Sirtuins: exploring next-gen therapeutics in the pathogenesis osteoporosis and associated diseases.

OBJECTIVE: Osteoporosis poses a substantial public health challenge due to an ageing population and the lack of adequate treatment options. The condition is marked by a reduction in bone mineral density, resulting in an elevated risk of fractures. The reduction in bone density and strength, as well as musculoskeletal issues that come with aging, present a significant challenge for individuals impacted by these conditions, as well as the healthcare system worldwide. METHODS: Literature survey was conducted until May 2023 using databases such as Web of Science, PubMed, Scopus, and Google Scholar. RESULT: Sirtuins 1-7 (SIRT1-SIRT7), which are a group of Nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, possess remarkable capabilities to increase lifespan and combat diseases related to aging. Research has demonstrated that these proteins play an important role in regular skeletal development and maintenance by directly impacting bone cells. Their dysfunction could be a factor in various bone conditions. Studies conducted on animals before clinical trials have shown that administering Sirtuins agonists to mice provides a safeguard against osteoporosis resulting from aging, menopause, and immobilization. These findings imply that Sirtuins may be a viable target for addressing the irregularity in bone remodeling and treating osteoporosis and other skeletal ailments. CONCLUSION: The purpose of this review was to present a thorough and current evaluation of the existing knowledge on Sirtuins biology, with a particular emphasis on their involvement in maintaining bone homeostasis and contributing to osteoporosis. Additionally, the review examines potential pharmacological interventions targeting Sirtuins for the treatment of osteoporosis.

Role of p53 suppression in the pathogenesis of hepatocellular carcinoma.

In the world, hepatocellular carcinoma (HCC) is among the top 10 most prevalent malignancies. HCC formation has indeed been linked to numerous etiological factors, including alcohol usage, hepatitis viruses and liver cirrhosis. Among the most prevalent defects in a wide range of tumours, notably HCC, is the silencing of the p53 tumour suppressor gene. The control of the cell cycle and the preservation of gene function are both critically important functions of p53. In order to pinpoint the core mechanisms of HCC and find more efficient treatments, molecular research employing HCC tissues has been the main focus. Stimulated p53 triggers necessary reactions that achieve cell cycle arrest, genetic stability, DNA repair and the elimination of DNA-damaged cells' responses to biological stressors (like oncogenes or DNA damage). To the contrary hand, the oncogene protein of the murine double minute 2 (MDM2) is a significant biological inhibitor of p53. MDM2 causes p53 protein degradation, which in turn adversely controls p53 function. Despite carrying wt-p53, the majority of HCCs show abnormalities in the p53-expressed apoptotic pathway. High p53 in-vivo expression might have two clinical impacts on HCC: (1) Increased levels of exogenous p53 protein cause tumour cells to undergo apoptosis by preventing cell growth through a number of biological pathways; and (2) Exogenous p53 makes HCC susceptible to various anticancer drugs. This review describes the functions and primary mechanisms of p53 in pathological mechanism, chemoresistance and therapeutic mechanisms of HCC.

Immunotherapy for hepatocellular carcinoma: Current status and future perspectives.

Hepatocellular carcinoma (HCC) is one of the world's deadliest and fastest-growing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery (liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying liver condition. Despite promising preclinical and early-phase clinical trials for some drugs, existing systemic therapeutic methods for advanced tumor stages remain limited, underlining an unmet clinical need. In current years, cancer immunotherapy has made significant progress, opening up new treatment options for HCC. HCC, on the other hand, has a variety of causes and can affects the body's immune system via a variety of mechanisms. With the speedy advancement of synthetic biology and genetic engineering, a range of innovative immunotherapies, such as immune checkpoint inhibitors [anti-programmed cell death-1 (PD-1), anti-cytotoxic T lymphocyte antigen-4, and anti-PD ligand 1 cell death antibodies], therapeutic cancer vaccines, engineered cytokines, and adoptive cell therapy have all been used for the treatment of advanced HCC. In this review, we summarize the present clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent clinical trial outcomes, and address future perspectives in the field of liver cancer.

Therapeutic implications of glycogen synthase kinase-3ß in Alzheimer's disease: a novel therapeutic target.

Alzheimer's disease (AD) is an extremely popular neurodegenerative condition associated with dementia, responsible for around 70% of the cases. There are presently 50 million people living with dementia in the world, but this number is anticipated to increase to 152 million by 2050, posing a substantial socioeconomic encumbrance. Despite extensive research, the precise mechanisms that cause AD remain unidentified, and currently, no therapy is available. Numerous signalling paths related to AD neuropathology, including glycogen synthase kinase 3-ß (GSK-3ß), have been investigated as potential targets for the treatment of AD in current years.GSK-3ß is a proline-directed serine/threonine kinase that is linked to a variety of biological activities, comprising glycogen metabolism to gene transcription. GSK-3ß is also involved in the pathophysiology of sporadic as well as familial types of AD, which has led to the development of the GSK3 theory of AD. GSK-3ß is a critical performer in the pathology of AD because dysregulation of this kinase affects all the main symbols of the disease such as amyloid formation, tau phosphorylation, neurogenesis and synaptic and memory function. The current review highlights present-day knowledge of GSK-3ß-related neurobiology, focusing on its role in AD pathogenesis signalling pathways. It also explores the possibility of targeting GSK-3ß for the management of AD and offers an overview of the present research work in preclinical and clinical studies to produce GSK-3ß inhibitors.

An Overview of Hepatocellular Carcinoma with Emphasis on Dietary Products and Herbal Remedies.

The most common principal malignant tumor that accounts for ∼80% of cases of liver cancer across the world is hepatocellular carcinoma (HCC). It is a multifacetedillness that is caused by several risk factors and often progresses in the context of underlying cirrhosis. It is tremendously difficult and essential for the screening of novel therapeutic medications to establish HCC preclinical models that are equivalent to clinical diseases settings, i.e., representing the tumor microenvironment of HCC. In the progress of HCC, numerous molecular cascades have been supposed to play a part. Sorafenib is the only drug permitted by the US Food and Drug Administration for the treatment of HCC. Yet because of the increasing resistance to the drug and its toxicity, clinical treatment methods are not completely adequate. Newer treatment therapy options are essential for the management of HCC in patients. Natural compounds can be afforded by the patients with improved results with less toxicity and fewer side effects, among different methods of liver cancer treatment. The treatment and management of HCC with natural drugs and their phytoconstituents are connected to several paths that can prevent the occurrence and progress of HCC in several ways. The present review summarizes the etiology of HCC, molecular pathways, newer therapeutic approaches, natural dietary products, herbal plants and phytoconstituents for HCC treatment.

Sarsasapogenin and fluticasone combination improves DNFB induced atopic dermatitis lesions in BALB/c mice.

OBJECTIVE: Atopic dermatitis (AD) is a pruritic, chronic, relapsing inflammatory skin disease. The research aims to study the effects of Sarsasapogenin and its combination with Fluticasone in 2, 4-Dinitrofluorobenzene (DNFB) induced atopic dermatitis in BALB/c mice. MATERIAL AND METHODS: Thirty male Balb/c mice were divided into 5 groups: (i) Normal control (NC), (ii) Disease control (DNFB), (iii) Sarsasapogenin (SG) (50 µg/mice), (iv) Fluticasone (FC) (50 µg/mice), (v) Sarsasapogenin + Fluticasone (SG + FC) combination (25 µg/mice). Dermatitis was induced by repeated application of DNFB in Balb/c mice. On topical application of SG, FC, and SG + FC combination on the ear and skin lesions, body weight, ear weight, ear thickness, erythema score, spleen weight, cytokines, immunoglobulin E (IgE) levels, nitric oxide (NO) level, hematological parameters, and oxidative stress markers were evaluated. Histological analysis of the ear tissue was also done. RESULTS: The results stated that SG and SG + FC treatment to mice considerably decrease the ear weight, ear thickness, spleen weight, serum IgE, cytokines, NO levels, and restoration of antioxidant stress markers with elevation in the hematological parameters. The observations were further confirmed by histopathological analysis of ear tissue. CONCLUSION: These data specify that SG has been demonstrated as a probable therapy for the treatment of allergic skin diseases in combination with FC by decreasing its dose from 50 to 25 µg/mice to avoid the chronic side effects of FC. Hence, it can be concluded that SG and SG + FC combination significantly improved the AD-like symptoms in the DNFB sensitized mice through mitigating the production of proinflammatory mediators and restoration of oxidative stress markers.

Protective effect of sarsasapogenin in TNBS induced ulcerative colitis in rats associated with downregulation of pro-inflammatory mediators and oxidative stress.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel condition considered by oxido-nitrosative stress and the release of pro-inflammatory cytokines that affects the mucosal lining of the colon. Sarsasapogenin (SG), as an active component, has been found in many plants, and it exhibits potential protective effects, such as anti-inflammatory, antioxidant, anti-psoriasis, anti-arthritis, anti-asthma, anti-depressant and anti-cancer. However, the effects of SG on UC remain unknown. OBJECTIVE: The purpose of this study was to investigate the effects of SG on 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced UC in rats. METHOD: Thirty Wistar rats were randomized into five groups: (i) Normal control, (ii) Disease control (TNBS), (iii) Sarsasapogenin (SG) (50 µg/rat), (iv) Fluticasone (FC) (50 µg/rat), (v) Sarsasapogenin + Fluticasone (SG + FC) (25 µg/rat). UC was induced in rats by trans-rectal instillation of TNBS (10 mg/kg). SG, FC and SG + FC were administered for 11 days and on the 8th day colitis was induced. Several molecular, biochemical and histological alterations were evaluated in the colon tissue. All treatment group results were compared to the TNBS group results. RESULT: The study results revealed that treatment of rats with SG and SG + FC combination significantly decreased the colon weight/length ratio, macroscopic inflammation score, lesions score, diarrhea score and adhesion score. Combination treatment in rats significantly reduced the production of biochemical parameters, proinflammatory cytokines, haematological parameters, serum IgE levels and restored the oxidative stress markers. SG and SG + FC treatment also considerably restored the histopathological changes induced by TNBS. CONCLUSION: Thus, SG and SG + FC combination could alter the disease progression and could be a hopeful therapeutic target for the management of UC by reducing its dose in combination with FC to elude the long term adverse effects of FC.

Atopic dermatitis: new insight into the etiology, pathogenesis, diagnosis and novel treatment strategies.

Atopic dermatitis (AD) is the long-lasting chronic inflammatory skin condition associated with cutaneous hyper-reactivity and triggered by environmental factors. The attributes of AD include dry skin, pruritus, lichenification and frequent eczematous abrasions. This has a strong heritable aspect and typically occurs with asthma and allergic rhinitis. The complex pathological mechanism behind AD etiology is epidermal barrier destruction resulting in the lack of filaggrin protein that can induce inflammation and T-cell infiltration. T-helper 2 cell-mediated pathways also bear the responsibility of damage to the epidermal barrier. Certain causative factors for AD include microbial imbalance of skin microbiota, immunoglobulin-E-induced sensitization and neuro-inflammation. Numerous beneficial topical and oral treatments have been available to patients and there are even more drugs in the pipeline for the treatment of AD. Topical moisturizers, corticosteroids, anti-inflammatory agents such as calcineurin inhibitors, phototherapy, cAMP-specific 3, 5 half-cyclic phosphodiesterase 4 inhibitors and systemic immunosuppressants are widely available for AD treatments. Different positions and pathways inside the immune system including JAK-STAT, phosphodiesterase 4, aryl hydrocarbon receptor and T-helper 2 cytokines are targeted by above-mentioned drug treatments. Instead of the severe side effects of topical steroids and oral antihistamines, herbal plants and their derived phytoconstituents are commonly used for the treatment of AD. A clear understanding of AD's cellular and molecular pathogenesis through substantial advancement in genetics, skin immunology and psychological factors resulted in advancement of AD management. Therefore, the review highlights the recent advancements in the understanding of clinical features, etiology, pathogenesis, treatment and management and non-adherence to AD treatment.

Hecogenin and fluticasone combination attenuates TNBS-induced ulcerative colitis in rats via downregulation of pro-inflammatory mediators and oxidative stress.

OBJECTIVE: Ulcerative colitis is common types of severe, progressive, idiopathic inflammatory bowel disease that involves the mucosal lining of the large intestine. The purpose of the study is to explore the effects of hecogenin in TNBS (2, 4, 6- trinitrobenzene sulfonic acid) induced ulcerative colitis model in rats. MATERIAL AND METHODS: Thirty Wistar rats were randomized into five groups: (i) Normal Control (NC), (ii) Disease Control (DC), (iii) Hecogenin (HG) (50 µg/rat), (iv) Fluticasone (FC) (50 µg/rat), (v) Hecogenin + Fluticasone (HG + FC) combination (25 µg/rat). Colitis was induced by trans-rectal administration of TNBS using a catheter inserted 8 cm into the rectal portion of the rat. Colitis was evaluated by an independent observer who was blinded to the treatment. All treatment group results were compared to the TNBS group results. RESULTS: The study results revealed that treatment of rats with HG and HG + FC significantly improved the body weight and colon length whereas; decreased the spleen weight, colon weight/length ratio, macroscopic lesions score, diarrhea score and adhesion score. The drug treatment in rats substantially decreased the development of inflammatory cytokines, levels of serum immunoglobulin E, colonic nitric oxide contents and restoration of antioxidant stress markers. Histopathological colon sample study significantly reduced colonic inflammation with a substantial decrease in inflammation score. CONCLUSION: Thus, HG and HG + FC combination could change the pathogenesis of the disease and may be a potential therapeutic target for the treatment of ulcerative colitis by a reduction in dose in conjunction with FC to prevent the persistent adverse effects associated with FC.

Nanocarrier-Based Approaches for the Efficient Delivery of Anti-Tubercular Drugs and Vaccines for Management of Tuberculosis.

Drug-resistant species of tuberculosis (TB), which spread faster than traditiona TB, is a severely infectious disease. The conventional drug therapy used in the management of tuberculosis has several challenges linked with adverse effects. Hence, nanotherapeutics served as an emerging technique to overcome problems associated with current treatment. Nanotherapeutics helps to overcome toxicity and poor solubility issues of several drugs used in the management of tuberculosis. Due to their diameter and surface chemistry, nanocarriers encapsulated with antimicrobial drugs are readily taken up by macrophages. Macrophages play a crucial role as they serve as target sites for active and passive targeting for nanocarriers. The surface of the nanocarriers is coated with ligand-specific receptors, which further enhances drug concentration locally and indicates the therapeutic potential of nanocarriers. This review highlights tuberculosis's current facts, figures, challenges associated with conventional treatment, different nanocarrier-based systems, and its application in vaccine development.

Herbal and Natural Dietary Products: Upcoming Therapeutic Approach for Prevention and Treatment of Hepatocellular Carcinoma.

The most common tumor linked with elevated death rates is considered the hepatocellular carcinoma (HCC), sometimes called the malignant hepatoma. The initiation and progression of HCC are triggered by multiple factors like long term alcohol consumption, metabolic disorders, fatty liver disease, hepatitis B and C infection, age, and oxidative stress. Sorafenib is the merely US Food and Drug Administration (FDA)-approved drug used to treat HCC. Several treatment methods are available for HCC therapy such as chemotherapy, immunotherapy and adjuvant therapy but they often lead to several side effects. Yet these treatment methods are not entirely adequate due to the increasing resistance to the drug and their toxicity. Many natural products help to prevent and treat HCC. A variety of pathways are associated with the prevention and treatment of HCC with herbal products and their active components. Accumulating research shows that certain natural dietary compounds are possible source of hepatic cancer prevention and treatments, such as black currant, strawberries, plum, grapes, pomegranate, cruciferous crops, tomatoes, French beans, turmeric, garlic, ginger, asparagus, and many more. Such a dietary natural products and their active constituents may prevent the production and advancement of liver cancer in many ways such as guarding against liver carcinogens, improving the effectiveness of chemotherapeutic medications, inhibiting the growth, metastasis of tumor cells, reducing oxidative stress, and chronic inflammation. The present review article represents hepatic carcinoma etiology, role of herbal products, their active constituents, and dietary natural products for the prevention and treatment of HCC along with their possible mechanisms of action.

New perspectives in bronchial asthma: pathological, immunological alterations, biological targets, and pharmacotherapy.

Asthma is the most common, long-lasting inflammatory airway disease that affects more than 10% of the world population. It is characterized by bronchial narrowing, airway hyperresponsiveness, vasodilatation, airway edema, and stimulation of sensory nerve endings that lead to recurring events of breathlessness, wheezing, chest tightness, and coughing. It is the main reason for global morbidity and occurs as a result of the weakening of the immune system in response to exposure to allergens or environmental exposure. In asthma condition, it results in the activation of numerous inflammatory cells like the mast and dendritic cells along with the accumulation of activated eosinophils and lymphocytes at the inflammation site. The structural cells such as airway epithelial cells and smooth muscle cells release inflammatory mediators that promote the bronchial inflammation. Long-lasting bronchial inflammation can cause pathological alterations, viz. the improved thickness of the bronchial epithelium and friability of airway epithelial cells, epithelium fibrosis, hyperplasia, and hypertrophy of airway smooth muscle, angiogenesis, and mucus gland hyperplasia. The stimulation of bronchial epithelial cell would result in the release of inflammatory cytokines and chemokines that attract inflammatory cells into bronchial airways and plays an important role in asthma. Asthma patients who do not respond to marketed antiasthmatic drugs needed novel biological medications to regulate the asthmatic situation. The present review enumerates various types of asthma, etiological factors, and in vivo animal models for the induction of asthma. The underlying pathological, immunological mechanism of action, the role of inflammatory mediators, the effect of inflammation on the bronchial airways, newer treatment approaches, and novel biological targets of asthma have been discussed in this review.

Combination of Sarsasapogenin and Fluticasone attenuates ovalbumin-induced airway inflammation in a mouse asthma model.

Objective: Asthma is a very common airway inflammatory disease for which the existing drug therapy options are insufficient. In this study, we explored the mechanisms underlying the anti-inflammatory potential of Sarsapogenin (SG) and its combination with Fluticasone (FC) in ovalbumin (OVA)-induced allergic asthma in mice.Methods: In a standard experimental model, asthma in mice was sensitized and challenged by OVA. The mice were treated with SG and SG + FC during OVA challenge. At the completion, lung weight, inflammatory cell count in bronchoalveolar lavage fluid (BALF), serum cytokines levels, immunoglobulin E (IgE) levels, lung nitrate/nitrite (NO) levels, and lung tissue oxidative stress biomarkers were determined. Histopathological evaluation of the lung tissue was also performed.Key findings: Treatment of mice with SG and SG + FC combination intensely diminished the trafficking of total and differential inflammatory cells count into BALF. SG and SG + FC administration significantly reduced the production of inflammatory cytokines, serum IgE levels and restoration of antioxidant stress markers. Histopathological analysis of lung samples effectually weakened bronchial inflammation and mucus production in the lung with a significant reduction in inflammation and mucus score.Conclusion: Our study results suggested that SG and SG + FC effectively reduced allergic airway inflammation via inhibiting pro-inflammatory cytokines, NO expressions and oxidative stress parameters. So, it could be used as a therapeutic potential agent for the treatment of asthma by decreasing its dose in combination with FC to avoid the chronic adverse effects of FC.

New insights into the novel anti-inflammatory mode of action of glucocorticoids.

Inflammation is a physiological intrinsic host response to injury meant for removal of noxious stimuli and maintenance of homeostasis. It is a defensive body mechanism that involves immune cells, blood vessels and molecular mediators of inflammation. Glucocorticoids (GCs) are steroidal hormones responsible for regulation of homeostatic and metabolic functions of body. Synthetic GCs are the most useful anti-inflammatory drugs used for the treatment of chronic inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD), allergies, multiple sclerosis, tendinitis, lupus, atopic dermatitis, ulcerative colitis, rheumatoid arthritis and osteoarthritis whereas, the long term use of GCs are associated with many side effects. The anti-inflammatory and immunosuppressive (desired) effects of GCs are usually mediated by transrepression mechanism whereas; the metabolic and toxic (undesired) effects are usually manifested by transactivation mechanism. Though GCs are most potent anti-inflammatory and immunosuppressive drugs, the common problem associated with their use is GC resistance. Several research studies are rising to comprehend these mechanisms, which would be helpful in improving the GC resistance in asthma and COPD patients. This review aims to focus on identification of new drug targets in inflammation which will be helpful in the resolution of inflammation. The ample understanding of GC mechanisms of action helps in the development of novel anti-inflammatory drugs for the treatment of inflammatory and autoimmune disease with reduced side effects and minimal toxicity.

Anti-inflammatory potential of hecogenin on atopic dermatitis and airway hyper-responsiveness by regulation of pro-inflammatory cytokines.

Objective: Hecogenin is a sapogenin found in Agave sisalana species that is used extensively for the treatment of anti-inflammatory, antifungal, hypotensive, anti-nociceptive activity and cancer. We have studied the anti-inflammatory effect of Hecogenin and its combination with Fluticasone on atopic dermatitis and airway hyper-responsiveness in Balb/c mice. Material and methods: Dermatitis was induced by repeated application of 2, 4-dinitrofluorobenzene in Balb/c mice. After a topical application of Hecogenin, Fluticasone and their combination on the skin lesions, the ear thickness, ear weight and erythema score were evaluated. Asthma was induced by sensitization and challenge of ovalbumin in Balb/c mice. Results: The topical application of Hecogenin and its combination with Fluticasone in mice effectively suppressed the ear swelling and weight. As well as the levels of pro-inflammatory cytokines were decreased by Hecogenin and its combination in-vivo. Whereas, intra-nasal administration of Hecogenin and its combination in ovalbumin induced airway hyper-responsiveness reveals a significant decrement in total cell count, differential cell count and cytokines levels. Similar observations were obtained for myeloperoxidase level in ear and lung tissue. The results were supported by histological studies of ear and lung tissue. Conclusion: These data indicate that Hecogenin has been proved as a potential therapy for allergic skin diseases and bronchial asthma treatments in combination with Fluticasone by reducing its dose from 50 to 25 µg/mice in combination to circumvent the long term side effects of Fluticasone. The beneficial effect of Hecogenin may be related to the diminution of TNF-α and IL-12 cytokines production in Balb/c mice.

Optimization and characterization of sertaconazole nitrate flexisomes embedded in hydrogel for improved antifungal activity.

The aim of the present research work was to develop, characterize and optimize sertaconazole nitrate (STZN) embedded flexisomes (STZN-FS) to improve the cutaneous anti-fungal activity of STZN. Flexisomes are self-aggregating, flexible, deformable lipidic vesicles possessing an aqueous core. A 32 factorial design was implemented to optimize the effects of the critical material attributes of concentration of phospholipid (X1) and edge activator (X2) on the critical quality attributes of particle size (Y1), entrapment efficiency (Y2), and deformability index (Y3). Statistical analysis was performed to be identify the best fit model and determine its significance. The sizes of the optimized STZN-FS were found to be 246.2 ± 2.49 nm with entrapment efficiencies of 86.16 ± 0.56% and deformability indices of 30.46 ± 0.41. Zeta potential analysis showed negatively charged surface with a zeta potential value of -30.9 mV. TEM analysis showed spherical shapes, confirming the vesicular characteristics. The optimized STZN-FS were further formulated into hydrogels. The % drug diffusion of STZN-FS hydrogels was found to be 13.24% and drug deposition in the skin layers was found to be 83.54%, showing that a high concentration of the drug was available at the site of action. The zone of inhibition STZN-FS hydrogel (30 mm) was higher than the marketed formulation (22 mm) and the plain STZN hydrogel (14 mm) against Candida albicans. From the above studies, it was concluded that STZN loaded STZN-FS shows high flexibility and enhanced antifungal activity. STZN-FS are thus found to be potential carriers for drug deposition in skin layers without disturbing their integrity.

A coupled bimodal SPECT-CT imaging and brain kinetics studies of zolmitriptan-encapsulated nanostructured polymeric carriers.

The present investigation deals with preparation and characterization of anti-migraine zolmitriptan (ZMT) nanostructured polymeric carriers for nose to brain drug targeting. The drug-loaded colloidal nanocarriers of ZMT were prepared by modified ionic gelation of cationic chitosan with anionic sodium tripolyphosphate and characterized for particle size, zeta potential, and entrapment efficiency. Further, in order to investigate nose to brain drug targeting, biodistribution, and brain kinetics studies were performed using 99mtechnetium radiolabeled nanocarriers (99mTc-ZMTNP) in Swiss albino mice. The results were compared with intranasal pure drug solution (99mTc-ZMT) and intravenous nanocarriers (99mTc-ZMTNP). A single photon emission computerized tomography (SPECT) radioimaging studies were also carried out to visualize and confirm brain uptake of nanocarriers. The optimized nanocarriers showed particle size of 161 nm, entrapment efficiency of 80.6%, and zeta potential of + 23.7 mV. The pharmacokinetic parameters, Cmax, and AUC0-∞ values for ZMT concentration in the brain expressed as percent radioactivity per gram of brain in intranasal and intravenous route of administration were calculated. The brain Cmax and AUC0-∞ values found in three groups, intranasal 99mTc-ZMTNP, intranasal 99mTc-ZMT, and intravenous 99mTc-ZMTNP were (0.427 and 1.889), (0.272 and 0.7157), and (0.204 and 0.9333), respectively. The higher Cmax values of intranasal 99mTc-ZMTNP suggests better brain uptake as compared to other routes of administration. The significant higher values of nose to brain targeting parameters namely, drug targeting index (5.57), drug targeting efficiency (557.08%), and nose to brain drug direct transport (82.05%) confirmed drug targeting to brain via nasal route. The coupled bimodal SPECT-CT scintigrams confirm the brain uptake of intranasal 99mTc-ZMTNP demonstrating major radioactivity accumulation in brain. This study conclusively demonstrated the greater uptake of ZMT-loaded nanocarriers by nose to brain drug targeting, which proves promising drug delivery system.

An emphasis on molecular mechanisms of anti-inflammatory effects and glucocorticoid resistance.

Glucocorticoids (GC) are universally accepted agents for the treatment of anti-inflammatory and immunosuppressive disorders. They are used in the treatment of rheumatic diseases and various inflammatory diseases such as allergy, asthma and sepsis. They bind with GC receptor (GR) and form GC-GR complex with the receptor and exert their actions. On activation the GC-GR complex up-regulates the expression of nucleus anti-inflammatory proteins called as transactivation and down-regulates the expression of cytoplasmic pro-inflammatory proteins called as transrepression. It has been observed that transactivation mechanisms are notorious for side effects and transrepressive mechanisms are identified for beneficial anti-inflammatory effects of GC therapy. GC hampers the function of numerous inflammatory mediators such as cytokines, chemokines, adhesion molecules, arachidonic acid metabolites, release of platelet-activating factor (PAF), inflammatory peptides and enzyme modulation involved in the process of inflammation. The GC resistance is a serious therapeutic problem and limits the therapeutic response of GC in chronic inflammatory patients. It has been observed that the GC resistance can be attributed to cellular microenvironment changes, as a consequence of chronic inflammation. Various other factors responsible for resistance have been identified, including alterations in both GR-dependent and GR-independent signaling pathways of cytokine action, hypoxia, oxidative stress, allergen exposure and serum-derived factors. The present review enumerates various aspects of inflammation such as use of GC for treatment of inflammation and its mechanism of action. Molecular mechanisms of anti-inflammatory action of GC and GC resistance, alternative anti-inflammatory treatments and new strategy for reversing the GC resistance have also been discussed.

Models of hepatotoxicity and the underlying cellular, biochemical and immunological mechanism(s): a critical discussion.

Liver is a primary organ involved in biotransformation of food and drugs. Hepatic diseases are a major worldwide problem. Hepatic disorders are mainly caused by toxic chemicals (alcohol), xenobiotics (carbon tetrachloride, chlorinated hydrocarbons and gases CO2 and O2) anticancer (azathioprine, doxorubicin, cisplatin), immunosuppressant (cyclosporine), analgesic anti-inflammatory (paracetamol, thioacetamide), anti-tubercular (isoniazid, rifampicin) drugs, biologicals (Bacillus-Calmette-Guerin vaccine), radiations (gamma radiations), heavy metals (cadmium, arsenic), mycotoxin (aflatoxin), galactosamine, lipopolysaccharides, etc. Various risk factors for hepatic injury include concomitant hepatic diseases, age, gender, alcoholism, nutrition and genetic polymorphisms of cytochrome P450 enzymes have also been emphasized. The present review enumerates various in vivo animal models and in vitro methods of hepatic injury using diverse toxicants, their probable metabolic pathways, and numerous biochemical changes viz. serum biomarkers enzymes, liver function, oxidative stress associated events like free radicals formation, lipid peroxidation, enzyme antioxidants and participation of cytokines (tumour necrosis factor-α, transforming growth factor-ß, tumour necrosis factor-related apoptosis inducing ligand), and other biomolecules (Fas and C-jun N-terminal kinase) are also discussed. The underlying cellular, molecular, immunological, and biochemical mechanism(s) of action responsible for liver damage (toxicity) are also been discussed. This review should be immensely useful for researchers especially for phytochemists, pharmacologists and toxicologists working on hepatotoxicity, hepatotoxic chemicals and drugs, hepatoprotective agents and drug research organizations involved especially in phytopharmaceuticals and other natural products.

Halobetasol propionate-loaded solid lipid nanoparticles (SLN) for skin targeting by topical delivery.

The clinical use of halobetasol propionate (HP) is related to some adverse effects like irritation, pruritus and stinging. The purpose of this work was to construct HP-loaded solid lipid nanoparticles (HP-SLN) formulation with skin targeting to minimizing the adverse side effects and providing a controlled release. HP-SLN were prepared by solvent injection method and formula was optimized by the application of 3(2) factorial design. The nanoparticulate dispersion was evaluated for particle size and entrapment efficiency (EE). Optimized batch was characterized for differential scanning calorimetry (DSC), scanning electron microscopy, X-ray diffraction study and finally incorporated into polymeric gels of carbopol for convenient application. The nanoparticulate gels were evaluated comparatively with the commercial product with respect to ex-vivo skin permeation and deposition study on human cadaver skins and finally skin irritation study. HP-SLN showed average size between 200 nm and 84-94% EE. DSC studies revealed no drug-excipient incompatibility and amorphous dispersed of HP in SLN. Ex vivo study of HP-SLN loaded gel exhibited prolonged drug release up to 12 h where as in vitro drug deposition and skin irritation studies showed that HP-SLN formulation can avoid the systemic uptake, better accumulative uptake of the drug and nonirritant to the skin compared to marketed formulation. These results indicate that the studied HP-SLN formulation represent a promising carrier for topical delivery of HP, having controlled drug release, and potential of skin targeting with no skin irritation.