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Berberine, an isoquinoline alkaloid, is reported for the treatment of Alzheimer's disease. Despite having substantial therapeutic potential, it exhibits poor absorption, low oral bioavailability and limited penetration in the brain. In this study, berberine-loaded nanostructured lipid carriers (Berb-NLCs) were developed by melt-emulsification and ultrasonication using Geleol, Miglyol 812 N, Solutol HS 15 as a solid lipid, liquid lipid and surfactant, respectively. The Berb-NLC formulation was statistically optimized by a 32 factorial design in which the effect of surfactant and berberine concentration was assessed on particle size and entrapment efficiency of Berb-NLCs. Optimized Berb-NLCs (Trial-5) exhibited particle size of 186 nm, polydispersity index of 0.108, the zeta potential of -36.86 mV and 88% entrapment efficiency. The in vitro release of berberine from Batch-B5 was 82% in phosphate buffer at the end of 24 h. The comparative results of pharmacodynamic studies involving behavioral assessment by locomotor activity, passive avoidance test, elevated plus maze test and spatial memory assessment by Morris water maze demonstrated improved behavioral parameters in vivo by Berb-NLCs compared to pure berberine in Albino Wistar rats. Thus, berberine-loaded nanostructured lipid carriers have the potential of brain targeting and were effective in an animal model of Alzheimer's disease. [Display omitted] [ABSTRACT FROM AUTHOR]

The present study evaluated the effect of chelidonic acid on paclitaxel-induced neuropathy in male Wistar rats. Neuropathy was induced by administering paclitaxel (2 mg/kg, i.p.) on 0, 2, 4, and 6 days of the protocol. Chelidonic acid treatment (at doses of 10, 20, and 40 mg/kg orally, for 21 days) was initiated simultaneously with paclitaxel administration. After completion of the protocol, mechanical allodynia, hyperalgesia, and thermal hyperalgesia were measured. Additionally, nerve conduction velocity was assessed. The study investigated inflammatory cytokines, oxidative stress, and histological changes in the sciatic nerve. Furthermore, the Nrf2 was measured, and the protein expression of pAMPK and HIF-1α was assessed using western blotting. The results showed that chelidonic acid significantly normalized mechanical allodynia, hyperalgesia, and thermal hyperalgesia. It also led to a significant improvement in motor and sensory nerve conduction velocity and reduced oxidative stress compared with paclitaxel alone. Inflammatory markers such as TNF-alpha, IL-6, and IL-1β concentrations, as well as nitric oxide and C-reactive protein, were significantly decreased in the chelidonic acid-treated group. Histopathological examination revealed reduced neuronal damage, demyelination, and leukocyte infiltration with chelidonic acid treatment. Chelidonic acid treatment also resulted in a considerable rise in Nrf2 levels (p < 0.001) and increased protein expression of pAMPK in the sciatic nerve. Conversely, HIF-1α expression was significantly declined in the chelidonic acid treatment. Overall, the findings suggest that chelidonic acid treatment attenuates paclitaxel-induced neuropathic pain., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Diabetic cardiomyopathy (DCM) is one of the serious complications of type 2 diabetes mellitus. Vasant Kusumakar Rasa (VKR) is a Herbo-metallic formulation reported in Ayurveda, an Indian system of medicine. The present work was designed to study the effect of VKR in cardiomyopathy in type 2 diabetic rats. Diabetes was induced by feeding a high-fat diet (HFD) for 2 weeks followed by streptozotocin (STZ) administration (35 mg/kg i.p.). VKR was administered orally at dose of 28 and 56 mg/kg once a day for 16 weeks. The results of the study indicated that VKR treatment significantly improved the glycemic and lipid profile, serum insulin, CK-MB, LDH, and cardiac troponin-I when compared to diabetic control animals. VKR treatment in rats significantly improved the hemodynamic parameters and cardiac tissue levels of TNF-α, IL-1β, and IL- 6 were also reduced. Antioxidant enzymes such as GSH, SOD, and catalase were improved in all treatment groups. Heart sections stained with H & E and Masson's trichome showed decreased damage to histoarchitecture of the myocardium. Expression of PI3K, Akt, and GLUT4 in the myocardium was upregulated after 16 weeks of VKR treatment. The study data suggested the cardioprotective capability of VKR in the management of diabetic cardiomyopathy in rats., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction and Objectives: The current study evaluates the effect of chelidonic acid on doxorubicin-induced cardiac toxicity. Chelidonic acid (CA) is a natural pyran-skeleton heterocyclic compound found in rhizomes of the perennial plant, celandine (Chelidonium majus)., Methods: Wistar rats were given an intraperitoneal injection of doxorubicin (1.25 mg/kg, cumulative dose of 20 mg/kg) four times per week for a duration of four weeks to induce cardiotoxicity. CA treatment (10, 20, and 40 mg/kg orally for four weeks) was started together with doxorubicin., Results: CA treatment reduced myocardial damage and improved cardiac dysfunction in doxorubicin-treated rats. It improved blood pressure, restored ST wave height and normalized the QTc interval compared to the rats treated only with doxorubicin. Administration of CA for four weeks reduced left ventricular end-diastolic pressure. Moreover, CA treatment decreased the level of cardiac markers such as creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and cardiac troponin-T. Masson's trichrome, hematoxylin, and eosin staining of heart tissue revealed that CA attenuated the deleterious effects of doxorubicin and prevented further damage and fibrosis in rats., Conclusion: The study findings confirm that CA treatment can protect the myocardium against doxorubicin-induced cardiotoxicity., (Copyright © 2024 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Neuropathy is the most common disorder comprising peripheral nerve damage in diabetic patients. Prolonged hyperglycaemia and oxidative stress cause metabolic imbalance and are the key reasons for the development of diabetic neuropathy. Daidzein, a soy isoflavone possesses potent anti-hyperglycaemic and antioxidant activity. The present study aims to check the protective effect of Daidzein in diabetic neuropathy in rats. The experimental animal model involved induction of diabetes in rats by intraperitoneal injection of streptozotocin (55 mg/kg). Following confirmation of diabetes, the diabetic rats were subjected to oral treatment with varying doses of Daidzein (25, 50, and 100 mg/kg) and pregabalin (30 mg/kg) for a duration of 4 weeks, initiated 6 weeks after diabetes induction. Results indicated that Daidzein treatment led to a significant reduction in plasma glucose levels and an improvement in body weight among diabetic animals. Moreover, Daidzein demonstrated a positive impact on sensory functions, as evidenced by the effect on tail withdrawal and response latency. Mechanical hyperalgesia and allodynia, common symptoms of diabetic neuropathy, were also significantly reduced with both Daidzein and pregabalin treatment. Notably, nerve conduction velocities exhibited improvement following the administration of Daidzein and pregabalin. Further investigation into the molecular mechanisms revealed that Daidzein treatment resulted in a notable enhancement of antioxidant enzyme levels and a reduction in the overexpression of NOX-4 in the sciatic nerve. This suggests that Daidzein's therapeutic effect is associated with the inhibition of oxidative stress via NOX-4. In summary, the findings of study suggests that, Daidzein treatment significantly attenuated diabetic neuropathy by inhibiting oxidative stress via NOX-4 inhibition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Laddha and Kulkarni.)

Alzheimer's disease (AD) is a primary cause of dementia that affects millions of people worldwide and its prevalence is likely to increase largely in the coming decades. Multiple complex pathways, such as oxidative stress, tau and amyloid-beta (Aβ) pathology, and cholinergic dysfunction, are involved in the pathogenesis of Alzheimer's disease. The conventional treatments provide only symptomatic relief and not a complete cure for the disease. On the other hand, recent studies have looked into the possibility of flavonoids as an effective therapeutic strategy for treating AD. Quercetin, a well-known flavonol, has been extensively studied for AD treatment. Therefore, this review mainly focuses on the pharmacokinetics properties of quercetin and its modes of action, such as antioxidant, anti-inflammatory, anti-amyloidogenic, and neuroprotective properties, which are beneficial in treating AD. It also highlights the nano delivery systems of quercetin, including liposomes, nanostructures lipid carriers, solid lipid nanoparticles, nanoemulsions, microemulsions, self-emulsifying drug delivery systems, and nanoparticles reported for AD treatment. The remarkable potential of quercetin nanocarriers has been reflected in enhancing its bioavailability and therapeutic efficacy. Therefore, clinical studies must be conducted to explore it as a therapeutic strategy for Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Phloretin is ubiquitous in apples (Malus domestica) and other fruits and has potential antidiabetic properties. Considering the preclinical potential of phloretin, its transition to clinical observations has unintentionally been neglected, particularly within the diabetic population. Furthermore, a comprehensive understanding of its pharmacokinetics remains elusive. This review seeks to offer valuable insights into phloretin's physical properties, pharmacokinetics, and pharmacodynamics, aiming to unveil opportunities for additional research on its therapeutic potential in the context of diabetes., Key Findings: All pharmacokinetic reports of phloretin confirm that the utilization of phloretin gets enhanced during diabetic conditions. Phloretin targets pathomechanisms such as glucose transporter 4 (GLUT4) and peroxisome proliferator's activity-activated receptor-γ (PPAR-γ) to decrease insulin resistance in diabetic conditions. Moreover, phloretin targets inflammatory, oxidative, and apoptotic signaling to minimize the progression of diabetes-associated macro- and microvascular complications., Summary: The pleiotropic antidiabetic action of phloretin is mainly dependent on its pharmacokinetics. Nevertheless, further investigation into the altered pharmacokinetics of phloretin during diabetic conditions is essential. Additionally, the results derived from clinical studies utilized apples, apple extract, and supplements containing phloretin. Greater emphasis should be placed on future clinical studies to assess the potential of phloretin as a standalone compound., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Diabetic cardiomyopathy is one of the most common complications of diabetes. Escin may significantly inhibit myocardial damage through its NF-κβ inhibitory, antidiabetic, neuroprotective, and potent anti-inflammatory activity. Hence, the study was carried out to evaluate the effect of escin in diabetic cardiomyopathy., Methods: Diabetes induction was done in rats with streptozotocin. After six weeks of induction, diabetic animals were administered with escin (5, 10, and 20 mg/kg) for the next four weeks., Results: Escin prevented the progression of abnormalities in the biochemical, hemodynamic parameters and electrocardiogram. Escin also prevented the progression of abnormality in the oxidative stress parameters. The expression of NF-κβ and MCP-1 was significantly reduced with escin treatment. Furthermore, escin also prevented damage to myocardial cells and reduced collagen deposition in the cardiomyocytes., Conclusion: Escin prevented the progression of cardiomyopathy in diabetic rats. Hence escin can be an alternative option for the management of diabetic cardiomyopathy.

Flavonoids have been reported to be vital in treating various chronic disorders. Luteolin (3',4',5,7-tetrahydroxyflavone) is a flavonoid present in a variety of plant sources such as celery, green pepper, olive oil, peppermint, thyme, rosemary, oregano, etc. It has been reported to have various pharmacological activities such as antioxidant, anti-inflammatory, anticancer, antidiabetic, anti-Alzheimer, antimicrobial, etc. Many scientific studies have been carried out on luteolin for its possible effects on diabetes and its associated complications. The present review focuses on the role of luteolin in diabetes mellitus and the associated complications. The antidiabetic impact of luteolin is linked with the increased expression of PPARγ and GLUT. Various in vitro and in vivo studies have been performed to explore the effects of luteolin on diabetic complications, and it has shown a significant impact in the management of the same., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Retinoblastoma (RB), a childhood retinal cancer is caused due to RB1 gene mutation which affects the child below 5 years of age. Angiogenesis has been proven its role in RB metastasis due to the presence of vascular endothelial growth factor (VEGF) in RB cells. Therefore, exploring angiogenic pathway by inhibiting VEGF in treating RB would pave the way for future treatment. In preclinical studies, anti-VEGF molecule have shown their efficacy in treating RB. However, treatment requires recurrent intra-vitreal injections causing various side effects along with patient nonadherence. As a result, delivery of anti-VEGF agent to retina requires an ocular delivery system that can transport it in a non-invasive manner to achieve patient compliance. Moreover, development of these type of systems are challenging due to the complicated physiological barriers of eye. Adopting a non-invasive or minimally invasive approach for delivery of anti-VEGF agents would not only address the bioavailability issues but also improve patient adherence to therapy overcoming the side effects associated with invasive approach. The present review focuses on the eye cancer, angiogenesis and various novel ocular drug delivery systems that can facilitate inhibition of VEGF in the posterior eye segment by overcoming the eye barriers.

Introduction: Cisplatin, an anti-cancer drug is used to treat a wide range of solid tumors. Nevertheless, nephrotoxicity is the major adverse effect that restricts its clinical application. The present study focuses on the effect of chelidonic acid in cisplatin-induced nephrotoxicity., Methods: Wistar rats were injected with cisplatin (5 mg/kg, intraperitoneally (i.p.), once in a week for 4 weeks) and chelidonic acid (10, 20, and 40 mg/kg, per oral (p.o.) for 4 weeks). Body weight, urine, biochemical, and oxidative stress parameters were performed to evaluate the effect of chelidonic acid in cisplatin-induced nephrotoxicity in rats. Pro-inflammatory cytokines and nuclear factor erythroid 2-related factor 2 (Nrf2) concentrations were determined. Expression of phospho-AMP activated protein kinase (phospho-AMP) and hypoxia-inducible factor 1-alpha (HIF-1α) was studied with western blot. Haematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome staining were used to study kidney tissues., Results: Relative kidney weight and urine output were significantly increased in cisplatin-administered rats. Whereas, albumin, and creatinine concentration were decreased, and treatment with chelidonic acid reverses these deleterious effects of cisplatin significantly. Kidney functions were improved by chelidonic acid treatment with a reduction in tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and transforming growth factor-beta (TGF-β1) concentration. The oxidative stress was decreased as compared to the cisplatin group. Furthermore, Nrf2 was significantly increased by chelidonic acid treatment. Chelidonic acid treatment significantly increased the expression of phospho-AMPK and HIF-1α in kidney tissue. Histopathological studies revealed that chelidonic acid reduced kidney damage., Conclusion: The findings showed that chelidonic acid increases phospho-AMPK and HIF-1α in the kidney tissue and significantly lowers the inflammatory cytokines, thus it is an effective molecule for providing protection against cisplatin-induced nephrotoxicity., Competing Interests: Declaration of Competing Interest The authors also declare that they do not have any conflict of interests., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by high blood glucose and is associated with high morbidity and mortality among the diabetic population. Uncontrolled chronic hyperglycaemia causes increased formation and accumulation of different oxidative and nitrosative stress markers, resulting in microvascular and macrovascular complications, which might seriously affect the quality of a patient's life. Conventional treatment strategies are confined to controlling blood glucose by regulating the insulin level and are not involved in attenuating the life-threatening complications of diabetes mellitus. Thus, there is an unmet need to develop a viable treatment strategy that could target the multi-etiological factors involved in the pathogenesis of diabetic complications. Stem cell therapy, a regenerative medicine approach, has been investigated in diabetic complications owing to their unique characteristic features of self-renewal, multilineage differentiation and regeneration potential. The present review is focused on potential therapeutic applications of stem cells in the treatment of microvascular diabetic complications such as nephropathy, retinopathy, and polyneuropathy., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chelidonic acid is a phytoconstituent found in rhizomes of the perennial plant celandine. The current study aims to evaluate the acute and repeated dose oral toxicity study of chelidonic acid as per the OECD guidelines 425 and 407. The pharmacokinetic and toxicity profile of chelidonic acid was predicted using online servers and tools. A single dose of chelidonic acid (2000 mg/kg) was administered to female Wistar rats in an acute toxicity study, and the animals were monitored for 14 days. We studied the toxicity profile of chelidonic acid at 10, 20, and 40 mg/kg doses in Wistar rats for repeated dose toxicity (28 days). Clinical biochemistry, haematological, and urine parameters were estimated. A gross necropsy and histopathology were performed. A single oral dose of chelidonic acid (2000 mg/kg) showed no signs of toxicity or mortality. The Administration of chelidonic acid showed no significant alterations in haematological, biochemical, and urine parameters. The histopathology showed normal structure and architecture in all the vital organs. A gross necropsy of vital organs showed no signs of toxicity. The chelidonic acid was found to be safe at all selected dose levels in the acute and repeated dose toxicity study in rats., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Daidzein, 7-hydroxy-3-(4-hydroxyphenyl)-4H-chromen-4-one is a naturally occurring compound present in leguminous plants, especially in soybeans. Chemically it belongs to the isoflavone class and possesses high nutritive value. Daidzein acts on estrogen receptor and is non-steroidal in nature hence it can also be called as non-steroidal phytoestrogenic compound. Daidzein has been studied by many researchers for its pharmacological activities. Daidzein metabolites were also studied in detail for their health benefits. Researchers have developed novel formulations of daidzein in the past few years to improve its aqueous solubility and bioavailability. Self-emulsified daidzein, poly(lactic-co-glycolic) acid daidzein nanoparticles, nanoemulsion, nanoemulsion gel, and co-crystals are a few of them. The present review provides detailed information on the chemistry, drug development aspects, pharmacokinetics, and pharmacodynamics of daidzein. A literature search was performed using various datasets like PubMed, EBSCO, ProQuest Scopus, and selected websites including the National Institutes of Health and the World Health Organization. Daidzein has a wide range of pharmacodynamic properties in the treatment of cancer, neurodegenerative disorders, cardiac disorders, diabetes and its complication, osteoporosis, and skin disorders. The pharmacokinetic, pharmacodynamics, and drug development aspects of daidzein will help researchers to design further research work on daidzein in the future., (© 2023 John Wiley & Sons Ltd.)

Background: Terminalia chebula Retz., Family Combretaceae ( T. chebula ) is one of the important plants mentioned in Ayurveda, a traditional system of medicine. The present work was designed to study the effect of the aqueous extract of T. chebula fruits in type 2 diabetic rats., Methods: The aqueous extract of the fruits was prepared by the double maceration technique. The extract was subjected to HPTLC analysis, which showed the presence of ellagic acid and gallic acid. Type 2 diabetes was induced in rats with a low dose of Streptozotocin (35 mg/kg) after administering a high-fat diet for fourteen days. Diabetic animals were treated with 500 and 1000 mg/kg of aqueous extract of T. chebula fruits for six weeks., Results: Diabetic rats showed a significantly (511.7 ± 17.6) ( p < 0.001) high plasma glucose level compared to the normal group (106 ± 3.358). The T. chebula treatment group showed a significant ( p < 0.001) reduction in plasma glucose at 500 mg/kg (394.3 ± 10.35) and 1000 mg/kg (368.6 ± 30.08) doses when compared with the diabetic control group. Treatment with aqueous extract significantly reduced lipid parameters in diabetic animals when compared to the animals in the diabetic control group. Treatment with extract at a dose of 500 mg/kg and 1000 mg/kg showed a significant reduction in AST ( p < 0.01, p < 0.001) when compared with diabetic control rats. Treatment with extract significantly reduced ALT at 500 mg/kg ( p < 0.05) and 1000 mg/kg ( p < 0.001) doses when compared with diabetic control rats. The extract treatment improved insulin sensitivity and insulin sensitivity index (ISI) and significantly decreased HOMR-IR. Treatment with T. chebula aqueous extract at 1000 mg/kg significantly increased the level of GSH ( p < 0.05) when compared to diabetic control rats. T. chebula treatment at 1000 mg/kg significantly increased levels of CAT ( p < 0.01). Histopathology of pancreatic tissue revealed that the extract has a protective effect against the damage caused by hyperglycemia. Immunohistochemistry of pancreatic tissue showed increased expression of SIRT1 in diabetic animals treated with the extract., Conclusions: The results of the present study indicate that the extract of T. chebula has significant effects in the management of type 2 diabetes.

Context: The prevalence of diabetic neuropathy is drastically increasing in the world. To halt the progression of diabetic neuropathy, there is an unmet need to have potential biomarkers for the diagnosis and new drug discovery., Objective: To study various biomarkers involved in the pathogenesis of diabetic neuropathy., Methods: The literature was searched with the help of various scientific databases and resources like PubMed, ProQuest, Scopus, and Google scholar from the year 1976 to 2020., Results: Biomarkers of diabetic neuropathy are categorised as inflammatory biomarkers such as MCP-1, VEGF, TRPV1, NF-κB; oxidative biomarkers such as adiponectin, NFE2L2; enzyme biomarkers like NADPH, ceruloplasmin, HO-1, DPP-4, PARP α; miscellaneous biomarkers such as SIRT1, caveolin 1, MALAT1, and microRNA. All biomarkers have a significant role in the pathogenesis of diabetic neuropathy., Conclusion: These biomarkers have a potential role in the progression of diabetic neuropathy and can be considered as potential targets for new drug discovery.

Alzheimer's disease (AD) is a neuronal condition causing progressive loss of memory and cognitive dysfunction particularly in elders. An upsurge in the global old age population has led to a proportionate increase in the prevalence of AD. The current treatments for AD are symptomatic and have debilitating side effects. A literature review and current research have directed scientists to explore natural products with better safety and efficacy profiles as new treatment options for AD. Baicalein, belonging to the flavone subclass of flavonoids, has been reported for its anti-oxidant, anti-inflammatory, AChE enzyme inhibitory activity and anti-amyloid protein aggregation activity, which collectively demonstrates its benefits as a neuroprotective agent. Presently, memantine, a NMDAR antagonist, is one of the important drugs used for treatment of Alzheimer's disease. The current study aims to investigate the effect of baicalein in combination with memantine in β-amyloid-induced AD in albino Wistar rats. Baicalein (10 mg/kg) alone, 5 mg/kg and 10 mg/kg in combination with memantine (20 mg/kg) was administered for 21 days. Treatment with baicalein in combination with memantine showed significant improvement in behavioural studies. The combination treatment decreased oxidative stress, β-amyloid plaque formation and increased the expression of brain-derived neurotrophic factor (BDNF) in the brain. From the results, it can be concluded that treatment with baicalein and memantine could be beneficial for reducing the progression of neurodegeneration in rats. Baicalein has an additive effect in combination with memantine, making it a potential option for the treatment of AD.

Alzheimer's disease is a progressive neurodegenerative condition. It is one of the most common 28 forms of dementia accounting for 60-80% of people suffering from dementia. There are very few medications that are approved for the treatment of Alzheimer's disease. Baicalein, belonging to the flavone subclass of flavonoids, has been reported to have a neuroprotective effect by reducing oxidative stress and neuroinflammation, inhibiting the AChE enzyme, and reducing amyloid protein aggregation and toxicity. Memantine is one of the most important drugs used for treating Alzheimer's disease. The purpose of this work was to study the effect of baicalein with memantine on aluminum chloride-induced neurotoxicity in Wistar rats. Aluminum chloride (100 mg/kg p.o.) was administered for 42 days in male Wistar rats to induce neurotoxicity. Baicalein alone (10 mg/kg) and a combination of baicalein (5 mg/kg and 10 mg/kg) with memantine (20 mg/kg) were administered for 42 days. Treatment of baicalein with memantine showed significant improvement in behavioral parameters. The combination reduced oxidative stress and the formation of β-Amyloid plaques and increased brain-derived neurotrophic factor (BDNF) expression. Based on findings, it can be concluded that treatment with baicalein and memantine may slow the progression of neurodegeneration in rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jadhav and Kulkarni.)

Background: Vascular endothelial dysfunction (VED) significantly results in catastrophic cardiovascular diseases with multiple aetiologies. Variations in vasoactive peptides, including angiotensin II and endothelin 1, and metabolic perturbations like hyperglycaemia, altered insulin signalling, and homocysteine levels result in pathogenic signalling cascades, which ultimately lead to VED. Endoplasmic reticulum (ER) stress reduces nitric oxide availability, causes aberrant angiogenesis, and enhances oxidative stress pathways, consequently promoting endothelial dysfunction. Moreover, the renin-angiotensin system (RAS) has widely been acknowledged to impact angiogenesis, endothelial repair and inflammation. Interestingly, experimental studies at the preclinical level indicate a possible pathological link between the two pathways in the development of VED. Furthermore, pharmacological modulation of ER stress ameliorates angiotensin-II mediated VED as well as RAS intervention either through inhibition of the pressor arm or enhancement of the depressor arm of RAS, mitigating ER stress-induced endothelial dysfunction and thus emphasizing a vital crosstalk., Conclusion: Deciphering the pathway overlap between RAS and ER stress may open potential therapeutic avenues to combat endothelial dysfunction and associated diseases. Several studies suggest that alteration in a component of RAS may induce ER stress or induction of ER stress may modulate the RAS components. In this review, we intend to elaborate on the crosstalk of ER stress and RAS in the pathophysiology of VED., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chemotherapy is a main treatment for cancer, and it benefits patients by controlling cancer relapse and metastasis, thereby leading to an increase in the overall survival rate. However, this treatment is associated with mild to severe side effects, one of which is cardiotoxicity. The severity of cardiotoxicity, a leading cause of cardiovascular diseases, depends on the type of cancer therapy employed and the time required for its management. A chemotherapeutic agent is used either alone or in combination with other drugs for cancer treatment. The exact mechanism of chemotherapeutic agent-induced cardiotoxicity remains unclear, although it is likely to be multifactorial and to include oxidative stress, apoptosis, and inflammation. There are many approaches to avoid the untoward effects of chemotherapeutic agents. However, the available options for cardiac protection are minimal, and they include renin-angiotensin system blockers, beta-blockers, herbal drugs, or iron chelators such as dexrazoxane. The present review provides information on the molecular mechanism of chemotherapy-induced myocardial infarction and cardiotoxicity along with scientifically studied synthetic molecules, herbal extracts, and natural products to manage chemotherapy-induced cardiotoxicity., (© 2022. The Pharmaceutical Society of Korea.)

Diabetes is linked with various microvascular and macrovascular complications. Nephropathy, neuropathy and retinopathy are important microvascular complications of diabetes. Different types of secondary metabolites including glycosides have been studied for their effects in diabetic complications. Various glycosides such as flavanoid glycosides and saponin glycosides are reported for their beneficial effects in diabetic nephropathy, neuropathy, retinopathy and cardiomyopathy by action on various pathways involved in the progression of these complications. Coumarin glycosides and cryanogenic glycosides have been studied for their effective role in diabetic nephropathy. Phenolic glycosides and anthraquinone glycosides also have beneficial role in diabetic neuropathy. The present review focuses on various classes of glycosides and their role in the prevention and treatment of vascular complications of diabetes., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Meroterpenoids are natural products synthesized by unicellular organisms such as bacteria and multicellular organisms such as fungi, plants, and animals, including those of marine origin. Structurally, these compounds exhibit a wide diversity depending upon the origin and the biosynthetic pathway they emerge from. This diversity in structural features imparts a wide spectrum of biological activity to meroterpenoids. Based on the biosynthetic pathway of origin, these compounds are either polyketide-terpenoids or non-polyketide terpenoids. The recent surge of interest in meroterpenoids has led to a systematic screening of these compounds for many biological actions. Different meroterpenoids have been recorded for a broad range of operations, such as anti-cholinesterase, COX-2 inhibitory, anti-leishmanial, anti-diabetic, anti-oxidative, anti-inflammatory, anti-neoplastic, anti-bacterial, antimalarial, anti-viral, anti-obesity, and insecticidal activity. Meroterpenoids also possess inhibitory activity against the expression of nitric oxide, TNF- α, and other inflammatory mediators. These compounds also show renal protective, cardioprotective, and neuroprotective activities. The present review includes literature from 1999 to date and discusses 590 biologically active meroterpenoids, of which 231 are from fungal sources, 212 are from various species of plants, and 147 are from marine sources such as algae and sponges., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fuloria, Raheja, Shah, Oza, Kulkarni, Subramaniyan, Sekar and Fuloria.)

The current research work was planned to study the effects of paeonol in the management of diabetic retinopathy. Diabetes was induced in male Sprague Dawley rats using Streptozotocin (55 mg/kg, i.p. ). After 4 weeks, the diabetic animals were treated with paeonol at a dose of 50, 100, and 200 mg/kg body weight daily for the next 4 weeks. At the end of treatment, retinal physiology was studied by recording an electroretinogram (ERG); biochemical parameters and oxidative stress were estimated. The histopathology of the retina was also carried out at the end of the study. The ERG of paeonol-treated animals showed a significant improvement in a-wave amplitude, b-wave amplitude, a-wave latency, and b-wave latency ( p < 0.001) at 15 cd s/m 2 when compared with the diabetic control animals. The paeonol treatment (200 mg/kg) in diabetic animals showed a significant decrease in the plasma glucose level ( p < 0.001) when compared to the animals in diabetic control group. Paeonol also significantly decreased the lactate dehydrogenase, aldose reductase, and sorbitol dehydrogenase levels when compared with the diabetic control animals. The oxidative stress in the eye was significantly reduced after the paeonol treatment in the diabetic rats. The histopathology showed a significant reduction ( p < 0.05) in the retinal thickness after the paeonol treatment. The results of the study indicate that paeonol can be considered an effective management option for diabetic retinopathy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Adki and Kulkarni.)

Reactive oxygen species via NADPH oxidase (NOX) activation are involved in the pathogenesis of many disease conditions such as diabetes and its complications. In the present study, we have examined the effect of daidzein in the management of diabetic cystopathy. Diabetes was induced in male Sprague Dawley rats via intraperitoneal injection of streptozotocin (STZ) at a dose of 55 mg/kg. After 6 weeks of diabetes induction, animals were treated with daidzein orally at a dose of 25, 50, and 100 mg/kg for 4 weeks. Diabetic animals showed increase (p < 0.001) in bladder capacity (4.32 ± 0.43 mL) and residual volume (2.53 ± 0.19 mL) when compared with normal control animals (2.10 ± 0.40 mL and 0.51 ± 0.12 mL res). Treatment with daidzein at dose of 50 and 100 mg/kg significantly reduced the elevated bladder capacity (2.91 ± 0.11 mL, p < 0.01 and 2.65 ± 1.13 mL, p < 0.001) and residual volume (1.40 ± 0.15 mL, p < 0.001 and 1.15 ± 0.05 mL, p < 0.001). Daidzein-treated animals also showed improvement in voiding efficiency. Elevated threshold and baseline pressure were also found to be reduced in diabetic animals after 4 weeks of daidzein treatment. Daidzein treatment also prevented the loss of antioxidant enzymes in the urinary bladder and also reduced the expression of NOX-4 and RAC-1 in the bladder. From the results, it can be concluded that daidzein showed a beneficial effect on urinary bladder dysfunction in diabetic animals., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Vascular adhesion protein-1 (VAP-1) is a bifunctional protein that has the ability to catalyze the deamination of primary amines and is involved in the production of hydrogen peroxide, aldehydes, and advanced glycation end products (AGEs). VAP-1 is usually stored in intracellular vesicles of endothelial cells, smooth muscles, and adipocytes. It is responsible for leukocyte transmigration and adhesion. Overexpression of VAP-1 exacerbates oxidative stress and modulates a variety of inflammatory mediators linked with diabetic complications. Numerous studies have suggested the association of increased insulin levels with serum VAP-1 (sVAP-1). Preclinical research evidence suggests the increased activity of sVAP-1 in type 1 and 2 diabetes. Scientific reports on VAP-1 inhibitors have shown a reduction in severity in diabetic animal models. VAP-1 is a potential target of a therapeutically effective line of treatment for diabetes and diabetic complications such as nephropathy and retinopathy. The primary focus of this review is the role of VAP-1 in diabetes and its associated microvascular complications., (© 2021. The Author(s) under exclusive licence to Maj Institute of Pharmacology Polish Academy of Sciences.)

Background: Bauhinia variegata , a ayurvedic medicinal plant reported for its valuable effects in various diseases. It has shown significant effects in type 1 and type 2 diabetes., Objective: The present work was designed to study effects of aqueous and alcoholic extract (AE and AlcE) of Bauhinia variegata Linn. leaves in diabetic neuropathy., Methods: Male Sprague Dawley rats become diabetic using intraperitoneal injection of streptozotocin (STZ) at 55 mg/kg dose. After 6 weeks, animals were divided and were treated with AE and AlcE at a dose of 250, 500, and 1000 mg/kg ( p. o. ) for the next four weeks. Various parameters such as glucose, thermal hyperagesia, mechanical allodynia, MNCV and oxidative stess were assessed at the end of the study., Results: Diabetic animals showed a significant reduction in response time in tail immersion and hot plate test as compared to animals in normal control group. AE and AlcE at 250, 500, and 1000 mg/kg dose significantly increased response time in the tail immersion test. Whereas, AE and AlcE at doses 500 and 1000 mg/kg showed significant improvement and in response time in the hot plate test.AlcE at 250, 500 and 1000 mg/kg dose increased the nociceptive threshold significantly. AE at doses 500 and 1000 mg/kg showed significant improvement in the nociceptive threshold. The decrease in motor nerve conduction velocity was observed in diabetic control animals, which was significantly improved after AlcE treatment as compared to AE treatment. Treatment with AE and AlcE decreased the lipid peroxidation and increased the antioxidant enzyme activity significantly in the sciatic nerve., Conclusion: The results showed that Bauhinia variegata extracts may be considered as a effective option for management of diabetic neuropathy., Competing Interests: Conflict of interestsThe authors declare that they have no conflict of interest., (© Springer Nature Switzerland AG 2021.)

Due to a tragic increase in the incidences of diabetes globally, diabetic kidney disease (DKD) has emerged as one of the leading causes of end-stage renal diseases (ESRD). Hyperglycaemia-mediated overactivation of the renin-angiotensin-aldosterone system (RAAS) is key to the development and progression of DKD. Consequently, RAAS inhibition by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is the first-line therapy for the clinical management of DKD. However, numerous clinical and preclinical evidences suggested that RAAS inhibition can only halt the progression of the DKD to a certain extent, and they are inadequate to cure DKD completely. Recent studies have improved understanding of the complexity of the RAAS. It consists of two counter-regulatory arms, the deleterious pressor arm (ACE/angiotensin II/AT1 receptor axis) and the beneficial depressor arm (ACE2/angiotensin-(1-7)/Mas receptor axis). These advances have paved the way for the development of new therapies targeting the RAAS for better treatment of DKD. In this review, we aimed to summarise the involvement of the depressor arm of the RAAS in DKD. Moreover, in modern drug discovery and development, an advance approach is the bispecific therapeutics, targeting two independent signalling pathways. Here, we discuss available reports of these bispecific drugs involving the RAAS as well as propose potential treatments based on neurohormonal balance as credible therapeutic strategies for DKD.

The present study was designed to evaluate the effect of sodium copper chlorophyllin (SCC) in adenine-induced chronic kidney disease (CKD). CKD was induced in male Wistar rats by feeding 0.3% w/w adenine diet for 28 days. After induction, animals were treated with sodium copper chlorophyllin at dose 2.7, 5.4, and 10.8 mg/kg for the next 28 days. The biochemical and urines parameters like creatinine, blood urea nitrogen (BUN), albumin, total protein creatinine clearance, urea clearance, and glomerular filtration rate were assessed on days 0, 14, and 28. Plasma TGF-β1, COX-2, and IL-6 levels were assessed. Various oxidative stress parameters and TGF-β1 expression were determined in the kidney. Histopathology of the kidney was studied with different stains. Sodium copper chlorophyllin-treated animals showed a significant reduction in urine output and relative kidney weight. The treatment with sodium copper chlorophyllin significantly improved kidney function by normalizing biochemical and urine parameters. Treatment with SCC significantly reduced circulatory inflammatory mediators-TGF-β1, COX-2, and IL-6. Additionally, the treatment also significantly reduced oxidative stress and TGF-β1 expression in kidney tissues. Histopathology studies showed inhibition in the kidney damage due to the treatment of SCC. The sodium copper chlorophyllin treatment attenuated adenine-induced chronic kidney disease in rats.

The endothelial cells play a crucial role in the progression of angiogenesis, which causes cell re-modulation, proliferation, adhesion, migration, invasion and survival. Angiogenic factors like cytokines, cell adhesion molecules, growth factors, vasoactive peptides, proteolytic enzymes (metalloproteinases) and plasminogen activators bind to their receptors on endothelial cells and activate the signal transduction pathways like epidermal growth factor receptor (EGFR phosphatidylinositol 3-kinase and (PI3K)/AKT/mammalian target of rapamycin (mTOR) which initiate the process of angiogenesis. Cytokines that stimulate angiogenesis include direct and indirect proangiogenic markers. The direct proangiogenic group of markers consists of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (FGF-2) and hepatocyte growth factor (HGF) whereas the indirect proangiogenic markers include transforming growth factor-beta (TGF-β), interleukin 6 (IL-6), interleukin 8 (IL-8) and platelet-derived growth factor (PDGF). VEGF and FGF-2 are the strongest activators of angiogenesis which stimulate migration and proliferation of endothelial cells in existing vessels to generate and stabilize new blood vessels. VEGF is released in hypoxic conditions as an effect of the hypoxia-inducible factor (HIF-1α) and causes re-modulation and inflammation of bronchi cell. Cell re-modulation and inflammation leads to the development of various lung disorders like pulmonary hypertension, chronic obstructive pulmonary disease, asthma, fibrosis and lung cancer. This indicates that there is a firm link between overexpression of VEGF and FGF-2 with lung disorders. Various natural and synthetic drugs are available for reducing the overexpression of VEGF and FGF-2 which can be helpful in treating lung disorders. Researchers are still searching for new angiogenic inhibitors which can be helpful in the treatment of lung disorders. The present review emphasizes on molecular mechanisms and new drug discovery focused on VEGF and FGF-2 inhibitors and their role as anti-angiogenetic agents in lung disorders., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Aim: Diabetic nephropathy is the commonly developed complication of vasculature in type 2 diabetic patients. Chronic hyperglycemia leads to nephropathy in diabetics because of the formation of excessive reactive oxygen species and advanced glycation end products which is reflected in the form of glomerulosclerosis, tubular atrophy and interstitial fibrosis. As per the various reports reduction in SIRT1 expression in kidney tissue is key factor in the development of nephropathy in diabetes because its reduction in tissue is linked with excessive formation of ROS. Formononetin is a polyphenolic compound reported for its effect on SIRT1 and ROS., Main Methods: Type 2 diabetes was induced in rats by diet modification using high fat diet for fifteen days prior to streptozotocin regimen (35 mg/kg, i.p.). Treatment of formononetin was started after confirmation of diabetes and continued for 16 weeks. Formononetin was administered orally to the diabetic animals at the dose of 10. 20 and 40 mg/kg., Key Findings: Formononetin treatment for 16 week was able to control hyperglycemia and insulin resistance in diabetic animals. It has also been reduced triglyceride and cholesterol in blood. Formononetin treatment reduced blood concentration of creatinine, blood urea nitrogen and increased albumin concentration. Formononetin treatment also enhanced creatinine clearance in diabetic animals. Oxidative stress burden was also reduced significantly after formononetin treatment along with increased SIRT1 expression in kidney tissues of diabetic animals., Significance: Formononetin is a potential molecule which increases the expression of SIRT1 in kidney tissue of diabetic. Thus formononetin is an effective molecule to control nephropathy in type 2 diabetes mellitus., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Phenolic compounds constitute one of the important classes of secondary metabolites in the plants. Flavonoids are primary phenolic compounds found in natural drugs. Naringenin is a flavanone, aglycone of Naringin, predominantly found in citrus fruits with various pharmacological activities. Large number of scientific papers has been published on Naringenin describing its structure, physicochemical properties and its therapeutic use in different diseases. This review provides highlights of Naringenin with respect to its distribution, pharmacokinetic and its use in conditions like oxidative stress, inflammation, cancer, diabetes, cardiovascular diseases and neurological disorders. Furthermore, the review also focuses on molecular level mechanisms of Naringenin for its therapeutic effect. Various attempts have been made to formulate advanced dosage forms to address issue of solubility of Naringenin. Systematic review of data published on formulation aspects of Naringenin has also been presented in the article., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Biochanin A (5,7-Dihydroxy-4'-methoxyisoflavone) is an O-methylated isoflavone known for its anti-inflammatory, lipid lowering and anti-cancer activity. The current study was designed to find out antidiabetic efficacy of Biochanin A in type 2 diabetes in rats. Induction of type 2 diabetes mellitus in experimental animals was carried out by manipulation of diet using high fat diet for fourteen days and then administration of streptozotocin at low dose of 35 mg/kg, i.p. The diabetic animals were treated with 10, 20 and 40 mg/kg of Biochanin A for 28 days. The effect of Biochanin A treatment in diabetic animals was evaluated by measuring changes in body weight, biochemical parameters, insulin sensitivity index, Homeostatic model assessment-Insulin resistance (HOMA-IR), oral glucose tolerance test, glycohaemoglobin and hepatic glycogen level. Changes in histopathological characteristics of pancreatic tissue were also evaluated after treatment with Biochanin A. Immunohistochemical analysis of pancreatic tissue was carried out for the expression of SIRT1. The results showed that the selected doses of (10, 20 and 40 mg/kg) Biochanin A significantly decreased blood glucose (p < 0.001). The higher dose (40 mg/kg) of Biochanin A significantly reduced glucose tolerance (p < 0.001) in diabetic animals. Biochanin A treatment significantly reduced insulin resistance (p < 0.001) and improved inulin sensitivity (p < 0.01 for 10 mg/kg, 20 mg/kg, p < 0.001 for 40 mg/kg) at all selected dose levels. It also improved lipid profile significantly (p < 0.001) at lower, middle and higher dose level. Glycohaemoglobin formation was significantly decreased in diabetic animals (p < 0.001) after treatment with Biochanin A at all three dose levels. Liver glycogen level was also improved significantly after treatment with Biochanin A in diabetic animals at 20 mg/kg and 40 mg/kg dose level. Biochanin A at dose of 40 mg/kg increased SIRT1 expression in pancreatic tissue. In conclusion, Biochanin A has significant effect in type 2 diabetes mellitus which might be linked to its effects on SIRT1., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Jyotishmati, scientifically known as Celastrus paniculatus Wild (Celastraceae) is one of the most important medicinal plants in Ayurveda. The plant has shown significant pharmacological activities like anti-arthritic, wound healing, hypolipidemic, and antioxidant., Objective: To study possible effects of alcoholic extract of Celastrus paniculatus seeds (AlcE) in experimentally induced pain and inflammation in mice., Materials and Methods: The antinociceptive activity was evaluated in Swiss albino mice by tail immersion, hot plate, and acetic-acid-induced writhing tests at doses of 250, 500, and 1,000 mg/kg. Anti-inflammatory activity was evaluated in model of carrageenan-induced acute plantar inflammation in Wistar rats., Results: In tail immersion test, AlcE showed significant (P < 0.05) increase in tail withdrawal response at dose of 250 mg/kg with maximum possible effect of 15.71%. The maximum possible effect of 23.32% and 30.16% (P < 0.001) was seen at dose of 500 and 1000 mg/kg at 3 hours after administration of extract, respectively. In hot plate test, increase in paw licking time was reported at dose of 500 and 1000 mg/kg. AlcE (1,000 mg/kg) showed maximum response (6.23 ± 0.46) when compared with control (3.20 ± 0.18) at 90 min. In acetic acid induced writhings, AlcE at dose of 250, 500, and 1,000 mg/kg body weight showed 32.35%, 49.01%, and 58.82% inhibition in writhings, respectively. AlcE treated animals (500 and 1,000 mg/kg) showed significant decrease in paw edema at 3 hours and 4 hours, when compared with control animals., Conclusion: Jyotishmati seed extract possesses significant antinociceptive and anti-inflammatory activity.

Background: Gmelina arborea Roxb (Verbenaceae), also known as "Gambhari", is an important medicinal plant in the Ayurveda. There are no meticulous scientific reports on effect of the plant on inflammation and pain., Objective: To study the anti-inflammatory and anti-nociceptive properties of aqueous extracts (AE) and methanol extracts (ME) of G. arborea., Materials and Methods: The AE and ME of stembark of G. arborea was prepared by cold maceration and Soxhlet extraction technique respectively. Anti-inflammatory activity was determined in Wistar albino rats in a model of acute plantar inflammation induced by carrageenan. The anti-nociceptive activity was evaluated by using hot plate test and writhing test in Swiss albino mice. Significant differences between the experimental groups were assessed by analysis of variance., Results: AE and ME at dose of 500 mg/kg showed maximum inhibition in carrageenan induced inflammation up to 30.15 and 31.21% respectively. In hot plate test, the AE and ME showed the maximum response of 8.8 ± 0.97 (P < 0.01) and 8.2 ± 1.24 (P < 0.01) respectively at dose of 500 mg/kg when compared with control. AE showed maximum inhibition of writhing response (84.3%) as compared to ME (77.9%) in writhing test at a dose of 500 mg/kg., Conclusion: The findings suggested that G. arborea possess significant anti-inflammatory and anti-nociceptive activities.