The Potential Radioprotective Effect of Piperine against Radiation-Induced Lung Injury in Mice: Histopathological and Biochemical Evaluations.

INTRODUCTION: It has been hypothesized that piperine, the main alkaloid component of black pepper, possesses a unique radioprotective effect. This study aimed to investigate the protective effect of piperine against Radiation-Induced Lung Injury (RILI) in mice. METHOD: Firstly, eighty male mice were divided into eight groups; the control group did not receive any dosage of piperine and radiation (6 Gy), and the other groups received piperine alone at doses 10, 25, and 50 mg/kg, radiation, and radiation-piperine combination (6 Gy + 10, 25, and 50 mg/kg). Animals received piperine by gavage for 7 consecutive days. To investigate the effect of piperine pretreatment in mice that were exposed to radiation, histopathological and biochemical evaluations (markers of oxidative stress) were performed. Irradiation led to an increase in oxidative stress (increase in MDA and PC). Pretreatment of piperine in all three doses in irradiated mice was able to reduce oxidative stress compared to mice that were only exposed to radiation. RESULTS: Piperine at a dose of 25 mg/kg exhibited the highest protective effect as compared to other doses. Also, in the histopathological examination, it was seen that pretreatment with piperine was able to improve the infiltration of inflammatory cells and reduce the thickness of the alveolar septum and air sac damage. CONCLUSION: The outcomes completely proved significant lung protection by piperine in mice through reducing oxidative stress. This natural compound could be considered a protective agent against lung injury induced by ionizing radiation.

Protective Effects of the Aqueous Extract of Malva sylvestris Plant against the Lethality and Histopathological Damage in Experimental Envenoming of Hemiscorpius lepturus Venom in Balb/c Mice.

INTRODUCTION: Hemiscorpius lepturus envenomation is a serious health problem in the southern provinces of Iran. The antiserum produced in Iran to counteract this scorpion venom is not entirely effective due to the risk of anaphylactic shock and other adverse effects. METHODS: Therefore, more efficient alternatives to treat patients deserve attention, and plants are extensively good candidates to be studied. This study aimed to assess the potential of the aqueous fraction of Malva sylvestris in inhibiting the toxic effects of H. lepturus venom. Injection of sub-lethal dose of H. lepturus venom leads to severe tissue damage in vital organs including the kidney, liver, heart and intestine, after 24 hours. RESULTS: By injecting 80 mg of the aqueous extract of M. sylvestris into the peritoneum helped treat the damaged tissues caused by H. lepturus venom in mice. CONCLUSION: Thus, Malva sylvestris could serve as an alternative treatment for scorpion sting envenomation and may be used as a drug to neutralize relevant toxic effects in patients stung by H. lepturus.

Luteolin-incorporated fish collagen hydrogel scaffold: An effective drug delivery strategy for wound healing.

In clinical practice, wound care has always been challenging. Hydrogels play a key role in facilitating active wound recovery by absorbing exudates, maintaining moisture, and alleviating pain through cooling. In this study, type I collagen was isolated from the skin of crucian carp (Carassius carassius) and verified by amino acid analysis, FTIR, and SDS-PAGE. By adopting a new approach, luteolin was added to collagen hydrogels in situ after being dissolved in an alkaline solution. XRD and SEM confirmed the luteolin was incorporated and entirely distributed throughout the hydrogel. The plastic compression improved the young's modulus of hydrogel to 15.24 ± 0.59 kPa, which is adequate for wound protection. The drug loading efficiency was 98 ± 1.47 % in the selected formulation. The luteolin-incorporated hydrogel enabled regulated drug release. We assessed the cytotoxicity using MTT and live-dead assays, as well as examined the hemocompatibility to determine the biocompatibility of the hydrogel. In vivo experiments showed that the hydrogel with luteolin had the highest wound closure rate (94.01 ± 2.1 %) and improved wound healing with granular tissue formation, collagen deposition, and re-epithelialization. These findings indicate that this efficient drug delivery technology can accelerate the process of wound healing.

5-HT3 antagonist, tropisetron, ameliorates age-related renal injury induced by D-galactose in male mice: Up-regulation of sirtuin 1.

Objectives: The kidney ages faster than other organs due to changes in energy metabolism, mitochondrial dysfunction, and oxidative stress. This study looked into the anti-aging effect of tropisetron. Materials and Methods: D-galactose was administrated subcutaneously in a mouse model for eight weeks in order to induce renal aging. Three separate intraperitoneal doses of tropisetron (1, 3, and 5 mg/kg body weight) were given at the same time. We assessed markers of mitochondrial dysfunction, oxidative stress, and inflammation. Via Real-Time PCR, the expressions of genes linked to aging (SIRT1) and apoptosis (Bax and Bcl-2) were ascertained. In addition, an assessment of histopathological changes, blood urea nitrogen, and creatinine concentrations was done. Results: In kidney tissue, tropisetron reduces mitochondrial dysfunction and oxidative stress, which are caused by D-galactose-induced overproduction of inflammatory mediators. Additionally, tropisetron demonstrated antiapoptotic activity in renal tissue and augmented the decrease in SIRT1 gene expression associated with D-galactose administration. Besides, tropisetron significantly improved the histological alterations in the renal tissues of aged mice and effectively decreased the elevated levels of creatinine and also blood urea nitrogen. Conclusion: The results provided additional insight into the effect of tropisetron on renal aging and the underlying mechanisms, particularly through its ability to modulate SIRT1 signaling.

Piperine mitigates oxidative stress, inflammation, and apoptosis in the testicular damage induced by cyclophosphamide in mice.

Although cyclophosphamide (CP) has been approved as an anticancer drug, its toxic effect on most organs, especially the testis, has been established. Piperine (PIP) is an alkaloid that has antioxidant, antiapoptotic, and anti-inflammatory activities. This study was investigated the protective effects of PIP on CP-induced testicular toxicity in the mice. In this experimental study, 48 adult male BALB/c mice (30-35 g) were divided into six groups (n = 8), receiving normal saline (C), 5 mg/kg of PIP (PIP5), 10 mg/kg of PIP (PIP10), 200 mg/kg of CP, 200 mg/kg of CP + PIP5, and 200 mg/kg of CP + PIP10. On the eighth day of the study, blood and testis samples were prepared for serum testosterone hormone quantification, sperm analysis, histological, and immunohistochemical assays. The results of this study showed that CP induced testicular toxicity with the decrease of sperm count, motility, and viability. Also, CP treatment caused histological structure alterations in the testis, including exfoliation, degeneration, vacuolation of spermatogenic cells, and reducing the thickness of the epithelium and the diameter of the seminiferous tubule. In addition, CP decreased glutathione (GSH) levels, increased malondialdehyde (MDA) levels, Caspase-3, and NF-κB. At the same time, PIP treatment reduced testicular histopathological abnormalities, oxidative stress, and apoptosis that were induced by CP. These results showed that PIP improved CP-induced testicular toxicity in mice, which can be related to its antioxidant, antiapoptotic, and anti-inflammatory activities.

Rutin mitigates perfluorooctanoic acid-induced liver injury via modulation of oxidative stress, apoptosis, and inflammation.

Objectives: Perfluorooctanoic acid (PFOA) is a persistent organic pollutant (POP), broadly present in the environment. Due to long biological half-life, it is accumulated in the body, especially the liver, causing hepatocellular damage. This study was designed to assess the effects of rutin on PFOA-induced liver damage in rats. Materials and Methods: Male Wistar rats were exposed to PFOA (10 mg/kg/day) alone, or in combination with different doses of rutin (25, 50, and 100 mg/kg/day) by oral gavage for 4 weeks. Results: PFOA altered the levels of liver enzymes, induced a notable change in the tissue structure of the liver, caused some levels of mitochondrial dysfunction, and increased the expression of pro-apoptotic and pro-inflammatory genes. Co-treatment with rutin mitigated the PFOA-induced elevation of liver enzymes, histopathological defects, oxidative damage, and mitochondrial dysfunction. In addition, rutin declined the stimulatory effects of PFOA on the Bax: Bcl2 ratio and reduced the PFOA-induced gene expression of TNF-α, IL-6, NF-ƙB, and JNK. Conclusion: These findings suggest rutin as a protective agent for PFOA-induced liver injury, albeit the protection was partial. Possible mechanisms are inhibition of oxidative stress, mitochondrial dysfunction, and inflammatory response.

Radioprotective effect of piperine, as a major component of black pepper, against radiation-induced colon injury: biochemical and histological studies.

BACKGROUND: Patients undergoing radiotherapy are prone to radiation-induced gastrointestinal injury. Piperine is an alkaloid component in black pepper with a unique chemopreventive activity against oxidative stress-related damage in healthy tissues. The purpose of this study was to investigate the effects of piperine on intestinal damage. METHODS: In this study, mice were divided into eight groups: including the control, piperine (10, 25, and 50 mg/kg), radiation (6 Gy), and piperine+radiation (10, 25 and 50 mg/kg + 6 Gy) groups. The radioprotective effects of piperine were evaluated by biochemical (MDA, GSH, and PC) and histopathological assessments in colon tissues. RESULTS: The 10 mg/kg dose of piperine significantly reduced the levels of oxidative stress biomarkers compared to the group that received only radiation. In addition, pre-treatment with 10 mg/kg piperine diminished the histopathological changes like vascular congestion in the submucosa, while the dose of 50 mg/kg led to the infiltration of inflammatory cells. CONCLUSION: Based on this study, it is concluded that piperine, at low dose, with its antioxidant properties, could reduce the colon damage caused by radiation.

Comparative evaluation of the effect of three types of fixatives (formalin, Bouin and Carnoy) on histomorphological features of various viscera.

Tissue shrinkage is one of the problems in preparing tissue sections. This study compares the use of 10% formalin, Bouin and Carnoy as fixatives on several mouse tissues to determine histomorphological features. In this experimental study, liver, kidney, heart, lung, testicle, spleen, brain and cartilage tissues were isolated from five BALB/c mice. Then, they were fixed with three types of fixatives. After dehydrating, clarifying and embedding, all samples were stained with haematoxylin and eosin. Then, the tissue structure of the viscera was evaluated qualitatively. The results showed that each fixative is more suitable for evaluating a specific part of the tissue. However, relative shrinkage appeared in the tissue sections fixed with 10% Formalin, (1) in the heart as spaces between muscle fibre bundles, (2) in the liver as the dilation of the liver sinusoidal spaces, (3) in the kidney tissue as the expansion of the lumens of the convoluted proximal and distal tubules, (4) in the spleen as open spaces inside the red and white pulps and (5) in the brain as an increase in the space between the cells of the granular and pyramidal cell layers of the cortex. In tissues that were soft and fragile, such as testis, liver and brain, Bouin's fixative was more suitable. Carnoy's fixative was more suitable for the spleen and kidney tissue. Based on the study results, formalin and Bouin were more suitable for heart and cartilage tissue. Considering that in the histopathological evaluation both the cytoplasm and the nucleus are evaluated, it is suggested to choose the fixative suitable for the type of tissue.

Sinapic acid attenuates cyclophosphamide-induced liver toxicity in mice by modulating oxidative stress, NF-κB, and caspase-3.

Objectives: Cyclophosphamide (CP) as an antineoplastic drug is widely used in cancer patients, and liver toxicity is one of its complications. Sinapic acid (SA) as a natural phenylpropanoid has anti-oxidant, anti-inflammatory, and anti-cancer properties. Materials and Methods: The purpose of the current study was to determine the protective effect of SA versus CP-induced liver toxicity. In this research, BALB/c mice were treated with SA (5 and 10 mg/kg) orally for one week, and CP (200 mg/kg) was injected on day 3 of the study. Oxidative stress markers, serum liver-specific enzymes, histopathological features, caspase-3, and nuclear factor kappa-B cells were then checked. Results: CP induced hepatotoxicity in mice and showed structural changes in liver tissue. CP significantly increased liver enzymes and lipid peroxidation, and decreased glutathione. The immunoreactivity of caspase-3 and nuclear factor kappa-B cells was significantly increased. Administration of SA significantly maintained histochemical parameters and liver function enzymes in mice treated with CP. Immunohistochemical examination showed SA reduced apoptosis and inflammation. Conclusion: The data confirmed that SA with anti-apoptotic, anti-oxidative, and anti-inflammatory activities was able to preserve CP-induced liver injury in mice.

The preclinical study of 177Lu-DOTA-LTVSPWY as a potential therapeutic agent against HER2 overexpressed cancer.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) has evolved in cancer therapy and diagnosis. LTVSPWY, as a peptide, can target HER2 receptor; on the other hand, 177Lu emits ß- which is helpful for cancer therapy. The radiolabeling of LTVSPWY with 177Lu results in a therapeutic agent (177Lu-DOTA-LTVSPWY) capable of cancer treatment. METHODS: 177Lu-DOTA-LTVSPWY was prepared with high radiochemical purity (RCP). The stability was investigated in saline and human serum. The radiotracer affinity toward the SKOV-3 cell line with overexpression of the HER2 receptor was evaluated. Then the impact of the radiotracer on the colony formation of the SKOV-3 cell line was investigated with colony assay. Moreover, the biodistribution of this radiotracer in SKOV-3 xenograft tumor-bearing nude mice were also studied to determine the radiotracer accumulation in the tumor site. The mice were treated with 177Lu-DOTA-LTVSPWY and subjected to histopathological evaluation. RESULTS: The RCP of 177Lu-DOTA-LTVSPWY after radiolabeling and stability tests was more than 97.7%. The radiotracer displayed high affinity toward the SKOV-3 cell line (KD = 6.6 ± 3.2 nM). Treatment of the SKOV-3 cell line with the radiotracer reduces the SKOV-3 colony survival to less than 3% for 5 MBq of the radiotracer. Tumor-to-muscle (T/M) ratio is the highest at 48 h and 1 h post-injection (2.3 and 4.75, respectively). The histopathological study also confirms the cellular damage to the tumor tissue. CONCLUSIONS: 177Lu-DOTA-LTVSPWY can recognize HER2 receptors in vivo and in vitro; hence, it can serve as a therapeutic agent.

The effect of source animal age, decellularization protocol, and sterilization method on bovine acellular dermal matrix as a scaffold for wound healing and skin regeneration.

BACKGROUND: Healing the full-thickness skin wounds has remained a challenge. One of the most frequently used grafts for skin regeneration is xenogeneic acellular dermal matrices (ADMs), including bovine ADMs. This study investigated the effect of the source animal age, enzymatic versus non-enzymatic decellularization protocols, and gamma irradiation versus ethylene oxide (EO) sterilization on the scaffold. METHODS: ADMs were prepared using the dermises of fetal bovine or calf skins. All groups were decellularized through chemical and mechanical methods, unless T-FADM samples, in which an enzymatic step was added to the decellularization protocol. All groups were sterilized with ethylene oxide (EO), except G-FADM which was sterilized using gamma irradiation. The scaffolds were characterized through scanning electron microscopy, differential scanning calorimetry, tensile test, MTT assay, DNA quantification, and real-time PCR. The performance of the ADMs in wound treatment was also evaluated macroscopically and histologically. RESULTS: All ADMs were effectively decellularized. In comparison to FADM (EO-sterilized fetal ADM), morphological, and mechanical properties of G-FADM, T-FADM, and CADM (EOsterilized calf ADM) were changed to different extents. In addition, the CADM and G-FADM were thermally more stable than the FADM and T-FADM. Although all ADMs were noncytotoxic, the wounds of the FADM, T-FADM, and G-FADM groups were contracted to almost 30.0% of the original area on day 7, significantly faster than the CADM (17.5% ± 1.7) and control (12.2% ± 1.59) groups. However, by day 21, all ADMs were mostly closed except for the untreated group (60.1 ± 1.8). CONCLUSION: Altogether, fetal source and EO-sterilized samples performed better than calf source and gamma-sterilized samples unless in some mechanical properties. There was no added value in using enzymatic treatment during the decellularization process. Our results suggest that the age, decellularization, and sterilization methods of animal source should be selected based on the clinical requirements.

Melissa Officinalis L. aqueous extract pretreatment decreases methotrexate-induced hepatotoxicity at lower dose and increases 99mTc-phytate liver uptake, as a probe of liver toxicity assessment, in rats.

OBJECTIVE: Hepatotoxicity remains amongst the restricting factors of Methotrexate (MTX)-associated cancer therapy, especially in high doses of chemo-drugs or prolonged treatment. Due to the known protective effects of Melissa officinalis (M. officinalis), the aqueous extract of this plant was evaluated to ameliorate MTX-associated hepatotoxicity in rats. METHODS: Adult female Wistar rats were received or not M. officinalis aqueous extract at doses of 100 mg/kg (for 14 and 24 consecutive days) and 2 g/kg (for 14 consecutive days) by gavage technique. MTX (20 mg/kg) was intraperitoneally injected on the 10th- and 20th-day post-M. officinalis treatment. 24 h after the last day of treatment, 99mTc-phytate was intravenously injected through the tail of rats. Animals were killed at 20 min after radiocolloid injection, and vital tissues including the liver and spleen were isolated, weighed, and their radioactivity was counted. As well, 99mTc-phytate scintigraphy and histopathology of the liver were performed for higher accuracy. RESULT: A significant increase in liver radioactivity was detected in M. officinalis+MTX receiving groups compared with the MTX rats which were more robust at a dose of 100 mg/kg for 14 days. Also, a significant reduction in liver radioactivity was evident with M. officinalis extract at a dose of 2 g/kg for 14 days in comparison with the control group, this reduction was not significant at the lower dose of 100 mg/kg. Gamma scintigraphy and histopathological examinations confirmed the hepatoprotective effect of M. officinalis vs MTX-induced liver injury in rats. CONCLUSION: In conclusion, we highlighted the liver uptake of 99mTc-phytate as a valuable method for assessment of liver toxicity and addressed that M. officinalis pretreatment (100 mg/kg for 14 days) ameliorates the MTX-associated hepatotoxicity in rats; however, M. officinalis itself induces liver toxicity at higher doses.

Radioprotective effects of gliclazide against irradiation-induced cardiotoxicity and lung injury through inhibiting oxidative stress.

Radiotherapy is one of the main treatments for localized primary cancer in patients. Cardiotoxicity and lung injury are two of the main side effects of oxidative stress following radiotherapy in patients with thoracic region cancer. Gliclazide (GLZ) as an antihyperglycemic drug has antioxidant, anti-inflammatory, and anti-apoptotic activities. This study aimed to evaluate the effect of GLZ in cardiotoxicity and lung injury induced by irradiation (IR). In this experimental study, 64 mice were divided into eight groups: control, GLZ (5, 10, and 25 mg/kg), IR (6 Gy), and IR + GLZ (in three doses). GLZ was administrated for 8 consecutive successive days and mice were exposed with IR on the 9th day of study. On the 10th day of study, tissue biochemical assay and at 14th day of study, histopathological assay were performed to evaluate for cardiotoxicity and lung injury. The findings revealed that IR induces atypical features in heart and lung histostructure, and oxidative stress (an increase of MDA, PC levels, and decrease of GSH content) in these tissues. GLZ administration preserved heart and lung damages and improves oxidative stress markers in mice. Data have authenticated that GLZ could protect heart and lung histostructure against oxidative stress-induced injury through inhibiting oxidative stress.

Hepatotoxicity in young adult rat offspring after prenatal exposure to benzo(a)pyrene, and protective effect of atorvastatin.

OBJECTIVES: Benzo[a]pyrene (BaP) is an environmental contaminant that interrupts the antioxidant defense and thus leads to oxidative stress and DNA damage in the liver. Atorvastatin (ATV) for reducing cholesterol has antioxidant and anti-apoptotic activities. This study investigated the effects of prenatal exposure of BaP on liver toxicity and the protective role of ATV in reducing liver toxicity. MATERIALS AND METHODS: In this study, rats were distributed randomly to seven groups: I. Saline control; II. ATV (10 mg/kg); III. Corn oil; IV and V. BaP (10 and 20 mg/kg); VI and VII. ATV + BaP (10 and 20 mg/kg). BaP and ATV were administrated from gestation day 7-16 (GD7-GD16), orally. Ten weeks after the birth, female offspring were examined for oxidative stress markers, liver enzymes, and histology. RESULTS: Data revealed that BaP significantly induced oxidative stress (decreased glutathione and increased malondialdehyde level), and disrupted the tissue structure of the liver. Moreover, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase increased in the offspring. ATV treatment along with BaP during gestation was able to bring the antioxidant status and serum liver enzymes levels relatively close to normal. As well as, histological findings showed that ATV was able to improve liver tissue structure caused by BaP. CONCLUSION: Based on the above studies we concluded that ATV at a low dose during gestation was able to reduce liver damage caused by BaP with antioxidant properties.

Mefenamic acid as a promising therapeutic medicine against colon cancer in tumor-bearing mice.

Although radiotherapy is an effective strategy for cancer treatment, tumor resistance to ionizing radiation (IR) and its toxic effects on normal tissues are limiting its use. The aim of this study is to evaluate the anti-cancer effects of mefenamic acid (MEF), as an approved medicine, and its combination with IR against colon tumor cells in mice. Tumor-bearing mice were received MEF at a dose of 25 mg/kg for 6 successive days. The tumor size was measured. In the second experiment, after MEF treatment, tumor-bearing mice locally received an X-ray at dose 6 Gy. Tumor growth and biochemical, histological, and immunohistological assay (caspase-3) were performed. MEF significantly decreased tumor size in mice in comparison to the control group. IR and/or MEF treatment significantly reduced the tumor volume and inhibited tumor growth by 49%, 55%, and 67% by MEF, IR, and MEF + IR groups as compared with the control group. Administration of MEF in combination with radiation had a synergistic effect on enhanced histopathological changes in tumor tissues. MEF treatment in IR exposure mice showed a significant increase in the immunoreactivity of caspase-3 in the colon tumor tissue. MEF has an anti-tumor effect in colon tumor-bearing mice. MEF in combination with IR increased pathological changes and apoptosis in tumor tissues, suggesting that MEF might be clinically useful in the treatment of colon cancer.

The Potential Usefulness of 99mTc-HYNIC-(Ser)3-LTVPWY Peptide for Predicting HER2 Status Alteration After Chemotherapy in Ovarian Tumor-Bearing Mice.

Purpose: The assessment of HER2 expression has a significant impact on optimizing cancer treatment protocol in patients. The aim of this study was to evaluate the potential usefulness of 99mTc-HYNIC-(Ser)3-LTVPWY peptide for detecting HER2 alteration after paclitaxel therapy of ovarian tumor xenografts in nude mice. Materials and Methods: Mice bearing SKOV-3 tumors were treated with paclitaxel and saline. The antitumor efficacy of paclitaxel was compared with the control group in tumor size and histopathological examinations. In biodistribution and imaging studies, the tumor uptakes of radiolabeled peptide were evaluated in mice-bearing ovarian tumors in both groups. The HER2 expressions in transplanted tumors were analyzed by immunohistochemistry (IHC). Results: Tumor size gradually increased in all mice during the treatment, whereas tumors had considerably faster growth in the saline group compared to those in the paclitaxel-treated mice. Paclitaxel could suppress ovarian tumor growth and prevent vascular and cell proliferation in the tumoral mass. Biodistribution and imaging results demonstrated nonsignificant radionuclide accumulations in transplanted tumors in the paclitaxel- and saline-treated groups. IHC staining confirmed the HER2 status that was similar in both groups. Conclusions: The response of HER2 status to paclitaxel in mice bearing HER2-expression tumors was profitably monitored by HER2 targeted 99mTc-HYNIC-(Ser)3-LTVPWY peptide that was agreement with IHC. The utilization of this radiolabeled peptide may be a valuable probe in evaluating HER2 status after chemotherapy.

Febuxostat, an inhibitor of xanthine oxidase, ameliorates ionizing radiation-induced lung injury by suppressing caspase-3, oxidative stress and NF-κB.

Febuxostat (FBX), a selective inhibitor of xanthine oxidase, has several biological properties such as antioxidant, anti-inflammatory and anti-apoptosis activities. The purpose of this study was to evaluate the protective effect of FBX against ionizing radiation (IR)-induced lung injury through mitigation of oxidative stress, inflammation and apoptosis. Sixty-four mice were randomized into eight groups as control, FBX (5, 10, and 15 mg/kg), IR (6 Gy), and IR + FBX (IR + FBX in three doses). Mice were received FBX for 8 consecutive days and then were exposed to IR at a single dose (6 Gy) of X-ray. At 1 and 7 days after irradiation, the biochemical parameters were analyzed in lung tissue, while histological and immunohistochemical examinations were evaluated 1 week after irradiation. Irradiation led to elevate of oxidative stress parameters (an increase of MDA, PC, NO, and decrease of GSH), inflammation and apoptosis in lung of mice. Furthermore, IR resulted in histopathological changes in the lung tissues. These changes were significantly mitigated by FBX treatment. FBX also inhibited immunoreactivity of caspase-3, NF-κB, and reduced oxidative stress. This study showed that FBX is able to protect lung injury induced by IR through inhibiting apoptosis (caspase-3), oxidative stress and inflammation (NF-κB).

Design, synthesis and biological evaluation of naphthalene-derived (arylalkyl)azoles containing heterocyclic linkers as new anticonvulsants: A comprehensive in silico, in vitro, and in vivo study.

In continuation of our research to find strong and safe anticonvulsant agents, a number of (arylalkyl)azoles (AAAs) containing naphthylthiazole and naphthyloxazole scaffolds were designed and synthesized. The in vivo anticonvulsant evaluations in BALB/c mice revealed that some of them had significant anticonvulsant activity in both maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy. The best profile of activity was observed with compounds containing imidazole and triazole rings (C1, C6, G1, and G6). In particular, imidazolylmethyl-thiazole C1 with median effective dose (ED50)= 7.9 mg/kg in the MES test, ED50= 27.9 mg/kg in PTZ test, and without any sign of neurotoxicity (in the rotarod test, 100 mg/kg) was the most promising compound. The patch-clamp recording was performed to study the mechanism of action of the representative compound C1 on hippocampal dentate gyrus (DG) cells. The results did not confirm any modulatory effect of C1 on the voltage-gated ion channels (VGICs) or GABAA agonism, but suggested a significant reduction of excitatory postsynaptic currents (EPSCs) frequency on hippocampal DG neurons. Sub-acute toxicity studies revealed that administration of the most active compounds (C1, C6, G1, and G6) at 100 mg/kg bw/day for two weeks did not result in any mortality or significant toxicity as evaluated by assessment of biochemical markers such as lipid peroxidation, intracellular glutathione, total antioxidant capacity, histopathological changes, and mitochondrial functions. Other pharmacological aspects of compounds including mechanistic and ADME properties were investigated computationally and/or experimentally. Molecular docking on the NMDA and AMPA targets suggested that the introduction of the heterocyclic ring in the middle of AAAs significantly affects the affinity of the compounds. The obtained results totally demonstrated that the prototype compound C1 can be considered as a new lead for the development of anticonvulsant agents.

Protective effects of sinapic acid against cyclophosphamide-induced testicular toxicity via inhibiting oxidative stress, caspase-3 and NF-kB activity in BALB/c mice.

Cyclophosphamide (CP), as a chemotherapeutic agent, with the generation of oxidative stress leads to testicular toxicity. Sinapic acid (SA), as a phenylpropanoid compound has therapeutic activities. This research was planned to evaluate the improving effects of SA versus testicular injury induced by CP. Forty-eight mice were distributed into six groups: untreated, SA (5 and 10 mg/kg), CP (200 mg/kg) and CP + SA (5 and 10 mg/kg). SA was administrated for 7 successive days and CP was administered intraperitoneally on the 3rd day of study. On the 10th day of research, testicular toxicity was evaluated by sperm parameters test, tissue (oxidative stress parameters) and serum (testosterone) biochemical, histopathological, and immunohistochemical (Caspase-3 and NF-kB) assays. The findings illustrated that CP induces atypical appearance in tissue structure, disorder of sperm parameters dysfunction, decrease of testosterone, oxidative stress (an increase of MDA and decrease of GSH), apoptosis and inflammation in testicular tissue. SA administration protected testis from oxidative stress and improves testosterone level and structure. Moreover, immunohistochemical findings also showed that SA can inhibit Caspase-3 and NF-kB activity. Data have confirmed that SA could protect testis structure and its functions against CP-induced injury through antioxidant, anti-inflammatory and anti-apoptotic activities.

Effect of prenatal exposure to Benzo[a]pyrene on ovarian toxicity and reproductive dysfunction: Protective effect of atorvastatin in the embryonic period.

As an environmental contaminant, Benzo[a]pyrene (B[a]P; BaP) disrupts the antioxidant signaling and thus leads to the induction of oxidative stress and the damage of DNA in the ovary. low-dose atorvastatin (ATV) has antioxidant and anti-apoptotic properties. The present study aimed to survey the effects of prenatal exposure to BaP on ovarian toxicity and also to investigate the protective role of ATV in reducing ovarian toxicity. In this study, rats were divided into seven groups: control, ATV (10 mg/kg), oil, BaP (10 and 20 mg/kg), and ATV + BaP (10 and 20 mg/kg). BaP and ATV were administrated from gestation day 7-16 (GD7 to GD16), orally. 10 weeks after the birth, female offsprings were examined for oxidative stress markers, sex hormones, ovarian and tubular tissue structure, and the apoptosis markers. Data showed that BaP significantly reduced glutathione, increased malondialdehyde level, and disrupted the tissue structure of the ovary. Moreover, estrogen and progesterone levels significantly decreased in the offsprings rats. Also, BaP increased caspase-3 immunoreactivity. Atorvastatin treatment along with BaP in the embryonic period were able to bring the antioxidant status and sex hormones levels relatively close to normal. Besides, histological findings showed that atorvastatin was able to improve ovarian and oviduct abnormalities caused by BaP. Based on the above studies be concluded that atorvastatin in the embryonic during was able to reduce ovarian damage caused by BaP with antioxidant and anti-apoptotic properties.