Novel spiroindoline derivatives targeting aldose reductase against diabetic complications: Bioactivity, cytotoxicity, and molecular modeling studies.

Despite significant developments in therapeutic strategies, Diabetes Mellitus remains an increasing concern, leading to various complications, e.g., cataracts, neuropathy, retinopathy, nephropathy, and several cardiovascular diseases. The polyol pathway, which involves Aldose reductase (AR) as a critical enzyme, has been focused on by many researchers as a target for intervention. On the other hand, spiroindoline-based compounds possess remarkable biological properties. This guided us to synthesize novel spiroindoline oxadiazolyl-based acetate derivatives and investigate their biological activities. The synthesized molecules' structures were confirmed herein, using IR, NMR (1H and 13C), and Mass spectroscopy. All compounds were potent inhibitors with KI constants spanning from 0.186 ± 0.020 µM to 0.662 ± 0.042 µM versus AR and appeared as better inhibitors than the clinically used drug, Epalrestat (EPR, KI: 0.841 ± 0.051 µM). Besides its remarkable inhibitory profile compared to EPR, compound 6k (KI: 0.186 ± 0.020 µM) was also determined to have an unusual pharmacokinetic profile. The results showed that 6k had less cytotoxic effect on normal mouse fibroblast (L929) cells (IC50 of 569.58 ± 0.80 µM) and reduced the viability of human breast adenocarcinoma (MCF-7) cells (IC50 of 110.87 ± 0.42 µM) more than the reference drug Doxorubicin (IC50s of 98.26 ± 0.45 µM and 158.49 ± 2.73 µM, respectively), thus exhibiting more potent anticancer activity. Moreover, molecular dynamic simulations for 200 ns were conducted to predict the docked complex's stability and reveal significant amino acid residues that 6k interacts with throughout the simulation.

Gossypin mitigates oxidative damage by downregulating the molecular signaling pathway in oleic acid-induced acute lung injury.

One of the leading causes of acute lung injury, which is linked to a high death rate, is pulmonary fat embolism. Increases in proinflammatory cytokines and the production of free radicals are related to the pathophysiology of acute lung injury. Antioxidants that scavenge free radicals play a protective role against acute lung injury. Gossypin has been proven to have antioxidant, antimicrobial, and anti-inflammatory properties. In this study, we compared the role of Gossypin with the therapeutically used drug Dexamethasone in the acute lung injury model caused by oleic acid in rats. Thirty rats were divided into five groups; Sham, Oleic acid model, Oleic acid+Dexamethasone (0.1 mg/kg), Oleic acid+Gossypin (10 and 20 mg/kg). Two hours after pretreatment with Dexamethasone or Gossypin, the acute lung injury model was created by injecting 1 g/kg oleic acid into the femoral vein. Three hours following the oleic acid injection, rats were decapitated. Lung tissues were extracted for histological, immunohistochemical, biochemical, PCR, and SEM imaging assessment. The oleic acid injection caused an increase in lipid peroxidation and catalase activity, pathological changes in lung tissue, decreased superoxide dismutase activity, and glutathione level, and increased TNF-α, IL-1ß, IL-6, and IL-8 expression. However, these changes were attenuated after treatment with Gossypin and Dexamethasone. By reducing the expression of proinflammatory cytokines and attenuating oxidative stress, Gossypin pretreatment provides a new target that is equally effective as dexamethasone in the treatment of oleic acid-induced acute lung injury.

Unlocking Synergistic Potential: Agomelatine Enhances the Chemotherapeutic Effect of Paclitaxel in Breast Cancer Cell Through MT1 Melatonin Receptors and ER-alpha Axis.

This study investigates the potential of agomelatine (AGO), a synthetic melatoninergic drug, in combination with paclitaxel (PTX) for the treatment of breast cancer. The effects of AGO, PTX and melatonin (MTN) on breast cancer cell viability were investigated, focusing on the role of MT1 receptors. Cell viability and gene expression were analyzed in MCF-7 and MDA-MB-231 breast cancer cell experiments. The results show that AGO has cytotoxic effects on breast cancer cells similar to MTN. Combining AGO and MTN with PTX showed synergistic effects in MCF-7 cells. The study also reveals differences in the molecular mechanisms of breast cancer between estrogen-positive MCF-7 cells and estrogen-negative MDA-MB-231 cells. Combination with AGO and PTX affects apoptosis-associated proteins in both cell types. The findings suggest that AGO, combined with PTX, may be a promising adjuvant therapy for breast cancer and highlight the importance of MTN receptors in its mechanism of action.

Novel beta-lactam substituted benzenesulfonamides: in vitro enzyme inhibition, cytotoxic activity and in silico interactions.

In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a-l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with KIs in the low nanomolar range (66.60-278.40 nM) than the reference drug acetazolamide (AAZ), which had a KI of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d-g and 5l, with KIs of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, KI of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had KIs ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a KI of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski's and Jorgensen's rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents.Communicated by Ramaswamy H. Sarma.

Antipsychotics Induced Reproductive Toxicity by Stimulating Oxidative Stress: A Comparative in Vivo and in Silico Study.

The pathophysiological mechanism behind the link between antipsychotic drugs and sexual dysfunction is still unknown. The goal of this research is to compare the potential effects of antipsychotics on the male reproductive system. Fifty rats were randomly assigned into the five groups indicated: Control, Haloperidol, Risperidone, Quetiapine and Aripiprazole. Sperm parameters were significantly impaired in all antipsychotics-treated groups. Haloperidol and Risperidone significantly decreased the level of testosterone. All antipsychotics had significantly reduced inhibin B level. A significant reduction was observed in SOD activity in all antipsychotics-treated groups. While GSH levels diminished, MDA levels were rising in the Haloperidol and Risperidone groups. Also, the GSH level was significantly elevated in the Quetiapine and Aripiprazole groups. By causing oxidative stress and altering hormone levels, Haloperidol and Risperidone are damaging to male reproductivity. This study represents useful starting point for exploring further aspects of the underlying mechanisms reproductive toxicity of antipsychotics.

Discovery of novel benzenesulfonamides incorporating 1,2,3-triazole scaffold as carbonic anhydrase I, II, IX, and XII inhibitors.

Sulfonamides are among the most promising potential inhibitors for carbonic anhydrases (CAs), which are pharmaceutically relevant targets for treating several disease conditions. Herein, a series of benzenesulfonamides bearing 1,2,3-triazole moiety as inhibitors of human (h) α-CAs (hCAs) were designed using the tail approach. The design method combines a benzenesulfonamide moiety with a tail of oxime and a zinc-binding group on a 1,2,3-triazole scaffold. Among the synthesized derivatives, the naphthyl (6m, KI of 68.6 nM, SI of 10.3), and methyl (6a, KI of 56.3 nM, SI of 11.7) derivatives (over hCA IX) and propyl (6c, KI of 95.6 nM, SI of 2.7), and pentyl (6d, KI of 51.1 nM, SI of 6.6) derivatives (over hCA XII) displayed a noticeable selectivity for isoforms hCA I and II, respectively. Meanwhile, derivative 6e displayed a potent inhibitory effect versus the cytosolic isoform hCA I (KI of 47.8 nM) and tumor-associated isoforms hCA IX and XII (KIs of 195.9 and 116.9 nM, respectively) compared with the reference drug acetazolamide (AAZ, KIs of 451.8, 437.2, and 338.9 nM, respectively). Derivative 6b showed higher potency (KI of 33.2 nM) than AAZ (KI of 327.3 nM) towards another cytosolic isoform hCA II. Nevertheless, substituting the lipophilic large naphthyl tail to the 1,2,3-triazole linked benzenesulfonamides (6a-n) raised inhibitory effect versus hCA I and XII and selectivity towards hCA I and II isoforms over hCA IX. Evaluation of the cytotoxic potential of the synthesized derivatives was conducted in L929, MCF-7, and Hep-3B cell lines. Several compounds in the series demonstrated significant antiproliferative activity and minimal cytotoxicity. In the molecular docking study, the sulfonamide moiety interacted with the zinc-ion and neatly fit into the hCAs active sites. The extension of the tail was found to participate in diverse hydrophilic and hydrophobic interactions with adjacent amino acids, ultimately influencing the effectiveness and specificity of the derivatives.

Novel acetic acid derivatives containing quinazolin-4(3H)-one ring: Synthesis, in vitro, and in silico evaluation of potent aldose reductase inhibitors.

Aldose reductase (AR) is a crucial enzyme of the polyol pathway through which glucose is metabolized under conditions of hyperglycemia related to diabetes. A series of novel acetic acid derivatives containing quinazolin-4(3H)-one ring (1-22) was synthesized and tested for in vitro AR inhibitory effect. All the target compounds exhibited nanomolar activity against the target enzyme, and all compounds displayed higher activity as compared to the reference drug epalrestat. Among them, Compound 19, named 2-(4-[(2-[(4-methylpiperazin-1-yl)methyl]-4-oxoquinazolin-3(4H)-ylimino)methyl]phenoxy)acetic acid, displayed the strongest inhibitory effect with a KI value of 61.20 ± 10.18 nM. Additionally, these compounds were investigated for activity against L929, nontumoral fibroblast cells, and MCF-7, breast cancer cells using the MTT assay. Compounds 16 and 19 showed lower toxicity against the normal L929 cells. The synthesized compounds' (1-22) absorption, distribution, metabolism, and excretion properties were also evaluated. Molecular docking simulations were used to look into the possible binding mechanisms of these inhibitors against AR.

Roflumilast as a Potential Therapeutic Agent for Cecal Ligation and Puncture-Induced Septic Lung Injury.

PURPOSE/AIMS: This study focused on delineating the possible effects of roflumilast (ROF), a selective phosphodiesterase 4 (PDE4) inhibitor, in rats with cecal ligation and puncture (CLP)-induced polymicrobial sepsis, and investigated whether ROF can act as a protective agent in sepsis-induced lung damage. MATERIAL AND METHODS: Four experimental groups were organized, each comprising eight rats: Control, Sepsis, Sepsis + ROF 0.5 mgkg-1, and Sepsis + ROF 1 mgkg-1 groups. A polymicrobial sepsis model was induced in the rats by cecal ligation and puncture under anesthesia. Twelve hours after sepsis induction, the lungs were obtained for biochemical, molecular, and histopathological analyses. RESULTS: In the sepsis group's lungs, the TNF-α, IL-1ß, and IL-6 mRNA expression levels peaked in the sepsis group's lung tissues, and ROF significantly decreased these levels compared with the sepsis group dose-dependently. ROF also significantly decreased MDA levels in septic lungs and increased antioxidant parameters (SOD and GSH) compared with the sepsis group. Histopathological analysis results supported biochemical and molecular results. CONCLUSIONS: ROF, a PDE4 inhibitor, suppressed the expression levels of pro-inflammatory cytokines, alleviated lung damage (probably by blocking neutrophil infiltration), and increased the capacity of the antioxidant system.

Protective Effects of Idebenone against Sepsis Induced Acute Lung Damage.

BACKGROUND/AIMS: Sepsis is an uncontrolled systemic infection, withcomplex pathophysiology that may result in acute lung organ damage and cause multiple organ failure. Although much research has been conducted to illuminate sepsis's complex pathophysiology, sepsis treatment protocols are limited, and sepsis remains an important cause of mortality andmorbidity in intensive care units.Various studies have shown that idebenone (IDE) possesses strong antioxidant properties, which inhibit lipid peroxidation and protect cells from oxidative damage. The present study aimed to evaluate the protective effects of IDE against lung injury in a cecal ligation and puncture (CLP)-induced sepsis rat model. METHODS: Male albino Wistar rats were used. The animals were divided into a healthy control (no treatment), CLP, IDE control (200 mg/kg), and CLP + IDE subgroups (50 mg/kg, 100 mg/kg, and 200 mg/kg), with nine rats in each group.IDE was administered 1 h after CLP induction.To evaluate the protective effects of IDE, lung tissues were collected 16 h after sepsis for biochemical, immunohistochemical staining, and histopathological examination. RESULTS: IDE significantly ameliorated sepsis-induced disturbances in oxidative stress-related factors, with its effects increasing in accordance with the dose.IDE also abolished histopathological changes in lung tissues associated with CLP.Furthermore, interleukin 1 beta (IL-1ß)and tumor necrosis factor-alpha (TNF-α) immunopositivity markedly decreased in the septic rats following IDE treatment. CONCLUSIONS: IDE largely mitigated the inflammatory response in sepsis-induced lung injury by decreasing free radicals and preventing lipid peroxidation. The results suggest that IDE may represent a potential novel therapeutic drug for sepsis treatment.

Evaluation of the protective effects of gossypin for ischemia/reperfusion injury in ovary tissue.

AIM: Ovarian ischemia-reperfusion (I/R) injury is a serious gynecological condition that affects women of reproductive age and reduces ovarian reserve. Management of I/R injury with detorsion causes reperfusion damage, in which oxidative stress plays a central role. This study aimed to investigate whether the gossypin (GOS) with antioxidant properties, a flavonoid, has beneficial effects on the biochemical, molecular, and histopathological aspects of ovarian I/R injury. METHODS: Thirty-three female Balb/c mice were randomly divided into five groups as follows: Healthy (Sham-operated control group), I/R (IR group), I/R + GOS 5 (I/R with GOS 5 mg/kg), I/R + GOS 10 (I/R with GOS 10 mg/kg), and I/R + GOS 20 (I/R with GOS 20 mg/kg). This was followed by 3 h of ischemia and subsequent reperfusion for 3 h after detorsion was exposed. GOS was injected 2 h before reperfusion. RESULTS: IL-1ß, IL-6, TNF-α, NF-κB, and CASP-3 mRNA expressions, SOD (superoxide dismutase) activity, GSH (glutathione), and MDA (malondialdehyde) levels, and histopathological changes were evaluated in ovarian tissue. Histological examination indicated that treatment of ovarian I/R injury with GOS led to the improvement of ovarian tissue, which was accompanied by an increase in SOD activity and GSH level and a decrease in MDA level, NF-κB, TNF-α, IL-1ß, and IL-6 expressions. GOS was also corrected by reducing the elevated expression of CASP-3 as apoptosis-change marker. CONCLUSION: These findings indicate that the treatment of GOS may be useful as a conservative approach to reverse I/R injury via amelioration of oxidative stress parameters and histopathological scores, attenuation of inflammation, and the suppression of apoptosis.

A New Target in Inflammatory Diseases: Lycopene.

Inflammation is a response to various injuries, illnesses, and severe trauma. The primary function of inflammation is to combat pathogens, eliminate them from the body, and initiate wound healing. However, inflammation also contributes to numerous diseases, such as cancer, cardiovascular disease, diabetes, obesity, osteoporosis, rheumatoid arthritis, inflammatory bowel disease, and asthma. As the importance of nutrition in maintaining human health has become increasingly recognized, the consumption of natural antioxidants has gained popularity, especially in developed countries. A growing body of research has shown that consuming foods rich in lycopene can protect individuals from a range of conditions, including cancer, heart disease, and other diseases. As a result, lycopene is gaining recognition as a potential protective antioxidant in the fields of medicine and pharmacology. This review aims to highlight the effects of lycopene on inflammatory diseases and provide a foundational understanding for researchers interested in further research on lycopene.

Does daily fasting shielding kidney on hyperglycemia-related inflammatory cytokine via TNF-α, NLRP3, TGF-ß1 and VCAM-1 mRNA expression.

This study aimed to investigate the effects of blood glucose control and the kidneys' functions, depending on fasting, in the streptozotocin-induced diabetes model in rats via TNF-α, NLRP-3, TGF-ß1 and VCAM-1 mRNA expression in the present study. 32 Wistar albino rats were allocated randomly into four main groups; H (Healthy, n = 6), HF (Healthy fasting, n = 6), D (Diabetes, n = 10), DF (Diabetes and fasting, n = 10). Blood glucose and HbA1c levels significantly increased in the D group compared to the healthy ones (p < 0.05). However, the fasting period significantly improved blood glucose and HbA1c levels 14 days after STZ induced diabetes in rats compared to the D group. Similar findings we obtained for serum (BUN-creatinine) and urine samples (creatinine and urea levels). STZ induced high glucose levels significantly up-regulated TNF-α, NLRP-3, TGF-ß1 and VCAM-1 mRNA expression and fasting significantly decreased these parameters when compared to diabetic rats. Histopathological staining also demonstrated the protective effects of fasting on diabetic kidney tissue. In conclusion, intermittent fasting regulated blood glucose level as well as decreasing harmful effects of diabetes on kidney tissue. The fasting period significantly decreased the hyperglycemia-related inflammatory cytokine damage on kidneys and also reduced apoptosis in favor of living organisms.

Investigation of the Role of Stimulation and Blockade of 5-HT7 Receptors in Ketamine Anesthesia.

Although several pieces of evidence have indicated the ability of the serotonin-7 receptor (5-HTR7) to modulate N-methyl-D-aspartate receptor (NMDAR) activation, the possible impact on ketamine anesthesia has not been examined directly. The purpose of the present study is thus to investigate the possible role of the 5-HTR7 in ketamine anesthesia using a 5-HTR7 agonist and/or antagonist. The influence of a 5-HTR7 agonist/antagonist on ketamine anesthesia for behavioral impact was assessed by testing potential anesthetic parameters. Its functional impact was assessed by mRNA expression with real-time PCR and immunostaining in the hippocampus and prefrontal cortex of mice. Two different doses of ketamine-high and low-were administered to induce anesthesia. In the high-dose ketamine-applied group in particular, the administration of both the 5-HTR7 agonist and antagonist intensified the anesthetic effect of ketamine. The reflection of the change in anesthesia parameters to 5-HTR7 expression was observed as an increase in the hippocampus and a decrease in the prefrontal cortex in the anesthetized groups by stimulation of 5-HTR7. It is noteworthy that the results of NMDAR expressions are parallel to the results of the 5-HTR7 expressions of both the hippocampus and the prefrontal cortex. The 5-HTR7 may play a role in ketamine anesthesia. It may act through NMDAR in ketamine anesthesia, depending on the parallelism between both receptors.

Protective Effect of Carvacrol against Paclitaxel-Induced Ototoxicity in Rat Model.

OBJECTIVE: This study aimed to explore whether carvacrol (CV) had a protective effect on paclitaxel-induced ototoxicity from biochemical, functional, and histopathological perspectives. METHODS: Forty Wistar albino male rats were randomly separated into five groups of eight rats. Group 1 was the control group, so Paclitaxel or CV was not administered. Group 2 was administered i.p. CV at 25 mg/kg once a week; Group 3, was administered i.p. paclitaxel at 5 mg/kg once a week; Group 4 was administered i.p. paclitaxel at 5 mg/kg followed (30 min later) by CV at 25 mg/kg once a week; and Group 5 was administered i.p. CV at 25 mg/kg followed (1 day later) by paclitaxel at 5 mg/kg. once a week. The drugs were administered intraperitoneally once a week for four consecutive weeks, and distortion product otoacoustic emissions (DPOAE) tests were performed at the beginning of the study before the first drug administration and at the end of the study after the last drug administration. All rats were sacrificed, and cochleae were removed for biochemical and histopathological analysis. RESULTS: Biochemical data indicated that paclitaxel caused oxidative stress in the cochlea. Histopathological findings revealed the loss of outer hair cells in the organ of Corti (CO) and moderate degenerative changes in the stria vascularis (SV). It was observed that DPOAE measurements were significantly reduced at high frequencies. In groups which CV was administered together with paclitaxel, these biochemical, histopathological, and functional changes were favorably reversed. CONCLUSION: CV may have a protective effect against paclitaxel-induced ototoxicity when given.

Carvacrol Protects Against Paclitaxel-Induced Retinal and Optic Nerve Cytotoxicity: A Histopathological Study.

OBJECTIVES: Carvacrol (CV) is a phenolic monoterpenoid found in the essential oil of a number of aromatic plants and herbs. The present study was an investigation of the potential protective effect of CV against paclitaxel (PTX)-induced retinal and optic nerve cytotoxicity in rats. METHODS: A total of 18 adult male Wistar albino rats (250-400g) were randomized into 3 equal groups comprising 6 animals each. Group 1 (control group) received intraperitoneal (IP) saline solution (0.5 mL/200 g) weekly for 4 weeks. Group 2 received an IP dose of PTX (5 mg/kg), and Group 3 received CV (25 mg/kg) 30 minutes after an IP dose of PTX (5 mg/kg) weekly for 4 weeks. At the conclusion of the experimental period, the retinal and optic nerve tissues of the subjects were evaluated histopathologically. RESULTS: All of the retinal specimens in Group 1 (control) were histopathologically normal. In Group 2 (PTX), all of the eyes (6/6) revealed increased retinal vascularity and rosette-like structures in the outer nuclear layer, and in Group 3 (PTX-CV), all of the eyes (6/6) demonstrated normal retinal vascularity and the absence of rosette-like structures. All of the optic nerve specimens in Group 1 (control) were histopathologically normal. In Group 2 (PTX), all of the eyes (6/6) demonstrated severe vacuolization and a decreased number of astrocytes and oligodendrocytes in the optic nerve specimens, while 3 eyes (3/6) showed marked single cell necrosis. None of the eyes in Group 3 (PTX-CV) demonstrated either vacuolization or a reduction in the number of astrocytes and oligodendrocytes. No remarkable single cell necrosis was observed in the optic nerve specimens of Group 3 (PTX-CV). CONCLUSION: The histopathological findings indicated that CV played a protective role against PTX-induced cytotoxicity. CV might be a promising resource to counteract oxidative stress-based cytotoxicity in the field of retinal and optic nerve disorders.

The investigation of possible roles of central 5-HT7 receptors in antipyretic effect mechanism of paracetamol in LPS-induced hyperthermia model of mice.

AIM: This study aimed to investigate the role of the 5-HT7 receptor in fever mechanisms and its possible effect on the antipyretic mechanism of paracetamol. MATERIALS AND METHODS: The study consisted of eight experimental groups and one control group. Group I: healthy, II: LPS, III: LPS + PARA, IV: LPS + AGO, V: LPS + ANTA, VI: LPS + AGO + ANTA, VII: LPS + AGO + PARA, VIII: LPS + ANTA + PARA, and IX: LPS + AGO + ANTA + PARA. Rectal temperatures were measured with a rectal thermometer. At the end of the experiment, tissues were examined molecularly. Real-time PCR mRNA expression analyses were performed for the 5-HT7 receptor, IL-6, and TNF-α in hypothalamus tissue. RESULTS: The mean differences in rectal temperature increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group and decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the healthy group. The IL-6 and TNF-α mRNA expression increased in the LPS, LPS + ANTA, and LPS + AGO + ANTA groups when compared to the healthy group in the 2nd and 4th hours. The IL-6 and TNF-α expression decreased in the LPS + PARA, LPS + AGO, LPS + AGO + PARA, and LPS + AGO + ANTA + PARA groups when compared to the LPS group in the 2nd and 4th hours. The 5-HT7 receptor mRNA expression increased in the LPS group when compared to the healthy group in the 2nd hour. The 5-HT7 receptor mRNA expression decreased in the LPS + AGO and LPS + AGO + PARA groups when compared to the LPS group in the 2nd hour. The 5-HT7 receptor mRNA expression increased the in LPS + ANTA and LPS + ANTA + PARA groups when compared to the LPS group in the 2nd hour. CONCLUSION: The 5-HT7 receptor is a potential defense mechanism in stopping fever and the antipyretic property of paracetamol is not due to the 5-HT7 receptor.

Carvone protects against paclitaxel-induced retinal and optic nerve cytotoxicity: a histopathological study.

Purpose: Carvone (CVN) is a natural monoterpene found in essential oils of many aromatic plant species. In this study, we investigated the protective effect of CVN against paclitaxel (PTX)-induced retinal and optic nerve cytotoxicity in rats. Methods: Twenty-four male adult Wistar albino rats (250-400 g) were randomized into four equal groups comprising six animals in each. Group 1 (control group) received intraperitoneal (i.p.) saline solution (0.5 mL/200 g) weekly for 4 weeks. Group 2 received i.p. CVN [(S)-(+)- CVN, (5S)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one, C10H14, 25 mg/kg], while Group 3 received i.p. PTX (5 mg/kg) weekly for 4 weeks. Group 4 received i.p. CVN (25 mg/kg) 30 min after i.p. PTX (5 mg/kg) weekly for 4 weeks. At the end of the experimental period, retinal and optic nerve tissues were evaluated histopathologically. Results: All retinal specimens in control and CVN groups were histopathologically normal. In PTX group all eyes (6/6) demonstrated increased retinal vascularity and rosette-like structures in the outer nuclear layer, while in PTX-CVN group all eyes (6/6) demonstrated normal retinal vascularity and absence of rosette-like structures. All optic nerve specimens in control and CVN groups were histopathologically normal. In PTX group all eyes (6/6) demonstrated severe vacuolization and decrease in the number of astrocytes and oligodendrocytes, while 3 eyes (3/6) demonstrated marked single cell necrosis. In PTX-CVN group, 4 eyes (4/6) demonstrated moderate vacuolization while, 2 eyes (2/6) had none. Compared with PTX group, 1 eye (1/6) in PTX-CVN group demonstrated a decrease in numbers of astrocytes and oligodendrocytes while 5 eyes (5/6) were normal. No remarkable single cell necrosis was observed in PTX-CVN group. Conclusions: Our histopathological findings demonstrated the potential protective role of CVN against PTX-induced retinal and optic nerve cytotoxicity. CVN might be a promising molecule in counteracting oxidative stress-based cytotoxicity in the field of retinal and optic nerve disorders.

Urotensin receptors as a new target for CLP induced septic lung injury in mice.

Sepsis is a life-threatening organ dysfunction condition response resulting in acute lung injury. Urotensin II (UII), an endogenous vasoactive peptide, is widely distributed in pulmonary, cardiovascular, central nervous, renal and metabolic systems, and especially in inflammatory regions. This study aimed to investigate whether urotensin II (UII) and UII receptor (UTR) antagonists play a role in the inflammatory response to sepsis-induced lung damage and they are possible therapeutic targets. In the study, 78 male Balb-c mice were used. A cecal ligation and puncture (CLP)-induced polymicrobial sepsis model was applied, and the effects of human urotensin II (agonist) and urantide and palosuran (antagonists) were investigated on lung tissues. Glutathione and malondialdehyde levels and SOD activity of lung tissues were investigated in addition to TNF-α, IL-1ß, IL-6, NF-κB, and UTR mRNA levels. Also, lung sections were histopathologically evaluated. Urantide and palosuran, UII receptor antagonists, decreased proinflammatory cytokines such as TNF-α, IL-1ß, IL-6, NF-κB, and also decreased oxidative stress parameters in lung tissue, which are markers of damage. UTR mRNA expression was increased in septic lungs, and both antagonists significantly decreased the elevated receptor level. Also, histopathological examination showed beneficial effects of both agonists on lung tissue. The results of this study help to understand the inflammatory and therapeutic contribution of the UII/UTR system on sepsis-induced lung damage. We can suggest that UTR receptor antagonists may be evaluated as a potential drug which reduces sepsis-induced lung damage in the future.

A new update for radiocontrast-induced nephropathy aggravated with glycerol in rats: the protective potential of epigallocatechin-3-gallate.

Contrast media (CM) is known to have nephrotoxic adverse effects. Epigallocatechin-3-gallate (EGCG) is the most abundant and active catechin in green tea, and has strong antioxidant and anti-inflammatory properties. This study investigated whether EGCG can reduce contrast-induced nephrotoxicity (CIN), alone or with glycerol (GLY)-induced renal damage, and to understand its mechanisms of protection against toxicity, using models of GLY and CIN in rats. The rats were separated into eight groups (n = 6 in each), as follows: Healthy, GLY, CM, GLY + CM, CM + EGCG 50 mg/kg (po), GLY + CM + EGCG 50 mg/kg (po), CM + EGCG 100 mg/kg (po), and GLY + CM + EGCG 100 mg/kg (po). Both doses of EGCG protected against CM-induced renal dysfunction, as measured by serum creatinine and blood urea nitrogen (BUN). In addition, EGCG treatment markedly improved CIN-induced oxidative stress, and resulted in a significant down-regulatory effect on tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB mRNA expression. Moreover, histopathological analysis showed that EGCG also attenuated CM-induced kidney damage. Considering the potential clinical use of CM and the numerous health benefits of EGCG, this study showed the protective role of multi-dose EGCG treatment on CIN and GLY-aggravated CIN through different mechanisms.