Evaluation of antidiabetic and antioxidant effects of Polygonum cognatum Meisn. and phytochemical analysis of effective extracts.

Polygonum cognatum Meisn. (Polygonaceae) is used both as food and as a folk medicine to treat diabetes. This study aimed to evaluate the effect of the extracts, along with isolated compounds, from P. cognatum aerial parts on diabetes. In vitro studies were conducted using an α-glucosidase inhibitory assay, while in vivo antidiabetic studies were carried out on streptozotocin-induced diabetic rats. Effective extracts were subjected to isolation studies, and structures of the compounds were elucidated by spectroscopic methods. The ethyl acetate and n-butanol extracts had the highest effect in both in vitro and in vivo experiments. They also decreased aspartate transaminase, alanine transaminase and malondialdehyde levels, while increasing glutathione and superoxide dismutase activity in rats. From the active extracts, 11 phenolic compounds were isolated and characterized. Among the isolated compounds, quercetin was found to be the most active according to α-glucosidase inhibitory activity studies. This study provided scientific evidence for the traditional use of P. cognatum as a folk medicine for treating diabetes. The findings suggest that the ethyl acetate and n-butanol extracts, as well as quercetin, have the potential for development as antidiabetic agents.

Antidiabetic and antioxidant properties of Paeonia mascula L.: In vitro and in vivo studies, and phytochemical analysis.

The medicinal plant Paeonia mascula L. is commonly used in Anatolian folk medicine for its antidiabetic properties. This study aimed to investigate the in vitro α-glucosidase enzyme inhibition effect, in vivo antidiabetic, and antioxidant activities of extracts obtained from P. mascula. The in vivo studies were conducted on diabetic rats induced with streptozotocin. The ethyl acetate and n-butanol extracts showed the highest efficacy in both in vitro and in vivo experiments, reducing AST, ALT, and MDA levels while increasing GSH and SOD activities in rats. In total, seven compounds were isolated from both extracts, and their structures were identified using spectroscopic methods such as 1D and 2D NMR and Mass Spectrometry. The in vitro α-glucosidase inhibition assay on purified compounds revealed that 1,2,3,4,6-penta-O-galloyl-ß-d-glucose was the most effective compound. These findings support the traditional use of P. mascula as an antidiabetic agent.

Protective effect of astaxanthin and metformin in the liver of rats in which the polycystic ovary syndrome model was formed by giving letrozole.

Objectives: In this study, the effects of astaxanthin on liver tissue in rats with polycystic ovary syndrome (PCOS) were evaluated. Materials and Methods: Fifty-four Spraque-Dawley rats were divided into 9 groups: Groups: Control, PCOS, PCOS+Metformin (Met), PCOS+ Astaxanthin (ASX)10, PCOS+ASX20, PCOS+ASX40, PCOS+Met+ASX10, PCOS+Met+ASX20, and PCOS+Met+ASX40. PCOS was induced in female rats by oral administration of letrozole (1 mg/kg) for 21 days. Rats were treated with ASX (10 mg/kg), ASX (20 mg/kg), ASX (40 mg/kg), and metformin (20 mg/kg) for 7 days after PCOS induction. At the end of the experiment, malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured in the liver tissue. The liver was stained with hematoxylin/eosin for histological examination. Additionally, NF-kB and caspase 3 were analyzed immunohistochemically. Results: A remarkable abnormality was observed in the biochemical and histological parameters in the liver tissue of the PCOS model rats. Astaxanthin dose-dependently normalized the MDA level. Additionally, astaxanthin showed a protective effect by increasing the SOD level and increasing its antioxidant activities. We observed that administration of astaxanthin in addition to metformin applied in the standard was more effective. Caspase 3 and NF-kB immune positivity was lower in the groups given astaxanthin compared with PCOS. Histologically, it was observed that astaxanthin improved the deteriorated liver morphology in the letrozole-induced PCOS group. Conclusion: According to our results, it was observed that astaxanthin had antioxidant, anti-inflammatory and anti-apoptotic effects on PCOS in the treatment groups. Therefore, it was concluded that astaxanthin may have a protective effect against PCOS side effects.

Potential role of angiotensin converting enzyme/neprilysin pathway and protective effects of omapatrilat for paracetamol­induced acute liver injury.

The renin-angiotensin-aldosterone system (RAAS) is an important pathway that contributes to the pathophysiology of acute liver injury due to paracetamol toxicity. Omapatrilat, a RAAS-acting agent, inhibits both angiotensin converting enzyme (ACE) and neprilysin/neutral endopeptidase (NEP). The aim of the present study was to investigate the hepatoprotective effects of omapatrilat and examine the role of ACE/NEP pathway on the physiopathology of paracetamol toxicity. A total of 56 BALB/c mice were separated into seven groups: Control, 40 mg/kg omapatrilat only, 400 mg/kg paracetamol only, paracetamol and 140 mg/kg N-acetylcysteine and three groups with paracetamol and 10-40 mg/kg omapatrilat. Blood and liver tissue samples were studied through histopathological imaging, alanine transaminase (ALT) and aspartate transaminase (AST) liver function tests and oxidant/antioxidant biomarker measurements including superoxide dismutase (SOD), glutathione (GSH) and malondialdehyde (MDA). ACE and NEP activities were also measured. Histopathological analysis revealed that paracetamol toxicity resulted in a number of apoptotic and necrotic cells in liver tissue samples. By contrast, with 40 mg/kg omapatrilat administration in toxicity-induced mice, hepatocytes were significantly improved and exhibited similar appearance to the control group. Biochemical measurements also supported these histopathological results. Omapatrilat pretreatment provided a dose-dependent reduction in oxidative stress and reversed paracetamol toxicity indications by reducing ALT and AST activities, increasing SOD activity and GSH levels and reducing MDA levels. Dose-dependent increase of ACE and NEP enzymes in omapatrilat groups was also observed. The results demonstrated promotion of antioxidant activity by omapatrilat and suppression of oxidative stress associated with acute liver injury. These findings revealed the potential role of ACE/NEP pathway in paracetamol toxicity and hepatoprotective effects of omapatrilat against oxidative stress.

Potential protective effect of astaxanthin on ovary ischemia-reperfusion injury.

Objectives: We thought that astaxanthin (ASX) might be a protective agent in oxidative stress damage that develops against ischemia and reperfusion injury in the rat ovary. Materials and Methods: The experimental groups consisted of healthy, I (Ischemia), I+ASX50, I+ASX100, I/R (Ischemia/Reperfusion), I/R+ ASX50, and I/R+ ASX100. Vascular clamps were applied to the ovaries for 3 hr to induce ischemia. For the reperfusion groups, the clamps were opened and blood flow was restored to the ovaries for 3 hr. At the end of the experiment, biochemical, histopathological, and immunohistochemical analyses were made from the tissue samples taken. Results: While MDA levels increased significantly in I and I/R groups, SOD levels decreased. It was found that ASX significantly decreased MDA levels and increased SOD activity in treatment groups depending on the dose. Caspase 3, IL-1 ß, and IL-6 expressions were severely increased in ischemia and I/R groups, while the severity of I+ASX50 and I/R+ASX100 immunoreactivity was decreased. While severe hemorrhage areas were observed in I and IR groups, minimal hemorrhage areas were observed in the treatment groups, especially in I/R+ASX100 groups. In addition, inflammatory cells and necrotic cells in the I/R group were not observed in I/R+ASX50 and I/R+ASX100 groups. Conclusion: As a result, it was determined that ASX has a strong protective role against oxidative damage in the treatment of ovarian ischemia-reperfusion injury.

A new approach to sepsis treatment by rasagiline: a molecular, biochemical and histopathological study.

AIM: We aimed to investigate the effects of rasagiline on acute lung injury that develops in the sepsis model induced with the cecal ligation and puncture in rats. MAIN METHODS: The rats were separated into the following six groups, Group 1: Sham, Group 2: Sham + Rasagiline 4 mg/kg, Group 3: Sepsis, Group 4: Sepsis + Rasagiline 1 mg/kg, Group 5: Sepsis + Rasagiline 2 mg/kg, Group 6: Sepsis + Rasagiline 4 mg/kg. A total of four holes were opened with a 16-gauge needle through the cecum distal to the point of ligation. KEY FINDINGS: Rasagiline treatment increased glutathione level and superoxide dismutase activity while decreased the malondialdehyde level after the sepsis. There was a statistically significant improvement in the doses of 2 mg/kg and 4 mg/kg. Rasagiline also increased Tnf-α, IL1ß, IL6, NF-κßand HMGB1 gene expressions in dose-dependent at 2 mg/kg and 4 mg/kg doses. In increased doses, rasagiline prevent the development of edema, the formation of inflammation, and hemorrhage. SIGNIFICANCE: Rasagiline exerts both antioxidant and anti-inflammatory effects on the cecal ligation and puncture induced acute lung injury in rats.

In Vivo and In Vitro Cardioprotective Effect of Gossypin Against Isoproterenol-Induced Myocardial Infarction Injury.

The aim of the study was to examine the protective effects and possible mechanism of gossypin against isoproterenol (ISO)-mediated myocardial damage in vivo and H9c2 cell damage in vitro. H9c2 cells were categorized into five groups. Viability was evaluated with MTT and LDH release in H9c2 cells. Apoptotic parameter analysis was performed with cytochrome c (Cyt-c), caspase-3 (CASP-3), and BCL2/Bax mRNA expression levels. In vivo, gossypin was administered orally to mice at doses of 5, 10, and 20 mg/kg for 7 days. ISO groups were injected with isoproterenol (150 mg/kg) subcutaneously (on 8th and 9th) for 2 days. Afterward, lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) levels and Troponin-I (Tn-I) amount from their serum, oxidative stress parameters superoxide dismutase (SOD) activity, glutathione (GSH) and malondialdehyde (MDA) levels, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1 ß), and NF-kB mRNA expression levels with inflammatory markers from heart tissue were evaluated. In addition, IL-1B, BCL-2, and cas-3 immunohistochemical staining was performed from heart tissue and TNF-a level was measured by ELISA method. Administration of Gossypin protected the cells by dose-dependent, eliminating the reduced cell viability and increased LDH release of ISO in H9c2 cells. In mice serum analyses, increased LDH, CK-MB levels, and Tn-I levels were normalized by gossypin. ISO administration in heart tissue is regulated by gossypin with increased SOD activity, GSH amount, TNF-α, IL-6, IL-1ß, and NF-kB mRNA expression levels and decreased MDA amount. Overall, the present results demonstrated that gossypin has a potential cardioprotective treatment for ischemic heart disease on in vivo and in vitro.

Aprepitant: an antiemetic drug, contributes to the prevention of acute lung injury with its anti-inflammatory and antioxidant properties.

OBJECTIVES: We investigated, the effects of aprepitant (APRE) on the lung tissues of rats with an experimental polymicrobial sepsis model (CLP: cecal ligation and puncture) biochemically, molecularly and histopathologically. METHODS: A total of 40 rats were divided into 5 groups with 8 animals in each group. Group 1 (SHAM), control group; Group 2 (CLP), cecal ligation and puncture; Group 3 (CLP + APRE10), rats were administered CLP + 10 mg/kg aprepitant; Group 4 (CLP + APRE20), rats were administered CLP + 20 mg/kg aprepitant; and Group 5 (CLP + APRE40), rats were administered CLP + 40 mg/kg aprepitant. A polymicrobial sepsis model was induced with CLP. After 16 h, lung tissues were taken for examination. Tumour necrosis factor α (TNF-α) and nuclear factor-kappa b (NFK-b) messenger ribonucleic acid (mRNA) expressions were analysed by real-time PCR (RT-PCR), biochemically antioxidant parameters such as superoxide dismutase (SOD) and glutathione (GSH) and oxidant parameters such as malondialdehyde (MDA) and lung damage histopathologically. KEY FINDINGS AND CONCLUSIONS: The GSH level and SOD activity increased while the MDA level and the expressions of TNF-α and NFK-b were reduced in the groups treated with APRE, especially in the CLP + APRE40 group. The histopathology results supported the molecular and biochemical results.

Phloretin and phloridzin guard against cisplatin-induced nephrotoxicity in mice through inhibiting oxidative stress and inflammation.

AIM: Cisplatin (Cis) is widely used chemotherapeutic and has some serious side effects as nephrotoxicity. Phloretin (PH) and Phloridzin (PZ) are known their anti-oxidant anti-inflammatory effects. We aimed to examine the protective effects of PH and PZ on cisplatin-induced nephrotoxicity. MAIN METHODS: Totally, 48 Balb/C female mice were separated into eight groups (n = 6). First day, single dose of cisplatin (20 mg/kg intraperitoneal) was administered to induce toxicity. PH and PZ were given (50 and 100 mg/kg orally) to treatment groups during 3 days. After the experimental procedures serum renal function enzymes (BUN and Creatinine), oxidative parameters (SOD, GSH and MDA), nuclear agent NFKß, inflammatory cytokines (Tnf-α and IL1ß) and HSP70 expressions and histopathological assessments were analyzed. KEY FINDINGS: Serum enzymes, tissue cytokines and oxidative stress were increased after the Cis treatment. PH and PZ treatments normalized all parameters compared to Cis administrated group. After the treatments, SOD activities and GSH levels were increased while MDA levels were decreased. PH and PZ treatments decreased Tnf-α, IL1ß and NFKß mRNA expressions. Cis significantly increased the HSP70 expression while PH and PZ administrations significantly decreased. Similar the biochemical and molecular results, PH and PZ showed positive effects on tissue pathological parameters. Cisplatin cause a lot of abnormal structures as tubular and glomeruli damages on the kidney. SIGNIFICANCE: PH and PZ play important physiological roles in the prevention of nephrotoxicity. Antioxidant and anti-inflammatory effects of PH and PZ demonstrated visible protective effects in the cisplatin-induced nephrotoxicity model.

The Protective Roles of Butein on Indomethacin Induced Gastric Ulcer in Mice.

OBJECTIVE: Butein is a potential agent first isolated from Rhus verniciflua that has medicinal value in East Asia and has been used in the treatment of gastritis, gastric cancer, and atherosclerosis since ancient times. The aim of our study is to show, for the first time, the anti-ulcerative effect of butein in indomethacin induced gastric ulcer in mice. MATERIALS AND METHODS: A total of 42 mice were fasted 24 hours for the ulcer experiment, and 10, 20, and 40 mg/kg doses of butein were evaluated for their antiulcer activity. Famotidine 40 mg/kg was used as a positive control group. For ulcer induction, 25 mg/kg dose of indomethacin was administered to the mice and after 6 hours all stomachs were dissected out. After macroscopic analyses, tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), COX-1, and COX-2 mRNA levels of stomachs were evaluated by Real Time PCR, and Superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) were determined by ELISA. RESULTS: Butein administration exerted 50.8%, 65.9%, and 87.1% antiulcer effects at 10, 20, and 40 mg/kg, respectively. Butein administration decreased oxidative stress and inflammatory parameters in stomach tissues dose dependently. Furthermore, butein administration increased stomach PGE2 levels and decreased COX-1 and COX-2 mRNA levels. CONCLUSION: Butein has been shown to have a healing effect on ulcers in macroscopic examinations in our study. We observed that butein has antioxidant and anti-cytokine properties in gastric tissue. Butein could be an important alternative in the treatment of indomethacin-induced ulcers. Whether butein is a partial agonist of the COX enzyme should be investigated in future studies.

Do peripheral melatonin agonists improve bone fracture healing? The effects of agomelatine and ramelteon on experimental bone fracture.

Melatonin improves fracture healing, but the long-term use of melatonin seems impracticable in the treatment of fracture due to side effects caused by hormonal stress on chronological rhythm. Ramelteon (RAMEL) and agomelatine (AGO) are non-selective peripheral melatonin receptor (MT) agonists. This study investigated the effects on bone fracture healing of these MT agonists, which do not affect the central nervous system. The rats were divided into 6 groups, including Group 1 (SHAM): sham operated group; Group 2 (FRACTURE): femoral fracture control; Group 3 (FR + AGO30): femoral fracture + agomelatine 30 mg/kg; Group 4 (FR + AGO60): femoral fracture + agomelatine 60 mg/kg; Group 5 (FR + RAMEL3): femoral fracture + ramelteon 3 mg/kg; and Group 6 (FR + RAMEL6): femoral fracture + ramelteon 6 mg/kg. After 21 days, the rats were subjected to X-ray imaging. Bone healing was evaluated with hematoxylin-eosin (HE) staining. Messenger RNA (mRNA) expressions of bone formation markers, such as bone alkaline phosphatase (ALP), osteocalcin (OC), and osteopontin (OP), were evaluated by real-time polymerase chain reaction (RT-PCR) and with immunohistochemistry (IHC) staining. The radiographic fracture healing scores were statistically significantly higher in the FR + AGO60 group and the FR + RAMEL3 group than in the FRACTURE group. The histopathology and molecular results supported the radiographic results. It was shown that agomelatine and ramelteon increase bone fracture healing, leading to the conclusion that a preference for agomelatine, an antidepressant, and ramelteon, a sleep aid, will increase bone fracture healing in patients with fractures.

Can aprepitant used for nausea and vomiting be good gastrointestinal complaints?

Aprepitant is a selective SP/NK-1 receptor antagonist and used in postoperative and chemotherapeutics induced emesis and vomiting. The aim of our study is to show aprepitant may have beneficial effects on gastrointestinal complaints in cancer patients undergoing chemotherapeutics by indomethacin-induced gastric ulcer model. A total of 48 rats were fasted 24 h for ulcer experiment. Aprepitant doses of 5, 10, 20, and 40 mg/kg were evaluated for their antiulcer activity. Omeprazole (20 mg/kg) was used as a positive control group. Six hours after 25 mg/kg indomethacin administration, all stomachs were dissected out. After macroscopic analyses, tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), COX-1, and COX-2 mRNA levels and SOD activity, and GSH and MDA levels of stomachs were determined. Histopathological examinations were evaluated. Aprepitant administration exerted 48.14%, 49.62%, 65.92%, and 76.77% ulcer inhibition effects at 5, 10, 20, and 40 mg/kg, respectively. Aprepitant administration decreased oxidative stress and inflammatory parameters in stomach tissues dose dependently. Aprepitant administration increased stomach COX-2 mRNA levels at 20 and 40 mg/kg doses. Although aprepitant appears to be disadvantageous in terms of treating gastric ulcer due to COX enzyme inhibition according to the previous studies, aprepitant has been shown to have ulcer healing effect in our study. When aprepitant is given as an anti-nausea and vomiting drug to cancer patients undergoing chemotherapy, we can argue that it will not be necessary to add a new gastric protective agent as it also shows beneficial effects in gastrointestinal complaints.

Possible contribution of the neprilysin/ACE pathway to sepsis in mice.

AIM: Omapatrilat is an antagonist of angiotensin-converting (ACE) and neprilysin-neuropeptidase (NEP) enzymes. The aim of our study is to show that omapatrilat may have beneficial effects as a treatment for polymicrobial sepsis. MAIN METHODS: A cecal ligation and puncture (CLP) sepsis model was used to evaluate 10 and 20 mg/kg doses of omapatrilat in mice (n = 30) fasted for 12 h. The lungs were removed 12 h after CLP, and lung levels of cytokines (tumor necrosis factor-alpha [TNF-α], interleukin-6 [IL-6], NF-κB), iNOS and eNOS mRNA expression, GSH and MDA levels, and ACE and NEP activities were determined. Histopathological examinations were also performed. KEY FINDINGS: Omapatrilat treatment provided a dose-dependent reduction in oxidative stress and inflammatory parameters in lung tissues. Omapatrilat administration decreased lung iNOS and eNOS mRNA levels at 20 mg/kg dose. Histopathological analysis revealed a decline in the thickening and edema areas in the alveolar septa in the Sepsis+OMA20 group. SIGNIFICANCE: Omapatrilat, a dual ACE and NEP inhibitor, protected lung tissue from sepsis damage by reducing ACE and NEP activities, by decreasing the mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and NF-κB), by suppressing leukocyte infiltration and edema, by restoring iNOS and eNOS levels, and by restoring SOD activity and GSH and MDA levels, thereby reducing oxidative stress.

A novel effect of Aprepitant: Protection for cisplatin-induced nephrotoxicity and hepatotoxicity.

Cisplatin is widely used chemotherapeutic drug and have some serious side effects as tissue toxicity and nausea and vomiting. Aprepitant is used in clinic as an anti-emetic drug for cisplatin treated patient to prevent nausea and vomiting. We aimed to investigate the protective effects of Aprepitant on cisplatin-induced nephrotoxicity and hepatotoxicity. In total 42 male rats were separated into six groups (n = 7). A single dose of cisplatin (10 mg/kg i.p.) was administered to induce toxicity on first day. Different doses of Aprepitant (5, 10 and 20 mg/kg, p.o.) were given to treatment groups during 3 days. After the experimental procedures serum enzymes (ALT, AST, ALP, BUN and Creatinin), kidney and liver oxidative parameters (SOD, GSH and MDA), inflammatory cytokines (TNF-α and NF-κB) and Cyp2e1 expressions analyzed. Histopathological investigations also performed for all groups. Cisplatin caused tissue toxicity in both kidney and liver. Serum enzymes, tissue cytokines and oxidative stress were increased after the Cis treatment. Aprepitant treatment normalized all parameters compared to cisplatin treated group. Cisplatin significantly increased the Cyp2e1 expression in the kidney while significantly decreased in the liver compared to Healthy group. Histopathologically, it was shown that cisplatin causes a lot of abnormal structures as inflammatory infiltration and necrosis on the liver and kidney. Similar the biochemical and molecular results, aprepitant showed positive effects on tissue pathological parameters. With its main anti-emetic effect, Aprepitant treatment may be an effective option for cancer patients if they have additional injury as nephrotoxicity and hepatotoxicity due to cisplatin.

Effects of soy isoflavonoids (genistein and daidzein) on endometrial receptivity.

OBJECTIVES: This study aimed to examine the effects of genistein and daidzein on endometrial receptivity by histopathological, immunohistochemical, and biochemical techniques. MATERIALS AND METHODS: In this study, 72 female Sprague-Dawley rats were randomly divided into 8 groups. The endometrial receptivity model was applied to identified groups. Experimental animals were given periorally 10 mg/kg and high 40 mg/kg doses of genistein and daidzein for 5 days by gavage. At the end of the experiment, uterine tissues were evaluated histopathologically, immunohistochemically, and biochemically. RESULTS: When histopathological findings were examined, significant decreases in pinopod formation were observed in high dose genistein and daidzein groups. When compared with the endometrial receptivity group, immunohistochemical staining findings showed a significant decrease in the expression of integrin ß3, integrin αvß3, LIF, and HOXA10 and an increase in MUC 1 expression in the high dose of genistein and daidzein groups. In biochemical evaluations, it was determined that genistein and daidzein increased estrogen levels and decreased progesterone levels in a dose-dependent manner. CONCLUSION: Genistein and daidzein have a negative effect on endometrial receptivity. Therefore, individuals with a risk of infertility should pay attention to the consumption of genistein and daidzein.

The effects of Beeswax, Olive oil and Butter impregnated bandage on burn wound healing.

BACKGROUND: Beeswax, Olive oil and Butter (BOB) are nutritive products that could support wound healing by adsorption to bandage. This study demonstrated the therapeutic effects of BOB on second degree burn. METHODS: Second degree burn model was created in rats. Experimental groups were assigned to Healthy, Burn, Silver Sulfadiazine (SS) and BOB. The effects of BOB were evaluated on skin regeneration, vesicles and bullae and fibroblast activity by histopathological analyses and wound contraction percent were determined. Transforming Growth Factor-Beta1 (TGF-ß1) and Vascular Endothelial Growth Factor-alpha (VEGF-α) mRNA expressions were analyzed with Real Time-Polymerase Chain Reaction. All parameters analyzed at 3rd, 7th, 14th days. RESULTS: The BOB treatment increased TGF-ß1 and VEGF-α expressions compared to Burn group. The histopathological analyses showed that epidermis and dermis layers injured due to burn. BOB treatment augmented the regeneration of these layers and increased fibroblast activity and keratinization which are play important role on the new blood vessels production. Also with the BOB treatment we showed wound contraction levels were higher than Burn and SS treatment. CONCLUSION: This study demonstrated that beeswax-olive oil-butter mixture impregnated bandage treatment in a second-degree burn rat model improved burn wound healing and encouraged skin renewal via modulating tissue TGF-ß1 and VEGF-α.

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.

The role of urotensin-II and its receptors in sepsis-induced lung injury under diabetic conditions.

This study aimed to investigate the potential role of urotensin-II receptors in sepsis-induced lung injury in diabetic mice using urotensin-II receptor agonists and antagonists. A total of 110 male CD1 mice were used in this study. Diabetes was induced by 200mg/kg streptozotocin. One month after diabetes induction, the cecal ligation and puncture-induced polymicrobial sepsis model was applied in the diabetic and non-diabetic mice. Low and high doses of human urotensin-II agonist (HU-II) and antagonist (palosuran) were administered one hour after sepsis induction. HU-II administration was repeated in two-hour intervals. Blood and tissue samples were collected at 6 and 12H after sepsis induction for biochemical, molecular, and histopathologic examinations. Regarding to the lungs mRNA expression and immunohistochemistry results of TNF-α, IL1 ß, IL6, and NF-κB, it was observed that cytokine levels significantly increased in the diabetes group and the sepsis groups compared to the healthy group; this increase was significantly higher in the diabetes-sepsis groups. Our biochemical (superoxide dismutase, glutathione, and malondialdehyde) and histopathological findings in the lungs also supported these results. All increased parameters were significantly reduced dose-dependently by the administration of palosuran, an urotensin receptor antagonist. mRNA expression of urotensin-II and its receptor were examined in the lung tissue. Palosuran administration significantly reduced the urotensin-II and urotensin-II receptor levels that increased in the damaged tissue. This study has shown that urotensin-II and urotensin-II receptors contribute to the aggravation of sepsis-induced lung injury in diabetic mice; palosuran prevents this damage by antagonizing urotensin-II receptors.

Sepsis and Septic Shock: Current Treatment Strategies and New Approaches.

Sepsis is a complex condition characterized by the simultaneous activation of inflammation and coagulation in response to microbial insult. These events manifest as systemic inflammatory response syndrome or sepsis symptoms through the release of proinflammatory cytokines, procoagulants, and adhesion molecules from immune cells and/or damaged endothelium. Today, sepsis is a severe multisystem disease with difficult treatments for its manifestations and high mortality rates. In the last two decades in particular, many studies have been conducted on sepsis that cause shock, multiorgan dysfunction, and organ failure by especially leading to hemodynamic changes. In sepsis, increasing antibiotic resistance and medicine-resistant hemodynamic changes have resulted in further research on new treatment modalities in addition to classical treatments. In the last decade, the sepsis physiopathology has been elucidated. Various therapeutic agents have been used in addition to antibiotherapy, but no satisfactory results have been obtained. This review summarizes the sepsis pathophysiology, current treatment protocols, and new approaches.

A Comparative Study of the Effects of Intravitreal Anidulafungin, Voriconazole, and Amphotericin B in an Experimental Candida Endophthalmitis Model.

PURPOSE: To compare the safety and efficacy of intravitreal anidulafungin injection with voriconazole and amphotericin B (Amp B) in an experimental Candida endophthalmitis (CE) model. METHODS: Intravitreal 1 × 105 CFU/0.1 ml Candida albicans was injected into the right eyes of 24 New Zealand rabbits, which were divided into 4 groups. Voriconazole 50 µg/0.1 ml, Amp B 10 µg/0.1 ml, and Anidulafungin 50 µg/0.1 ml were injected by intravitreal injection 72 h after inoculation. The control group was injected with 0.1 ml 0.9% NaCl. Clinical scoring was performed by assessing the cornea, conjunctiva, iris, and vitreous on days 3 and 7 of therapy. At the end of the study, the right eyes of all rabbits were enucleated and histopathological evaluation was performed. Therapy groups were compared according to the clinical, histopathological, and microbiological analysis scores. RESULTS: Total clinical scores were significantly different between treatment groups and the control group (p < 0.05). On day 7 of the therapy, clinical scores of the anidulafungin group were found to be significantly lower when compared with the other therapy groups, while a significant improvement was observed in the eyes of rabbits in the anidulafungin group (p < 0.05). Also, microbiological scores of the anidulafungin group were lower than those of the control group (p < 0.05). Histopathological scores of the anidulafungin treatment group were significantly better than the voriconazole and control groups. Inflammation was evidently suppressed and marked retinal toxicity was not observed with anidulafungin. CONCLUSIONS: This is the first study comparing the efficacy of anidulafungin with other antifungal agents. In this CE model, an intravitreal single dose of anidulafungin was shown to be noninferior to voriconazole and Amp B. As an alternative to Amp B or voriconazole, intravitreal anidulafungin is suggested as an effective antifungal agent for the treatment of CE.