection. However, normal pictures of the other tested groups. SIGNIFICANCE: The previously mentioned findings support that LDR purveyed novel anticonvulsant activity which could offer a possible contributor in the basic treatment of convulsions. This effect might be due to modulation of AkT/m-TOR pathway, reduction of oxidative stress and modulation of neurotransmitters.

Tumor necrosis factor-α -308 A/G gene polymorphism in children with juvenile idiopathic arthritis: relation to disease activity, damage, and functional status.

The study aims to evaluate the clinical significance of serum levels of tumor necrosis factor alpha (TNF-α) and -308 A/G promoter polymorphism in juvenile idiopathic arthritis (JIA) patients and find any association to the subsets, clinical and laboratory features, disease activity, and damage as well as functional disability. Forty-eight JIA children and 30 controls were included in the present study. Juvenile arthritis disease activity score in 27 joints (JADAS-27) was calculated, juvenile arthritis damage index (JADI) was assessed, and Childhood Health Assessment Questionnaire (CHAQ) measured the functional status. Serum TNF-α was assayed by ELISA and gene (-308) promoter polymorphism was determined by polymerase chain reaction. The 48 JIA children (mean age 11.5 ± 2.8 years) were 13 systemic, 17 oligoarticular, and 18 polyarticular onset. The serum TNF-α was significantly higher in patients (90.4 ± 6.3 ng/ml) compared to control (3.5 ± 2.6 ng/ml) (p < 0.0001) with a tendency to be higher in the polyarticular subtype. All controls had TNF-α -308 GG alleles. The frequency of GG genotype tended to be higher in systemic onset compared to oligoarticular and polyarticular subtypes. The serum TNF-α significantly correlated with JADAS-27 (r = 0.32, p = 0.03) and CHAQ (r = 0.37, p = 0.01) and negatively with the presence of GG alleles (r = -0.48, p = 0.001). The GG alleles were significantly negatively associated with C-reactive protein (r = -0.32, p = 0.03) with a tendency to negatively correlate with JADAS-27, CHAQ, and JADI-extrarticular (r = -0.28, p = 0.06; r = -0.25, p = 0.09 and r = -0.25, p = 0.09, respectively). There is evidence of a possible influence of the -308 SNP promoter position on the production of TNF-α, the severity of JIA which may consequently influence the response to anti-TNF-α treatment.

The neuroprotective effect of mesenchymal stem cells on an experimentally induced model for multiple sclerosis in mice.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating neurodegenerative central nervous system disorder. The aim of the present study was to investigate the prophylactic effect exerted by the one-time intraperitoneal injection of mesenchymal stem cells (MSCs) 1 × 106 and 14-day intraperitoneal injection of methylprednisolone (MP) 40 mg/kg in an experimental autoimmune encephalomyelitis (EAE). EAE was induced by intradermal injection of rat spinal cord homogenate with complete Freund's adjuvant in Swiss mice. Results of MSCs and MP-treated mice showed a significantly milder disease and fewer clinical scores compared to control mice. They suppressed tumor necrosis factor-alpha and myeloperoxidase and increased interleukin 10, whereas thiobarbituric acid reactive substances and nitric oxide brain contents were reduced to comparable levels between treatment groups. Brain content of GSH was significantly higher in MSCs-treated mice than control mice. It is evident that MSCs have relevant prophylactic effect in an animal model of MS and might represent a valuable tool for stem cell based therapy in MS.

Evidences for amelioration of reserpine-induced fibromyalgia in rat by low dose of gamma irradiation and duloxetine.

OBJECTIVE: Fibromyalgia is a prevalent disorder characterized by chronic widespread pain and complex symptoms. This study was conducted to investigate the potential therapeutic effect of low-dose irradiation (LDI) alone or in combination with duloxetine on the reserpine-induced fibromyalgia in rats. METHODS: Fibromyalgia was induced by administration of reserpine (1 mg/kg/s.c) for 3 consecutive days. Duloxetine (30 mg/kg, p.o) was administered 60 min before a forced swimming test (FST), and rats were exposed to a single dose of γ-radiation (0.5 Gy) 1 day before the FST. RESULTS: Reserpine significantly increased immobility time in the FST, decreased the amount of 5-hydroxytryptamine, dopamine, and norepinephrine in cerebral cortex. It also increased malondialdehyde and nitric oxide and reduced glutathione contents in brain tissue. LDI alone or combined with duloxetine completely antagonized reserpine-induced fibromyalgia as assessed by the measured parameters. One of the most significant findings in this study was that the therapeutic effect of duloxetine was more pronounced by its combination with LDI. A possible mechanism of action of LDI and duloxetine responsible for their therapeutic effect was discussed. CONCLUSION: On the basis of the presented evidences, it could be concluded that LDI alone or combined with duloxetine could be of value in the management of fibromyalgia.

Pyrrolidinedithiocarbamate attenuates bleomycin-induced pulmonary fibrosis in rats: Modulation of oxidative stress, fibrosis, and inflammatory parameters.

OBJECTIVE: The current study aimed to investigate the modulatory effects of pyrrolidinedithiocarbamate (PDTC; 100 mg/kg) on bleomycin-induced pulmonary fibrosis (5 mg/kg; intratracheal) in rats. MATERIALS AND METHODS: Rats were randomly assigned to three groups: normal control, bleomycin control, and PDTC-treated groups. Lung injury was evaluated through histological examination, immunohistochemical detection of inducible nitric oxide synthase (iNOS) in lung tissue and evaluating the total and differential leucocytes count in bronchoalveolar lavage fluid. Lung tissue was used for biochemical assessment of lung content of hydroxyproline, transforming growth factor beta-1 (TGF-ß1), tumor necrosis factor-alpha (TNF-α) as well as analysis of lipid peroxides, reduced glutathione (GSH), and total nitrite contents. RESULTS: PDTC attenuated bleomycin-induced pulmonary fibrosis as evidenced by histological observations, decreased iNOS expression and prevention of bleomycin-induced altered total and differential leukocytes count. Additionally, PDTC caused a significant decrease in lung contents of hydroxyproline, TGF-ß1, TNF-α, lipid peroxides, and total nitrite coupled with increase in lung GSH content as compared to bleomycin control group. CONCLUSION: PDTC attenuated bleomycin-induced pulmonary fibrosis in rats via its anti-inflammatory, antioxidant, and antifibrotic activities.

Wharton's jelly-derived mesenchymal stem cells combined with praziquantel as a potential therapy for Schistosoma mansoni-induced liver fibrosis.

Liver fibrosis is one of the most serious consequences of S. mansoni infection. The aim of the present study was to investigate the potential anti-fibrotic effect of human Wharton's jelly-derived mesenchymal stem cells (WJMSCs) combined with praziquantel (PZQ) in S. mansoni-infected mice. S. mansoni-infected mice received early (8(th) week post infection) and late (16(th) week post infection) treatment with WJMSCs, alone and combined with oral PZQ. At the 10(th) month post infection, livers were collected for subsequent flow cytometric, histopathological, morphometric, immunohistochemical, gene expression, and gelatin zymographic studies. After transplantation, WJMSCs differentiated into functioning liver-like cells as evidenced by their ability to express human hepatocyte-specific markers. Regression of S. mansoni-induced liver fibrosis was also observed in transplanted groups, as evidenced by histopathological, morphometric, and gelatin zymographic results besides decreased expression of three essential contributors to liver fibrosis in this particular model; alpha smooth muscle actin, collagen-I, and interleukin-13. PZQ additionally enhanced the beneficial effects observed in WJMSCs-treated groups. Our results suggest that combining WJMSCs to PZQ caused better enhancement in S. mansoni-induced liver fibrosis, compared to using each alone.

Vitamin D status in rheumatoid arthritis patients: relation to clinical manifestations, disease activity, quality of life and fibromyalgia syndrome.

AIM: To assess vitamin D levels in rheumatoid arthritis (RA) patients and to find their relation to clinical parameters, fibromyalgia syndrome (FMS), quality of life (QoL) and disease activity. METHODS: The study included 63 RA patients and 62 controls. Clinical examination and laboratory investigations were performed. For patients, the Disease Activity Score (DAS-28), QoL index, Health Assessment Questionnaire II (HAQ II) and Modified Larsen score were calculated. 25-OH-vitamin D was measured in patients and controls. RESULTS: The patients' mean age was 41.59 ± 9.69 years and disease duration 5.89 ± 3.67 years. The level of vitamin D in RA patients was significantly lower (23.11 ± 12.71 ng/mL) than that in the controls (32.59 ± 13.06 ng/mL) (P = 0.005) being deficient in 50.8%, insufficient in 23.8% and normal in 25.4%. The RA patients with FMS (n = 33) had significantly lower levels of vitamin D (19.08 ± 10.59 ng/mL) than those without (27.55 ± 13.51 ng/mL) (P = 0.008). The difference was significant on comparing those receiving hydroxychloroquine (17.39 ± 7.84 ng/mL) to those not (31.85 ± 13.85 ng/mL) (P < 0.001). Vitamin D significantly correlated with QoL index (r = 0.58, P < 0.001) and negatively with HAQ II (r = -0.36, P = 0.004) and BMI (r = -0.39, P = 0.001). CONCLUSION: Special attention is required regarding vitamin D levels in RA patients with FMS and decreased QoL. Vitamin D should be corrected and supplementation considered among the RA management armamentarium.

Pinocembrin attenuates hippocampal inflammation, oxidative perturbations and apoptosis in a rat model of global cerebral ischemia reperfusion.

BACKGROUND: Pinocembrin is a major flavonoid molecule isolated from honey and propolis. It has versatile pharmacological and biological activities including antimicrobial, anti-inflammatory, antioxidant, and anticancer activities as well as neuroprotective effects against cerebral ischemic injury. The purpose of the current study was to determine the possible mechanisms of neuroprotection elicited by pinocembrin with specific emphasis on chronic prophylactic use before the induction of global cerebral ischemia reperfusion. METHODS: Global cerebral ischemia-reperfusion (I/R) was induced by bilateral carotid artery occlusion for 15min followed by 60min reperfusion period. Animals were randomly allocated into 3 groups (n=28): Sham operated, I/R control and rats treated with pinocembrin (10mg/kg, po) daily for 7 days then I/R was induced 1h after the last dose of pinocembrin. After reperfusion rats were killed by decapitation, brains were removed and both hippocampi separated and the following biochemical parameters were estimated; lactate dehydrogenase activity, oxidative stress markers (lipid peroxides, nitric oxide and reduced glutathione), inflammatory markers (myeloperoxidase, tumor necrosis factor-alpha, nuclear factor kappa-B, interleukin-6 and interleukin-10), apoptotic biomarkers (caspase 3 and cytochrome C), neurotransmitters (glutamate, gamma aminobutyric acid) and infarct size were assessed. RESULTS: Pinocembrin ameliorated damage induced by I/R through suppressing oxidative stress, inflammatory and apoptotic markers as well as mitigating glutamate and lactate dehydrogenase activity. One of the more significant findings to emerge from this study is that pinocembrin normalized the infarct size elevated by I/R. CONCLUSIONS: Pinocembrin showed a neuroprotective effects through antioxidant, anti-inflammatory and antiapoptotic mechanisms.