Cannabinoid 2 Receptor Activation Protects against Diabetic Cardiomyopathy through Inhibition of AGE/RAGE-Induced Oxidative Stress, Fibrosis, and Inflammasome Activation.

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)-receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of ß-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor ß (TGF-ß)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms. SIGNIFICANCE STATEMENT: BCP, a CB2R agonist, shows protection against DCM. BCP attenuates oxidative stress, inflammation, and fibrosis in DCM via activating CB2Rs. BCP mediating CB2R activation favorably modulates AGE/RAGE, PI3K/AKT/Nrf2ß and TGF-ß/Smad and (NLRP3) inflammasome in diabetic cardiomyopathy.

Does Hypertension Affect the Recovery of Renal Functions after Reversal of Unilateral Ureteric Obstruction?

Research has demonstrated that hypertension can lead to an exaggeration in the renal functional and histological changes caused by ureteral obstruction. These changes were particularly observed shortly after the release of a relatively brief period of unilateral ureteral obstruction (UUO). However, the long-term impact of hypertension on the recovery of renal functions has not been investigated beyond the immediate period after UUO reversal. In order to investigate this effect, a group of spontaneously hypertensive rats (G-SHR, n = 11) and a group of normotensive Wistar Kyoto rats (G-NTR, n = 11) were subjected to a 48 h reversible left UUO. The impact of UUO was then examined 45 days after the reversal of obstruction. The glomerular filtration rate, renal blood flow, and the fractional excretion of sodium in the post-obstructed left kidney (POK) showed similarities to the non-obstructed right kidney (NOK) in both groups. However, the changes in the albumin creatinine ratio, renal injury markers, pro-apoptotic markers, and histological changes in the G-SHR were much more pronounced compared to the G-NTR. We conclude that hypertension continues to have a significant impact on various aspects of renal injury and function, even several weeks after UUO reversal.

Limonene, a Monoterpene, Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Modulating Neuroinflammation, Hippo Signaling and Apoptosis in Rats.

Rotenone (ROT) is a naturally derived pesticide and a well-known environmental neurotoxin associated with induction of Parkinson's disease (PD). Limonene (LMN), a naturally occurring monoterpene, is found ubiquitously in citrus fruits and peels. There is enormous interest in finding novel therapeutic agents that can cure or halt the progressive degeneration in PD; therefore, the main aim of this study is to investigate the potential neuroprotective effects of LMN employing a rodent model of PD measuring parameters of oxidative stress, neuro-inflammation, and apoptosis to elucidate the underlying mechanisms. PD in experimental rats was induced by intraperitoneal injection of ROT (2.5 mg/kg) five days a week for a total of 28 days. The rats were treated with LMN (50 mg/kg, orally) along with intraperitoneal injection of ROT (2.5 mg/kg) for the same duration as in ROT-administered rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers following activation of glial cells (astrocytes and microglia). ROT treatment enhanced oxidative stress, altered NF-κB/MAPK signaling and motor dysfunction, and enhanced the levels/expressions of inflammatory mediators and proinflammatory cytokines in the brain. There was a concomitant mitochondrial dysfunction followed by the activation of the Hippo signaling and intrinsic pathway of apoptosis as well as altered mTOR signaling in the brain of ROT-injected rats. Oral treatment with LMN corrected the majority of the biochemical, pathological, and molecular parameters altered following ROT injections. Our study findings demonstrate the efficacy of LMN in providing protection against ROT-induced neurodegeneration.

Tannic Acid Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Inhibiting Inflammation, Oxidative Stress, Apoptosis, and Glutamate Toxicity in Rats.

Parkinson's disease (PD), a movement disorder, is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) region of the brain. The etiopathogenesis of PD involves increased oxidative stress, augmented inflammation, impaired autophagy, accumulation of α-synuclein, and α-Glutamate neurotoxicity. The treatment of PD is limited and there is a lack of agents to prevent the disease/delay its progression and inhibit the onset of pathogenic events. Many agents of natural and synthetic origin have been investigated employing experimental models of PD, mimicking human PD. In the present study, we assessed the effect of tannic acid (TA) in a rodent model of PD induced by rotenone (ROT), a pesticide and an environmental toxin of natural origin reported to cause PD in agricultural workers and farmers. Rotenone (2.5 mg/kg/day, i.p.) was administered for 28 days, and TA (50 mg/kg, orally) was administered 30 min before ROT injections. The study results showed an increase in oxidative stress, as evidenced by the depletion of endogenous antioxidants and enhanced formation of lipid peroxidation products, along with the onset of inflammation following a rise in inflammatory mediators and proinflammatory cytokines. ROT injections have also augmented apoptosis, impaired autophagy, promoted synaptic loss, and perturbed α-Glutamate hyperpolarization in rats. ROT injections also induced the loss of dopaminergic neurons subsequent to the activation of microglia and astrocytes. However, TA treatment was observed to reduce lipid peroxidation, prevent loss of endogenous antioxidants, and inhibit the release and synthesis of proinflammatory cytokines, in addition to the favorable modulation of apoptosis and autophagic pathways. Treatment with TA also attenuated the activation of microglia and astrocytes along with preservation of dopaminergic neurons following reduced loss of dopaminergic neurodegeneration and inhibition of synaptic loss and α-Glutamate cytotoxicity. The effects of TA in ROT-induced PD were attributed to the antioxidant, anti-inflammatory, antiapoptotic, and neurogenesis properties. Based on the present study findings, it can be concluded that TA may be a promising novel therapeutic candidate for pharmaceutical as well as nutraceutical development owing to its neuroprotective properties in PD. Further regulatory toxicology and translational studies are suggested for future clinical usage in PD.

The Effect of Hypertension on the Recovery of Renal Dysfunction following Reversal of Unilateral Ureteral Obstruction in the Rat.

Both ureteral obstruction (UO) and hypertension are common conditions that affect kidney functions. Hypertension and chronic kidney disease are closely associated with an overlapping and intermingled cause-and-effect relationship. The effect of hypertension on the renal dysfunction following reversible UO has not been studied previously. To study this effect, spontaneously hypertensive (G-HT, n = 10) and normotensive Wistar (G-NT, n = 10) rats underwent 48-h reversible left unilateral UO (UUO), and the effect of UUO was studied 96 h following UUO reversal. The glomerular filtration rate, renal blood flow, and renal tubular functions such as the fractional excretion of sodium in the post-obstructed left kidney (POK) in both groups were significantly altered compared with the non-obstructed right kidney (NOK). However, the alterations in the G-HT were significantly more exaggerated when compared with the G-NT. Similar findings were observed with the histological features, gene expression of kidney injury markers, pro-inflammatory, pro-fibrotic and pro-apoptotic cytokines, and pro-collagen, as well as tissue levels of apoptotic markers. We conclude that hypertension has significantly exaggerated the alterations in renal functions and other parameters of renal injury associated with UUO.

α-Bisabolol, a Dietary Sesquiterpene, Attenuates Doxorubicin-Induced Acute Cardiotoxicity in Rats by Inhibiting Cellular Signaling Pathways, Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3ß, NF-κB/p38/MAPK, and NLRP3 Inflammasomes Regulating Oxidative Stress and Inflammatory Cascades.

Cancer chemotherapy with doxorubicin (DOX) may have multiorgan toxicities including cardiotoxicity, and this is one of the major limitations of its clinical use. The present study aimed to evaluate the cardioprotective role of α-Bisabolol (BSB) in DOX-induced acute cardiotoxicity in rats and the underlying pharmacological and molecular mechanisms. DOX (12.5 mg/kg, single dose) was injected intraperitoneally into the rats for induction of acute cardiotoxicity. BSB was given orally to rats (25 mg/kg, p.o. twice daily) for a duration of five days. DOX administration induced cardiac dysfunction as evidenced by altered body weight, hemodynamics, and release of cardio-specific diagnostic markers. The occurrence of oxidative stress was evidenced by a significant decline in antioxidant defense along with a rise in lipid peroxidation and hyperlipidemia. Additionally, DOX also increased the levels and expression of proinflammatory cytokines and inflammatory mediators, as well as activated NF-κB/MAPK signaling in the heart, following alterations in the Nrf2/Keap-1/HO-1 and Akt/mTOR/GSK-3ß signaling. DOX also perturbed NLRP3 inflammasome activation-mediated pyroptosis in the myocardium of rats. Furthermore, histopathological studies revealed cellular alterations in the myocardium. On the contrary, treatment with BSB has been observed to preserve the myocardium and restore all the cellular, molecular, and structural perturbations in the heart tissues of DOX-induced cardiotoxicity in rats. Results of the present study clearly demonstrate the protective role of BSB against DOX-induced cardiotoxicity, which is attributed to its potent antioxidant, anti-inflammatory, and antihyperlipidemic effects resulting from favorable modulation of numerous cellular signaling regulatory pathways, viz., Nrf2/Keap-1/HO-1, Akt/mTOR/GSK-3ß, NF-κB/p38/MAPK, and NLRP3 inflammasomes, in countering the cascades of oxidative stress and inflammation. The observations suggest that BSB can be a promising agent or an adjuvant to limit the cardiac injury caused by DOX. Further studies including the role in tumor-bearing animals as well as regulatory toxicology are suggested.

Myrcene Salvages Rotenone-Induced Loss of Dopaminergic Neurons by Inhibiting Oxidative Stress, Inflammation, Apoptosis, and Autophagy.

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta, resulting in motor deficits. The exact etiology of PD is currently unknown; however, the pathological hallmarks of PD include excessive production of reactive oxygen species, enhanced neuroinflammation, and overproduction of α-synuclein. Under normal physiological conditions, aggregated α-synuclein is degraded via the autophagy lysosomal pathway. However, impairment of the autophagy lysosomal pathway results in α-synuclein accumulation, thereby facilitating the pathogenesis of PD. Current medications only manage the symptoms, but are unable to delay, prevent, or cure the disease. Collectively, oxidative stress, inflammation, apoptosis, and autophagy play crucial roles in PD; therefore, there is an enormous interest in exploring novel bioactive agents of natural origin for their protective roles in PD. The present study evaluated the role of myrcene, a monoterpene, in preventing the loss of dopaminergic neurons in a rotenone (ROT)-induced rodent model of PD, and elucidated the underlying mechanisms. Myrcene was administered at a dose of 50 mg/kg, 30 min prior to the intraperitoneal injections of ROT (2.5 mg/kg). Administration of ROT caused a considerable loss of dopaminergic neurons, subsequent to a significant reduction in the antioxidant defense systems, increased lipid peroxidation, and activation of microglia and astrocytes, along with the production of pro-inflammatory cytokines (IL-6, TNF-α, IL-1ß) and matrix metalloproteinase-9. Rotenone also resulted in impairment of the autophagy lysosomal pathway, as evidenced by increased expression of LC3, p62, and beclin-1 with decreased expression in the phosphorylation of mTOR protein. Collectively, these factors result in the loss of dopaminergic neurons. However, myrcene treatment has been observed to restore antioxidant defenses and attenuate the increase in concentrations of lipid peroxidation products, pro-inflammatory cytokines, diminished microglia, and astrocyte activation. Myrcene treatment also enhanced the phosphorylation of mTOR, reinstated neuronal homeostasis, restored autophagy-lysosomal degradation, and prevented the increased expression of α-synuclein following the rescue of dopaminergic neurons. Taken together, our study clearly revealed the mitigating effect of myrcene on dopaminergic neuronal loss, attributed to its potent antioxidant, anti-inflammatory, and anti-apoptotic properties, and favorable modulation of autophagic flux. This study suggests that myrcene may be a potential candidate for therapeutic benefits in PD.

α-Bisabolol abrogates isoproterenol-induced myocardial infarction by inhibiting mitochondrial dysfunction and intrinsic pathway of apoptosis in rats.

Mitochondrial dysfunction plays crucial role in the pathologenesis of myocardial infarction (MI). The present study evaluated the protective effect of α-bisabolol against isoproterenol (ISO)-induced mitochondrial dysfunction and apoptosis in rats. Male albino Wistar rats were pre- and co-treated with intraperitoneal injection of α-bisabolol (25 mg/kg body weight) daily for 10 days. To induce experimental MI, ISO (85 mg/kg body weight) was injected subcutaneously to the rats at an interval of 24 h for 2 days (9th and 10th day). ISO-induced MI was indicated by the decreased activities of heart creatine kinase and lactate dehydrogenase in rats. ISO administration also enhanced the concentrations of heart mitochondrial lipid peroxidation products and decreased the activities/concentrations of mitochondrial antioxidants, Kreb's cycle dehydrogenases and mitochondrial electron transport chain complexes I, II + III and IV in rats. Furthermore, ISO triggers calcium overload and ATP depletion in the rat's heart mitochondria followed by the mitochondrial cytochrome-C release and the activation of intrinsic pathway of apoptosis by upregulating the myocardial pro-apoptotic Bax, P53, APAF-1, active caspase-3, active caspase-9 and down regulating the expressions of anti-apoptotic Bcl-2. α-Bisabolol pre and co-treatment showed considerable protective effects on all the biochemical and molecular parameters studied. Transmission electron microscopic study and mitochondrial swelling assay confirmed our biochemical and molecular findings. The in vitro study on hydroxyl radical also revealed the potent free radical scavenging activity of α-bisabolol. Thus, α-bisabolol attenuates mitochondrial dysfunction and intrinsic pathway of apoptosis in ISO-induced myocardial infarcted rats.

Lycopodium Attenuates Loss of Dopaminergic Neurons by Suppressing Oxidative Stress and Neuroinflammation in a Rat Model of Parkinson's Disease.

Parkinson's disease, a chronic, age related neurodegenerative disorder, is characterized by a progressive loss of nigrostriatal dopaminergic neurons. Several studies have proven that the activation of glial cells, presence of alpha-synuclein aggregates, and oxidative stress, fuels neurodegeneration, and currently there is no definitive treatment for PD. In this study, a rotenone-induced rat model of PD was used to understand the neuroprotective potential of Lycopodium (Lyc), a commonly-used potent herbal medicine. Immunohistochemcial data showed that rotenone injections significantly increased the loss of dopaminergic neurons in the substantia nigra, and decreased the striatal expression of tyrosine hydroxylase. Further, rotenone administration activated microglia and astroglia, which in turn upregulated the expression of α-synuclein, pro-inflammatory, and oxidative stress factors, resulting in PD pathology. However, rotenone-injected rats that were orally treated with lycopodium (50 mg/kg) were protected against dopaminergic neuronal loss by diminishing the expression of matrix metalloproteinase-3 (MMP-3) and MMP-9, as well as reduced activation of microglia and astrocytes. This neuroprotective mechanism not only involves reduction in pro-inflammatory response and α-synuclein expression, but also synergistically enhanced antioxidant defense system by virtue of the drug's multimodal action. These findings suggest that Lyc has the potential to be further developed as a therapeutic candidate for PD.

Protective effects of α-bisabolol on altered hemodynamics, lipid peroxidation, and nonenzymatic antioxidants in isoproterenol-induced myocardial infarction: In vivo and in vitro evidences.

The effect of α-bisabolol on hemodyanimcs, lipid peroxidation, and nonenzymatic antioxidants was evaluated in isoproterenol-induced myocardial infarction in rats. They were pre- and cotreated with α-bisabolol (25 mg/kg body weight) daily for 10 days along with the subcutaneous injection of isoproterenol (85 mg/kg body weight) at an interval of 24 hours for 2 days (9th and 10th days). Increased activities of serum creatine kinase and creatine kinase-MB along with altered levels/concentrations of lipid peroxidation products and nonenzymatic status were observed in the plasma and heart tissues of rats. Treatment with α-bisabolol showed protective effects by reversing the altered biochemical parameters and hemodynamics studied. The in vitro reducing power of α-bisabolol confirmed its potent antioxidant action. These biochemical benefits were translated into functional recovery by the maintenance of the hemodynamics in rats. The findings showed that α-bisabolol has the potential to protect against isoproterenol-induced myocardial infarction due to its potent antilipid peroxidation and antioxidant properties.

Therapeutic Potential of Plants and Plant Derived Phytochemicals against Acetaminophen-Induced Liver Injury.

Acetaminophen (APAP), which is also known as paracetamol or N-acetyl-p-aminophenol is a safe and potent drug for fever, pain and inflammation when used at its normal therapeutic doses. It is available as over-the-counter drug and used by all the age groups. The overdose results in acute liver failure that often requires liver transplantation. Current clinical therapy for APAP-induced liver toxicity is the administration of N-acetyl-cysteine (NAC), a sulphydryl compound an approved drug which acts by replenishing cellular glutathione (GSH) stores in the liver. Over the past five decades, several studies indicate that the safety and efficacy of herbal extracts or plant derived compounds that are used either as monotherapy or as an adjunct therapy along with conventional medicines for hepatotoxicity have shown favorable responses. Phytochemicals mitigate necrotic cell death and protect against APAP-induced liver toxicityby restoring cellular antioxidant defense system, limiting oxidative stress and subsequently protecting mitochondrial dysfunction and inflammation. Recent experimental evidences indicat that these phytochemicals also regulate differential gene expression to modulate various cellular pathways that are implicated in cellular protection. Therefore, in this review, we highlight the role of the phytochemicals, which are shown to be efficacious in clinically relevant APAP-induced hepatotoxicity experimental models. In this review, we have made comprehensive attempt to delineate the molecular mechanism and the cellular targets that are modulated by the phytochemicals to mediate the cytoprotective effect against APAP-induced hepatotoxicity. In this review, we have also defined the challenges and scope of phytochemicals to be developed as drugs to target APAP-induced hepatotoxicity.

Sesamol: A Phenolic Compound of Health Benefits and Therapeutic Promise in Neurodegenerative Diseases.

Sesamol, one of the key bioactive ingredients of sesame seeds (Sesamum indicum L.), is responsible for many of its possible nutritional benefits. Both the Chinese and Indian medical systems have recognized the therapeutic potential of sesame seeds. It has been shown to have significant therapeutic potential against oxidative stress, inflammatory diseases, metabolic syndrome, neurodegeneration, and mental disorders. Sesamol is a benign molecule that inhibits the expression of inflammatory indicators like numerous enzymes responsible for inducing inflammation, protein kinases, cytokines, and redox status. This review summarises the potential beneficial effects of sesamol against neurological diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, sesamol has been shown to reduce amyloid peptide accumulation and attenuate cognitive deficits in AD models. Sesamol has also been demonstrated to reduce the severity of PD and HD in animal models by decreasing oxidative stress and inflammatory pathways. The mechanism of sesamol's pharmacological activities against neurodegenerative diseases will also be discussed in this review.

Prospective multi-centre sentinel surveillance for Haemophilus influenzae type b & other bacterial meningitis in Indian children.

BACKGROUND & OBJECTIVES: Haemophilus influenzae type b (Hib) is one of the leading bacterial causes of invasive disease in populations without access to Hib conjugate vaccines (Hib-CV). India has recently decided to introduce Hib-CV into the routine immunization programme in selected States. Longitudinal data quantifying the burden of bacterial meningitis and the proportion of disease caused by various bacteria are needed to track the impact of Hib-CV once introduced. A hospital-based sentinel surveillance network was established at four places in the country and this study reports the results of this ongoing surveillance. METHODS: Children aged 1 to 23 months with suspected bacterial meningitis were enrolled in Chennai, Lucknow, New Delhi, and Vellore between July 2008 and June 2010. All cerebrospinal fluid (CSF) samples were tested using cytological, biochemical, and culture methods. Samples with abnormal CSF (≥10 WBC per µl) were tested by latex agglutination test for common paediatric bacterial meningitis pathogens. RESULTS: A total of 708 patients with abnormal CSF were identified, 89 of whom had a bacterial pathogen confirmed. Hib accounted for the majority of bacteriologically confirmed cases, 62 (70%), while Streptococcus pneumoniae and group B Streptococcus were identified in 12 (13%) and seven (8%) cases, respectively. The other eight cases were a mix of other bacteria. The proportion of abnormal CSF and probable bacterial meningitis that was caused by Hib was 74 and 58 per cent lower at Christian Medical College (CMC), Vellore, which had a 41 per cent coverage of Hib-CV among all suspected meningitis cases, compared to the combined average proportion at the other three centres where a coverage between 1 and 8 per cent was seen (P<0.001 and P= 0.05, respectively). INTERPRETATION & CONCLUSIONS: Hib was found to be the predominant cause of bacterial meningitis in young children in diverse geographic locations in India. Possible indications of herd immunity was seen at CMC compared to sites with low immunization coverage with Hib-CV. As Hib is the most common pathogen in bacterial meningitis, Hib-CV would have a large impact on bacterial meningitis in Indian children.

ß-Caryophyllene, a Dietary Phytocannabinoid, Alleviates Diabetic Cardiomyopathy in Mice by Inhibiting Oxidative Stress and Inflammation Activating Cannabinoid Type-2 Receptors.

Diabetes mellitus (DM) and its associated complications are considered one of the major health risks globally. Among numerous complications, diabetic cardiomyopathy (DCM) is characterized by increased accumulation of lipids and reduced glucose utilization following abnormal lipid metabolism in the myocardium along with oxidative stress, myocardial fibrosis, and inflammation that eventually result in cardiac dysfunction. The abnormal metabolism of lipids plays a fundamental role in cardiac lipotoxicity following the occurrence and development of DCM. Recently, it has been revealed that cannabinoid type-2 (CB2) receptors, an essential component of the endocannabinoid system, play a crucial role in the pathogenesis of obesity, hyperlipidemia, and DM. Provided the role of CB2R in regulating the glucolipid metabolic dysfunction and its antioxidant as well as anti-inflammatory activities, we carried out the current study to investigate the protective effects of a selective CB2R agonist, ß-caryophyllene (BCP), a natural dietary cannabinoid in the murine model of DCM and elucidated the underlying pharmacological and molecular mechanisms. Mice were fed a high-fat diet for 4 weeks followed by a single intraperitoneal injection of streptozotocin (100 mg/kg) to induce the model of DCM. BCP (50 mg/kg body weight) was given orally for 12 weeks. AM630, a CB2R antagonist, was given 30 min before BCP treatment to demonstrate the CB2R-dependent mechanism of BCP. DCM mice exhibited hyperglycemia, increased serum lactate dehydrogenase, impaired cardiac function, and hypertrophy. In addition, DCM mice showed alternations in serum lipids and increased oxidative stress concomitant to reduced antioxidant defenses and enhanced cardiac lipid accumulation in the diabetic heart. DCM mice also exhibited activation of TLR4/NF-κB/MAPK signaling and triggered the production of inflammatory cytokines and inflammatory enzyme mediators. However, treatment with BCP exerted remarkable protective effects by favorable modulation of the biochemical and molecular parameters, which were altered in DCM mice. Interestingly, pretreatment with AM630 abrogated the protective effects of BCP in DCM mice. Taken together, the findings of the present study demonstrate that BCP possesses the capability to mitigate the progression of DCM by inhibition of lipotoxicity-mediated cardiac oxidative stress and inflammation and favorable modulation of TLR4/NF-κB/MAPK signaling pathways mediating the CB2R-dependent mechanism.

Protective effects of thymol on altered plasma lipid peroxidation and nonenzymic antioxidants in isoproterenol-induced myocardial infarcted rats.

This study evaluates the protective effects of thymol on altered plasma lipid peroxidation products and nonenzymic antioxidants in isoproterenol (ISO)-induced myocardial infarcted rats. Male albino Wistar rats were pre and cotreated with thymol (7.5 mg/kg body weight) daily for 7 days. ISO (100 mg/kg body weight) was subcutaneously injected into rats on 6th and 7th day to induce myocardial infarction (MI). Increased activity/levels of serum creatine kinase-MB (CK-MB), plasma thiobarbituric acid reactive substances, lipid hydroperoxides, and conjugated dienes with decreased levels of plasma reduced glutathione (GSH), vitamin C, and vitamin E were observed in ISO-induced myocardial infarcted rats. Pre and cotreatment with thymol (7.5 mg/kg body weight) showed normalized activity of serum CK-MB and near normalized levels of plasma lipid peroxidation products, reduced GSH, vitamin C, and vitamin E in myocardial infarcted rats. Furthermore, the in vitro study on reducing power of thymol confirmed its potent antioxidant action. Thus, thymol protects ISO-induced MI in rats by its antilipid peroxidation and antioxidant properties.

α-Bisabolol Attenuates NF-κB/MAPK Signaling Activation and ER-Stress-Mediated Apoptosis by Invoking Nrf2-Mediated Antioxidant Defense Systems against Doxorubicin-Induced Testicular Toxicity in Rats.

The present study investigated the effects of α-bisabolol on DOX-induced testicular damage in rats. Testicular damage was induced in rats by injecting DOX (12.5 mg/kg, i.p., single dose) into rats. α-Bisabolol (25 mg/kg, i.p.) was administered to the rats along with DOX pre- and co-treatment daily for a period of 5 days. DOX-injected rats showed a decrease in absolute testicular weight and relative testicular weight ratio along with concomitant changes in the levels/expression levels of oxidative stress markers and Nrf2 expression levels in the testis. DOX injection also triggered the activation of NF-κB/MAPK signaling and increased levels/expression levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) and inflammatory mediators (iNOS and COX-2) in the testis. DOX triggered apoptosis, manifested by an increment in the expression levels of pro-apoptotic markers (Bax, Bcl2, cleaved caspase-3 and -9, and cytochrome-C) and a decline in the expression levels of anti-apoptotic markers (Bcl-xL and Bcl2) in the testis. Additionally, light microscopy revealed the changes in testicular architecture. α-Bisabolol rescued alterations in the testicular weight; restored all biochemical markers; modulated the expression levels of Nrf2-mediated antioxidant responses, NF-κB/MAPK signaling, endoplasmic reticulum (ER) stress, and apoptosis markers in DOX-injected testicular toxicity in rats. Based on our findings, it can be concluded that α-bisabolol has the potential to attenuate DOX-induced testicular injury by modifying NF-κB/MAPK signaling and the ER-stress-mediated mitochondrial pathway of apoptosis by invoking Nrf2-dependent antioxidant defense systems in rats. Based on the findings of the present study, α-bisabolol could be suggested for use as an agent or adjuvant with chemotherapeutic drugs to attenuate their deleterious effects of DOX on many organs including the testis. However, further regulatory toxicology and preclinical studies are necessary before making recommendations in clinical tests.

Protective effects of N-acetyl cysteine on lipid peroxide metabolism on isoproterenol-induced myocardial infarcted rats.

The present study was designed to evaluate the preventive effects of N-acetyl cysteine on lipid peroxide metabolism in isoproterenol (ISO) induced myocardial infarcted rats. Male albino Wistar rats were pretreated with N-acetyl cysteine (5 and 10 mg/kg) daily for a period of 14 days. After the pretreatment period, ISO (100 mg/kg) was subcutaneously injected to rats twice at an interval of 24 h. Increased activities of serum creatine kinase, creatine kinase-MB, lactate dehydrogenase, and increased intensities of serum lactate dehydrogenase-isoenzyme bands (LDH-1, LDH-2) were observed in ISO-induced rats. The heart lipid peroxidation products were significantly increased, and the antioxidant system was significantly reduced in ISO-induced rats. Pretreatment with N-acetyl cysteine (5 and 10 mg/kg) to ISO-induced rats showed significant effects on all the biochemical parameters studied. Histopathological findings of the myocardium also showed the protective role of N-acetyl cysteine in ISO-induced rats. Furthermore, in vitro study confirmed the potent-free radical scavenging activity of N-acetyl cysteine. The effect at a dose of 10 mg/kg of N-acetyl cysteine was more pronounced than the dose, 5 mg/kg. The results of our study show that N-acetyl cysteine protects the heart against ISO-induced myocardial infarction by its free radical scavenging effect.

Carvacrol, a Plant Metabolite Targeting Viral Protease (Mpro) and ACE2 in Host Cells Can Be a Possible Candidate for COVID-19.

The recent outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in December 2019, resulting in the coronavirus disease-19 (COVID-19) pandemic. Coronaviruses are solely accountable for rising mortality and socioeconomic saddles. Presently, there are few repurposed drugs such as remdesivir or favipiravir approved for the treatment of COVID-19, although vaccines and plasma therapy is also subject to emergency approval. However, some potential natural treatments and cures have also been proposed. Molecules of natural origin showed therapeutic importance such as antiviral, anti-inflammatory, and antioxidant activity, and could be useful drug candidates for treating COVID-19. In recent years, essential oils have shown promising therapeutic effects against many viral diseases. Carvacrol is one of the monoterpene phenol with abundant presence in essential oils of many aromatic plants, including thyme and oregano. It is being used as food flavoring, additive, and preservatives. Carvacrol is also used as a fragrance in cosmetic products. A number of research studies have shown biological actions of carvacrol with its therapeutic potential is of clinical significance. The in vitro and in vivo studies have shown multiple pharmacological properties such as anticancer, anti-fungal, anti-bacterial, anti-oxidant, anti-inflammatory, vasorelaxant, hepatoprotective, and spasmolytic. This review highlights the various biological and pharmacological properties of carvacrol within the scope of COVID-19.

Therapeutic Potential of ß-Caryophyllene: A Dietary Cannabinoid in Diabetes and Associated Complications.

Diabetes mellitus (DM), a metabolic disorder is one of the most prevalent chronic diseases worldwide across developed as well as developing nations. Hyperglycemia is the core feature of the type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), following insulin deficiency and impaired insulin secretion or sensitivity leads insulin resistance (IR), respectively. Genetic and environmental factors attributed to the pathogenesis of DM and various therapeutic strategies are available for the prevention and treatment of T2DM. Among the numerous therapeutic approaches, the health effects of dietary/nutraceutical approach due to the presence of bioactive constituents, popularly termed phytochemicals are receiving special interest for pharmacological effects and therapeutic benefits. The phytochemicals classes, in particular sesquiterpenes received attention because of potent antioxidant, anti-inflammatory, and antihyperglycemic effects and health benefits mediating modulation of enzymes, receptors, and signaling pathways deranged in DM and its complications. One of the terpene compounds, ß-caryophyllene (BCP), received enormous attention because of its abundant occurrence, non-psychoactive nature, and dietary availability through consumption of edible plants including spices. BCP exhibit selective full agonism on cannabinoid receptor type 2 (CB2R), an important component of endocannabinoid system, and plays a role in glucose and lipid metabolism and represents the newest drug target for chronic inflammatory diseases. BCP also showed agonist action on peroxisome proliferated activated receptor subtypes, PPAR-α and PPAR-γ, the main target of currently used fibrates and imidazolidinones for dyslipidemia and IR, respectively. Many studies demonstrated its antioxidant, anti-inflammatory, organoprotective, and antihyperglycemic properties. In the present review, the plausible therapeutic potential of BCP in diabetes and associated complications has been comprehensively elaborated based on experimental and a few clinical studies available. Further, the pharmacological and molecular mechanisms of BCP in diabetes and its complications have been represented using synoptic tables and schemes. Given the safe status, abundant natural occurrence, oral bioavailability, dietary use and pleiotropic properties modulating receptors and enzymes, BCP appears as a promising molecule for diabetes and its complications.

Plant Extracts and Phytochemicals Targeting α-Synuclein Aggregation in Parkinson's Disease Models.

α-Synuclein (α-syn) is a presynaptic protein that regulates the release of neurotransmitters from synaptic vesicles in the brain. α-Syn aggregates, including Lewy bodies, are features of both sporadic and familial forms of Parkinson's disease (PD). These aggregates undergo several key stages of fibrillation, oligomerization, and aggregation. Therapeutic benefits of drugs decline with disease progression and offer only symptomatic treatment. Novel therapeutic strategies are required which can either prevent or delay the progression of the disease. The link between α-syn and the etiopathogenesis and progression of PD are well-established in the literature. Studies indicate that α-syn is an important therapeutic target and inhibition of α-syn aggregation, oligomerization, and fibrillation are an important disease modification strategy. However, recent studies have shown that plant extracts and phytochemicals have neuroprotective effects on α-syn oligomerization and fibrillation by targeting different key stages of its formation. Although many reviews on the antioxidant-mediated, neuroprotective effect of plant extracts and phytochemicals on PD symptoms have been well-highlighted, the antioxidant mechanisms show limited success for translation to clinical studies. The identification of specific plant extracts and phytochemicals that target α-syn aggregation will provide selective molecules to develop new drugs for PD. The present review provides an overview of plant extracts and phytochemicals that target α-syn in PD and summarizes the observed effects and the underlying mechanisms. Furthermore, we provide a synopsis of current experimental models and techniques used to evaluate plant extracts and phytochemicals. Plant extracts and phytochemicals were found to inhibit the aggregation or fibril formation of oligomers. These also appear to direct α-syn oligomer formation into its unstructured form or promote non-toxic pathways and suggested to be valuable drug candidates for PD and related synucleinopathy. Current evidences from in vitro studies require confirmation in the in vivo studies. Further studies are needed to ascertain their potential effects and safety in preclinical studies for pharmaceutical/nutritional development of these phytochemicals or dietary inclusion of the plant extracts in PD treatment.