Chlorogenic acid protects against cisplatin-induced testicular damage: a biochemical and histological study

Gentisic acid ameliorates cisplatin-induced reprotoxicity through suppressing endoplasmic reticulum stress and upregulating Nrf2 pathway

BackgroundNeonatal hypoxic-ischemic brain injury (HIE) is caused by perinatal asphyxia, which is associated with various confounding factors. Although studies on the pathogenesis and treatment of HIE have matured, sub-hypothermia is the only clinical treatment available for HIE. Previous evidence indicates that chlorogenic acid (CGA) exerts a potential neuroprotective effect on brain injury. However, the role of CGA on neonatal HI brain damage and the exact mechanism remains elusive.Here, we investigate the effects of CGA on HI models in vivo and in vitro and explore the underlying mechanism.MethodsIn the in vivo experiment, we ligated the left common carotid artery of 7-day-old rats and placed the rats in a hypoxic box for 2 h. We did not ligate the common carotid artery of the pups in the sham group since they did not have hypoxia. Brain atrophy and infarct size were evaluated by Nissl staining, HE staining and 2,3,5-triphenyltetrazolium chloride monohydrate (TTC) staining. Morris Water Maze test (MWM) was used to evaluate neurobehavioral disorders. Western-blotting and immunofluorescence were used to detect the cell signaling pathway. Malondialdehyde (MDA) content test, catalase (CAT) activity detection and Elisa Assay was used to detect levels of inflammation and oxidative stress. in vitro experiments were performed on isolated primary neurons.ResultIn our study, pretreatment with CGA significantly decreased the infarct volume of neonatal rats after HI, alleviated brain edema, and improved tissue structure in vivo. Moreover, we used the Morris water maze to verify CGA’s effects on enhancing the learning and cognitive ability and helping to maintain the long-term spatial memory after HI injury. However, Sirt1 inhibitor EX-527 partially reversed these therapeutic effects. CGA pretreatment inhibited neuronal apoptosis induced by HI by reducing inflammation and oxidative stress. The findings suggest that CGA potentially activates Sirt1 to regulate the Nrf2-NF-κB signaling pathway by forming complexes thereby protecting primary neurons from oxygen-glucose deprivation (OGD) damage. Also, CGA treatment significantly suppresses HI-induced proliferation of glial.ConclusionCollectively, this study uncovered the underlying mechanism of CGA on neonatal HI brain damage. CGA holds promise as an effective neuroprotective agent to promote neonatal brain recovery from HI-induced injury.Graphical 8NePktn-RrRjrUAHAHCXyYVideo

The objective of this study was to evaluate inducible nitric oxide synthase (iNOS) and nuclear factor-kappaB inhibitor (NF-kappaB) expression and the potential chemoprotective effects of an NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC), against cisplatin-induced testicular damage in rats. Rats were divided into 4 equal groups: group 1, control; group 2, injected with cisplatin (CIS) for 5 days (7 mg/kg/day intraperitoneally [IP]); group 3, injected with PDTC alone; group 4, injected with CIS plus PDTC (100 mg/kg IP). Body and testicular weights, plasma testosterone levels, and histopathologic structure of the testicular tissue were determined. The iNOS and NF-kappaB activity were evaluated immunohistochemically by staining p65 to define NF-kappaB activity. Malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) levels and glutathione peroxidase (GSH-Px) activity were assessed in testicular tissue. Body and testicular weights, plasma testosterone levels, activity of GSH-Px, and GSH levels were all significantly decreased, whereas the levels of MDA and NO were significantly increased in rats of the CIS group. PDTC treatment increased plasma testosterone levels. A significant increase in GSH levels and GSH-Px activity and a decrease in MDA and NO levels in testicular tissue were observed in the CIS + PDTC group. Immunohistochemically, there was a marked staining for iNOS and NF-kappaB/p65 expression in rats injected with CIS compared with the control (P < .001). CIS caused irregular seminiferous tubules, reduction of seminiferous epithelial layers, significant arrest of maturation, and perivascular fibrosis. Moreover, PDTC administration to CIS-treated rats significantly prevented these histopathologic chances, as well. CIS induces iNOS expression through activation of NF-kappaB/p65, and CIS-induced testicular toxicity may be prevented by PDTC, which is a selective NF-kappaB inhibitor.

PurposeTo investigate the effects of all-trans retinoic acid (ATRA) in cisplatin (CP)-induced testicular damage in rats.Materials and MethodsTwenty-eight male Wistar rats were divided into four groups: Control, ATRA alone, ATRA+CP, and CP alone. Body weight, testicular weight, sperm count, sperm motility, percentage of abnormal sperm, total antioxidant status (TAS), total oxidant status (TOS), oxidative stress index (OSI) in testicular tissue, and testicular histopathology were compared among groups.ResultsThe sperm count and motility significantly decreased and the percentage of abnormal sperm significantly increased in the CP group compared to the control and ATRA groups. CP+ATRA administration significantly increased the sperm count and motility, but reduced the abnormal sperm count. CP administration significantly increased TOS and OSI compared to the control group and the other groups. Administering CP+ATRA significantly decreased TOS and the OSI in testicular tissue and reduced spermatogenesis, but increased the Johnsen score.ConclusionsThe destructive effects of CP treatment on testicular tissue and spermatogenesis were reduced by administering ATRA.

Chlorogenic acid (CGA), a polyphenolic compound, exists widely in medicinal herbs, which has been shown a strong antioxidant and anti-inflammatory effect. This study investigated the protective effects and mechanism of CGA on lipopolysaccharide (LPS)-induced acute kidney injury (AKI). Treatment of CGA successfully ameliorates LPS-induced renal function and pathological damage. Moreover, CGA dose-dependently suppressed LPS-induced blood urea nitrogen (BUN), creatinine levels, and inflammatory cytokines TNF-α, IL-6, and IL-1β in serum and tissue. The relative proteins' expression of TLR4/NF-κB signal pathway was assessed by western blot analysis. Our results showed that CGA dose-dependently attenuated LPS-induced kidney histopathologic changes, serum BUN, and creatinine levels. CGA also suppressed LPS-induced TNF-α, IL-6, and IL-1β production both in serum and kidney tissues. Furthermore, our results showed that CGA significantly inhibited the LPS-induced expression of phosphorylated NF-κB p65 and IκB as well as the expression of TLR4 signal. In conclusion, our results provide a mechanistic explanation for the anti-inflammatory effects of CGA in LPS-induced AKI mice through inhibiting TLR4/NF-κB signaling pathway.

Chlorogenic acid (CGA) is a polyphenolic compound widely distributed in the diet. It has been shown to have a variety of potential health benefits and is also administered as a food supplement. However, the report on its safety assessment is sparse. This study is therefore designed to assess the effect of acute exposure to CGA. Forty-eight Swiss mice were weight-matched into eight groups (n = 6). Groups I and II received distilled water and 1% ethanol; Groups III-VIII received 30, 60, 120, 240, 480 and 1000 mg/kg doses of CGA, respectively. Twenty-four hours post-treatment, the liver and kidneys were excised and used for antioxidant assays and kidney and liver function tests. Sections were prepared for histology. Results showed that the concentration of hydrogen peroxide was significantly elevated at all the doses of CGA in the kidney and also in the liver. The liver function parameters were affected in the liver of mice treated with CGA. CGA variably affected potassium ion concentration at the different doses in the kidney. Results were complemented by the histology. CGA manifests a deleterious effect, as evidenced by the perturbations in some of the biochemical parameters in the liver at all the doses, and in particular from the 240 mg/kg dose.

Reports over the years have demonstrated toxic side effect-including reproductive toxicity- of tamoxifen (TAM), a drug of choice in the management of primary breast cancer. Chlorogenic acid (CGA), a dietary polyphenol, reportedly elicits beneficial pharmacological effects. However, the impact of CGA on TAM-associated reproductive toxicity is absent in the literature. We, therefore, experimented on CGA's effect and TAM-mediated reproductive toxicity in rats. Cohorts of rats were treated with TAM (50mg/kg) or co-treated with CGA (25 or 50mg/kg) for 14 consecutive days. The result showed that treatment of CGA significantly increases testosterone, LH, and FSH levels compared to the TAM group. However, prolactin level was markedly decreased after pretreatment of CGA in TAM-treated rats. CGA abated TAM-induced decreases acid phosphatase, alkaline phosphatase, and antioxidant enzymes in the testis. CGA alleviated TAM-facilitated surges of reactive oxygen and nitrogen species, myeloperoxidase, nitric oxide, interleukin-1β, and tumor necrosis factor-alpha in rats epididymis and testes. Additionally, CGA increased anti-inflammatory cytokine -interleukin-10-, suppressed caspase-3 activity, and reduced pathological lesions in the examined organs of rats co-treated with CGA and TAM. CGA phytoprotective effect improved reproductive function occasioned by TAM-mediated toxicities in rats, by abating oxido-inflammatory damages and downregulating apoptotic responses. PRACTICAL APPLICATIONS: CGA protects against the damaging oxido-inflammatory responses incumbent on TAM metabolism. As an antioxidant abundant in plant-derived foods, CGA reportedly protects against inflammatory damage, hypertension, and neurodegenerative diseases. We present evidence that CGA ameliorates TAM-induced reproductive dysfunction by suppressing oxidative and inflammation stress downregulate apoptosis and improve reproductive function biomarker in rats.

Chlorogenic acid improves SPS-induced PTSD-like behaviors in rats by regulating the crosstalk between Nrf2 and NF-κB signaling pathway.

Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats

Chlorogenic acid ameliorates chronic stress-induced prefrontal cortex injury through activating the 5-HT/BDNF signaling pathway in rats

Brown adipose tissue (BAT) prevents obesity and related diseases by uncoupling oxidative phosphorylation with adenosine triphosphate. Previous studies have demonstrated that polyphenols can promote the thermogenesis of BAT in mice. Chlorogenic acid (CGA) is a common phenolic acid found in fruits and vegetables, as well as traditional Chinese medicine, which is responsible for a variety of physiological activities. However, it is still unclear whether CGA has positive effects on the thermogenesis of BAT. In this study, CGA enhances the thermogenesis and proton leak of brown adipocytes, however, no changes are evident regarding the differentiation of C3 H10 T1/2 into brown adipocytes. Surprisingly, CGA promotes the uptake of glucose by upregulating the glucose transporter 2 and phosphofructokinase. Moreover, CGA increases the number and the function of mitochondrial. Taken together, CGA stimulates thermogenesis of brown adipocytes by promoting the uptake of glucose and the function of mitochondria. PRACTICAL APPLICATION: Chlorogenic acid (CGA) is widely found in fruits, vegetables, and traditional Chinese medicines, which has been considered to have antibacterial and anti-inflammatory function. However, whether it has the function of resisting obesity and promoting thermogenesis is still unclear. In this study, brown adipocyte was used to explore the function and mechanism of CGA on thermogenesis. It provides new ideas for the utilization of foods rich in CGA and traditional Chinese medicine.

Sepsis-induced cardiomyopathy (SICM) is a severe complication of sepsis, characterized by myocardial inflammation, oxidative stress, and cardiac dysfunction. Chlorogenic acid (CGA), a natural polyphenol with known anti-inflammatory and antioxidant properties, is abundant in many traditional medicinal plants used for cardiovascular and inflammatory disorders. However, its cardioprotective effects in SICM and the underlying mechanisms remain unclear. An invivo cecal ligation and puncture (CLP) model was used to induce SICM in rats, followed by CGA treatment. Cardiac function and myocardial injury markers were assessed, while NLRP3 inflammasome activation and CaMKIIα involvement were investigated using molecular docking, gene overexpression, and site-directed mutagenesis. H9c2 cardiomyocytes were treated with lipopolysaccharide (LPS) and hypoxia/reoxygenation (H/R) to establish an invitro SICM model. Mitochondrial function and pyroptosis were evaluated using oxygen consumption rate (OCR), extracellular acidification rate (ECAR), scanning electron microscopy (SEM), and key protein expression analysis. CGA improved cardiac function, reduced myocardial injury markers, and alleviated inflammation and fibrosis in SICM rats. CGA (25 μM) improved H9c2 cell viability in LPS + H/R-induced SICM by reducing LDH, CK-MB, and cTnT levels and suppressing inflammation, oxidative stress, and pyroptosis. It preserved mitochondrial function and cristae structure. Molecular docking and functional studies confirmed CGA binds to CaMKIIα and NLRP3, inhibiting inflammasome activation via the Ca2+/CaMKIIα pathway. Mutation of the GLU60 binding site abolished CGA's protective effects both invitro and invivo. CGA ameliorates SICM by suppressing NLRP3 inflammasome activation and pyroptosis through the Ca2+/CaMKIIα pathway. These findings offer new insights into CGA's cardioprotective effects and highlight its potential as a therapeutic agent for SICM.

Chlorogenic acid improves the cognitive deficits of sleep-deprived mice via regulation of immunity function and intestinal flora

Hyperglycemia-induced cardiac fibrosis is one of the main causes of diabetic cardiomyopathy (DM). Chlorogenic acid (CGA) found in many foods has excellent hypoglycemic effectiveness, but it is not known whether CGA can improve DM by inhibiting cardiac fibrosis caused by hyperglycemia. Type I diabetic mice are induced by streptozotocin, and after treatment with CGA for 12 weeks, cardiac functions and fibrosis are determined. CGA significantly attenuates hyperglycemia-induced cardiac fibrosis and improves cardiac functions. The mechanism of CGA on fibrotic inhibition is further studied by immunofluorescence, western blot and RNA interference technology in vivo and in vitro. The results show CGA exerted its anti-fibrotic effects through activating the cyclic GMP/protein kinase G pathway (cGMP/PKG) to block hyperglycemia-induced nuclear translocation of p-Smad2/3, and then inhibiting pro-fibrotic gene expression in cardiac fibroblasts without depending on its hypoglycemic function. Moreover, the data also revealed that CGA increased cGMP level and activated PKG in cardiac fibroblasts by enhancing endothelial nitric oxide synthase (eNOS) activity and NO production. Besides lowering blood glucose, CGA also has an independent ability to inhibit cardiac fibrosis. Therefore, long-term consumption of foods rich in CGA for diabetic patients will have great benefits to improve diabetic cardiomyopathy.

In the present investigation, the effect of olive leaf extract (OLE) on testicular damage induced in rats by an intraperitoneal injection of cisplatin (cis-diamminedichloroplatinum (CDDP)) at a dose of 5 mg/kg was tested. Rats were randomly divided into 4 groups: control, CDDP, OLE, and OLE + CDDP. After 5 days of CDDP treatment, body and testicular weights, histopathological alteration, and serum male sex hormone levels were determined. In addition to the biochemical and immunohistochemical changes in the testes, CDDP caused the disorganization of germinal epithelium and apoptosis by inducing Bax and inhibiting Bcl-2 protein expression. Testicular weights, catalase, serum testosterone, testicular enzymatic (including glutathione peroxidase, glutathione reductase, and superoxide dismutase) along with nonenzymatic (glutathione) antioxidants, and levels of luteinizing and follicle-stimulating hormones were significantly reduced in addition to a significant increase in testicular malondialdehyde and nitrite/nitrate levels when compared with the control group. OLE treatment markedly attenuated both biochemical and histopathological changes. The reproductive beneficial effects of OLE were mediated, at least partly, by inducing the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway.