Artificial intelligence revolutionizing drug development: Exploring opportunities and challenges.

By harnessing artificial intelligence (AI) algorithms and machine learning techniques, the entire drug discovery process stands to undergo a profound transformation, offering a myriad of advantages. Foremost among these is the ability of AI to conduct swift and efficient screenings of expansive compound libraries, significantly augmenting the identification of potential drug candidates. Moreover, AI algorithms can prove instrumental in predicting the efficacy and safety profiles of candidate compounds, thus endowing invaluable insights and reducing reliance on extensive preclinical and clinical testing. This predictive capacity of AI has the potential to streamline the drug development pipeline and enhance the success rate of clinical trials, ultimately resulting in the emergence of more efficacious and safer therapeutic agents. However, the deployment of AI in drug discovery introduces certain challenges that warrant attention. A primary hurdle entails the imperative acquisition of high-quality and diverse data. Furthermore, ensuring the interpretability of AI models assumes critical importance in securing regulatory endorsement and cultivating trust within scientific and medical communities. Addressing ethical considerations, including data privacy and mitigating bias, represents an additional momentous challenge, requiring assiduous navigation. In this review, we provide an intricate and comprehensive overview of the multifaceted challenges intrinsic to conventional drug development paradigms, while simultaneously interrogating the efficacy of AI in effectively surmounting these formidable obstacles.

Effect of Curcumin and Coenzyme Q10 Alone and in Combination on Learning and Memory in an Animal Model of Alzheimer's Disease.

The most frequent neurodegenerative illness among senior people and the main cause of dementia is Alzheimer's disease. The present dementia medications available only help with the symptoms of cognitive deficits and have several negative effects. The current study's goal is to assess the effects of curcumin and coenzyme Q10, two herbal medicines, both separately and in combination, on learning and memory before comparing them to the industry standard drug. A total of 42 adult healthy Wistar rats were used in our study. In this experiment, rats were given daily doses of 2.5 mg/kg of body weight of scopolamine hydrobromide for 7 days to induce Alzheimer's disease. On the eighth day, behavioural testing was conducted. Following testing, scopolamine and the test medications were given daily for the following 21 days. On days 29 and 30, behavioural testing was conducted once more, and then animals were slaughtered. Brain homogenate was produced for the estimation of molecular and biochemical markers. Curcumin has demonstrated a dose-response relationship, with a higher dose (200 mg/kg b.w. p.o.) being more effective than a lower dose (100 mg/kg b.w. p.o.). Similar to the greater dose of curcumin, coenzyme Q10 (200 mg/kg b.w. p.o.) has also been found to improve memory and learning. Higher doses of curcumin and coenzyme Q10 had more pronounced and meaningful effects. Acetylcholinesterase and TNF levels increased in scopolamine-induced memory impairment, but these effects were restored by the test medications, and improved by the combined therapy. These outcomes are comparable to those of the common medication memantine. As a result, we may infer from our results that curcumin at higher doses and its combination with coenzyme Q10 (200 mg/kg b.w. p.o.) have a significant impact on cognitive impairment in animal models of Alzheimer's disease and can be utilised alone or as an add-on therapy for the condition.

Comparative evaluation of intranasal midazolam-ketamine, dexmedetomidine-ketamine, midazolam-fentanyl, and dexmedetomidine-fentanyl combinations for procedural sedation and analgesia in pediatric dental patients: a randomized controlled trial.

Background: In order to assess the effectiveness of various analgesio-sedative combinations for pain relief and sedation in pediatric dental patients, a thorough evaluation of clinical studies and patient outcomes is necessary. Methods: A total of 128 healthy, uncooperative pediatric dental patients were randomly allocated to receive one of the four combinations of drugs via the intranasal (IN) route: Group I received midazolam-ketamine (MK), Group II received dexmedetomidine-ketamine (DK), Group III received midazolam-fentanyl (MF), and Group IV received dexmedetomidine-fentanyl (DF) in a parallel-arm study design. The efficacy and safety of the combinations were evaluated using different parameters. Results: The onset of sedation was significantly faster in the DF group than in the DK, MF, and MK groups (P < 0.001). The depth of sedation was significantly higher in the DK and DF groups than in the MK and MF groups (P < 0.01). DK and DF produced significant intra- and postoperative analgesia when compared with combinations of MK and MF. No significant adverse events were observed for any of the combinations. Conclusions: The DK and DF groups showed potential as analgesio-sedatives in view of their anxiolytic and analgesic effects.

Anti-oxidative and anti-neuroinflammatory role of Necrostatin-1s and docosahexaenoic acid in RIP-1-mediated neurotoxicity in MPTP-induced Parkinson's disease model.

Parkinson's disease (PD) is a neuromuscular ailment that affects people in their later years and causes both motor and non-motor deficits. Receptor-interacting protein-1 (RIP-1) is a critical participant in necroptotic cell death, possibly through an oxidant-antioxidant imbalance and cytokine cascade activation in PD pathogenesis. The present study examined the role of RIP-1-mediated necroptosis and neuroinflammation in the MPTP-induced PD mouse model, as well as their protection by Necrostatin-1s (an RIP signalling inhibitor), antioxidant DHA and their functional interaction. BALB/c mice were given acute MPTP therapy (4 injections of 15 mg/kg i.p. at 2-h intervals) on day 1. After MPTP intoxication, Necrostatin-1s (Nec-1s; 8 mg/kg/day, i.p.) and DHA (300 mg/kg/day, p.o.) treatments were given once daily for 7 days. The Nec-1s treatment prevented MPTP-induced behavioural, biochemical and neurochemical alterations, and the addition of DHA increases Nec-1s' neuroprotective impact. In addition, Nec-1s and DHA significantly improve the survival of TH-positive dopaminergic neurons and lower expression levels of the inflammatory cytokines, IL-1ß and TNF-α. Furthermore, Nec-1s dramatically reduced RIP-1 expression, whereas DHA had little effect. Our research raises the possibility that neuroinflammatory signalling and acute MPTP-induced necroptosis are both mediated by TNFR1-driven RIP-1 activity. In this study, RIP-1 ablation through Nec-1s and the addition of DHA showed a reduction in the levels of pro-inflammatory and oxidative markers, as well as protection from MPTP-driven dopaminergic degeneration and neurobehavioural changes, suggesting potential therapeutic applications. For a better understanding, additional research about the mechanism(s) behind Nec-1s and DHA is required.

Neuroprotective role of chloroquine via modulation of autophagy and neuroinflammation in MPTP-induced Parkinson's disease.

Parkinson's disease (PD) is a neuro-motor ailment that strikes adults in their older life and results in both motor and non-motor impairments. In neuronal and glial cells, PD has recently been linked to a dysregulated autophagic system and cerebral inflammation. Chloroquine (CQ), an anti-malarial drug, has been demonstrated to suppress autophagy in a variety of diseases, including cerebral ischemia, Alzheimer's disease (AD), and Traumatic brain injury (TBI), while its involvement in PD is still unclear. BALB/c mice were randomly allocated to one of four groups: 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), CQ treatment with or without MPTP, or control. The CQ treatment group received CQ (intraperitoneally, 8 mg/kg body weight) after 1 h of MPTP induction on day 1, and it lasted for 7 days. CQ therapy preserves dopamine levels stable, inhibits tyrosine hydroxylase (TH) positive dopaminergic cell death, and lowers oxidative stress. CQ reduces the behavioural, motor, and cognitive deficits caused by MPTP after injury. Furthermore, CQ therapy slowed aberrant neuronal autophagy (microtubule-associated protein-1 light chain 3B; LC3B & Beclin1) and lowered expression levels of the inflammatory cytokines interleukin 1 (IL-1ß) and tumour necrosis factor (TNF-α) in the mice brain. In addition, CQ's antioxidant and anti-inflammatory effects were also tested in MPTP-mediated cell death in PC12 cells, demonstrating that CQ has a neurorestorative impact by successfully rescuing MPTP-induced ROS generation and cell loss. Our findings show that CQ's can help to prevent dopaminergic degeneration and improve neurological function after MPTP intoxication by lowering the harmful effects of neuronal autophagy and cerebral inflammation.

Effects of mangiferin and its combination with nNOS inhibitor 7-nitro-indazole (7-NI) in 6-hydroxydopamine (6-OHDA) lesioned Parkinson's disease rats.

Nitric oxide (NO), generated by nitric oxide synthase enzymes (NOS), has an important role in maintaining synapse plasticity, neuro-modulation, and other physiological functions in the brain. NO thus generated also has a key role in formation of reactive oxygen and reactive nitrite species and subsequent neuronal damage due to sustained oxidative stress. Due to its property of ROS and RNOS generation, NO plays a significant role in Parkinson's disease (PD) pathogenesis. Therefore, we evaluated the effect of mangiferin alone and in combination with nNOS inhibitor 7-nitro-indazole (7-NI) in 6-OHDA lesioned rats. Male Wistar rats weighing 200-250 g (n = 8/group) were used in the study. Stereotactic surgeries of rats were done to induce 6-OHDA lesioning in rats. Then, treatment with mangiferin alone and in combination with 7-NI 10 mg/kg was done from days 14 to 42 for 28 days. On day 42, rats were subjected to behavioral studies, and their brains were taken out after euthanasia to perform biochemical and molecular studies. Treatment with mangiferin and 7-NI significantly increases locomotor parameters in 6-OHDA lesioned rats. Treatment with mangiferin 45 µg and 7-NI 10 mg/kg alone and in combination significantly reduces oxidative stress along with decrease in concentration of pro-inflammatory cytokines, cyclooxygenase 2, total nitrite (NOx) and FOS B concentration. Results of this study suggest that treatment with 7-NI 10 mg/kg further enhances anti-inflammatory and anti-parkinsonism activity of mangiferin owing to its property of inhibiting nNOS mediated FOS B signaling and thereby inhibiting mRNA formation of TNF-α and IL-6.

A prospective observational study to evaluate Glutathione S-transferase gene polymorphism and its association with Antitubercular drugs induced liver injury in tertiary hospital.

BACKGROUND: Anti-TB drugs are most common cause of idiosyncratic hepatotoxicity worldwide. Reactive metabolite formed during drug metabolism has been involved in a clinical toxicity are described as 'idiosyncratic' drug induce liver injury (DILI). We have observed the distribution of glutathione S -transferase (GST) gene polymorphism & its association with drug-induced liver injury in patients taking anti-tubercular treatment. METHODS: A prospective observational study including 96 patients receiving anti-tubercular treatment. Blood sample was collected for LFT and gene extraction after ruling out other cause of liver injury. DNA extraction for GST gene was done follow by polymerase chain reaction to identify homozygous null mutation at GSTM1 and GSTT1 loci. Association of GSTM1 and GSTT1 gene with DILI was seen. RESULTS: Out of 96 tubercular patients under treatment, drug induced liver injury was found in 21 (21.9%) patients and 75 does not develop DILI, GST M1 gene null mutation was observed in 14 (66.7%), GST T1 gene null mutation was observed in 9 (42.9%), Both GST gene null mutation was observed in 8 (38.1%) in DILI group. CONCLUSION: The GSTM1 gene null mutation and both GSTM1 and T1 gene null mutation were a risk factor for the development of DILI. But there is no significant association between GSTT1 gene null mutation and DILI in TB patients.

SNPs of FOXO1 and Their Interactions Contributes to the Enhanced Risk of Diabetes Among Elderly Individuals.

We have assessed the impact of three single nucleotide polymorphisms (SNPs) of Forkhead Box O1 (FOXO1) and their interaction on susceptibility of type 2 diabetes mellitus in geriatric population from northern India. We genotyped three SNPs (rs2721068, rs17446614, and rs4581585) of FOXO1 gene in 190 elderly individuals with diabetes and 182 unrelated healthy controls of similar ethnicity by using TaqMan SNP assays. SNP-SNP and SNP-environment interactions among polymorphic loci were studied by the multifactor dimensionality reduction (MDR) method. The AA genotype carriers of rs17446614 was associated with the increased susceptibility of diabetes in both adjusted and unadjusted model, whereas rs4581585 was associated with the risk in unadjusted model only. Genotype and minor allele interaction with quantitative parameters revealed that AA genotype of rs17446614 had significantly higher fasting plasma glucose (FPG) in diabetic subjects, also minor allele (A) in patients was positively associated with FPG and glycated hemoglobin. Haplotype Trs2721068Grs17446614Trs4581585 increases the risk of diabetes, whereas carrier of haplotypes Crs2721068Grs17446614Crs4581585 and Crs2721068 Grs17446614Trs4581585 were protective. The MDR analysis revealed that interaction of rs17446614 with body mass index (BMI) increased the susceptibility of diabetes. Therefore presence of rs17446614 variant and its interaction with BMI and haplotype Trs2721068Grs17446614Trs4581585 modulates the risk of diabetes and can be used as a promising tool for identifying high-risk individuals.

No Association Between a Genetic Variant of FOXO3 and Risk of Type 2 Diabetes Mellitus in the Elderly Population of North India.

Aging can be considered an evolutionary process that is modulated by various genetic and biochemical processes. Therefore the genetic variants may interplay a role in human longevity as well as age related illness. Forkhead Box O (FOXO) gene is one of the major defensive genes that are known for ameliorating lifespan. FOXO proteins act as nuclear transcription factors that facilitate the action of insulin or insulin-like growth factor (IGF-1) in various physiological processes. The rationale of our study is to find out association between genetic variant rs2253310 of FOXO3 and risk of Type 2 Diabetes Mellitus (T2DM) in elderly population. This case control study involved 172 age sex matched elderly subjects while patients were recruited as per IDF criteria. Clinical, biochemical, ELISA methods were employed for assesement of clinical samples while Taqman method was used for genotyping analysis. Our results revealed that there was no significant difference in genotypic and allelic frequencies for the tested SNP (p > 0.05) between elderly T2DM patients and controls. The SNP rs2253310 was not associated with risk of T2DM in any genetic model. Also no association was found among the studied group between FOXO3 variant and HOMA-IR, HOMA-B index and Fasting plasma glucose. Serum level of inflammatory markers like CRP and TNF-α was significantly higher in patients but its not associated with SNP rs2253310. Our study concluded that, this intronic longevity-associated variant rs2253310 in FOXO3 is not associated with type 2 diabetes in geriatric patients of northern India.

Pharmacological, Biochemical and Immunological Studies on Protective Effect of Mangiferin in 6-Hydroxydopamine (6-OHDA)-Induced Parkinson's Disease in Rats.

Background: Parkinson's disease is a neurodegenerative disorder and is marked by inflammation and death of neurons in the striatum region of the midbrain. It has been reported that expression of NF-κB increases during Parkinson's disease, which promotes oxidative stress, stimulates release of proinflammatory cytokines, and induces expression of nitric oxide. Therefore, in this study, we have used mangiferin a specific NF-κB inhibitor. Mangiferin is a polyphenolic compound traditionally used for its antioxidant and anti-inflammatory properties. Methods: The study utilized male Wistar rats weighing 200-250 g (56 rats; n = 8/group). On day "0," stereotaxic surgery of rats was done to induce 6-hydroxydopamine lesioning in rats. Coordinates for substantia nigra were anteroposterior-2 mm, mediolateral-5 mm and dorsoventral-8.2 mm. After 14 days, those rats which show at least 210 contralateral rotations after administration of apomorphine (0.5 mg/kg S.C.) were selected for the study and were given treatment for 28 days. On day 28 of treatment, rats were subjected to behavioral studies to evaluate the effect of mangiferin and their brains were taken out after euthanasia to perform biochemical, molecular and immunological studies. Results: Treatment with mangiferin significantly improves the key parameters of locomotor activity and oxidative stress and reduces the parameters of inflammatory stress. Also, the activity of caspases was reduced. Significant decrease in activity of both cyclooxygenase 1 and 2 was also observed. Maximum improvement in all parameters was observed in rats treated with grouping of mangiferin 45 µg/kg and levodopa 10 mg/kg. Treatment with levodopa alone has no significant effect on biochemical and molecular parameters though it significantly improves behavioral parameters. Conclusion: Current treatment of Parkinson's disease does not target progression of Parkinson's disease. Results of this study suggest that mangiferin has protective effect in hemi-Parkinsonian rats. Therefore, the combination therapy of mangiferin and levodopa can be helpful in management of Parkinson's disease.

Synthesis and biological evaluation of imidazoline derivatives as potential CNS and CVS agents.

A series of substituted imidazoline derivatives were synthesized and characterized. Compounds were tested in-vivo for their antihypertensive, analgesic, antiaggressive, depressant, antidepressant, and ALD50 activities. The compounds 3a, 3c, 4c, 5a, and 6c showed cardiovascular as well as central nervous system activities and are potential candidate as drug among all fifteen compounds tested. All these compounds have shown better activity for antihypertensive, analgesic, antiaggressive, and depressant-antidepressant, properties than reference compounds clonidine, morphine, diazepam, and imipramine respectively. Most of the compounds have shown ALD50 > 500 mg/kg with maximum in 4a and 5a (>1000 mg/kg).

QSAR modeling and docking analysis of D2 receptor with known olanzapine derivatives.

Dopamine (D2) receptors are known drug targets for various antipsychotics used in Schizophrenia. Therefore, it is of interest to analyze the binding features of D2 receptors with known olanzapine derivatives for further consideration using molecular docking and QSAR analysis. A 2D QSAR model was built using energy-based descriptors generated by docking as independent variable and known Ki value of Olanzapine derivatives with D2 Receptor as dependent variable. QSAR model provided coefficient of determination of r2 of 0.7 in multiple linear regression analysis. The predictive performance of QSAR model was assessed using different cross-validation procedures. Thus, data shows that a ligand-receptor binding interaction for D2 Receptor using a QSAR model is promising approach to design novel and potent inhibitors of D2 Receptor.

Omega-3 fatty acid attenuates oxidative stress in cerebral cortex, cerebellum, and hippocampus tissue and improves neurobehavioral activity in chronic lead-induced neurotoxicity.

Objectives: In view of the increasing risk of lead on human health, the present study has been carried out to investigate the neuroprotective effect of omega-3 fatty acid on chronic lead-induced neurotoxicity and behavioral impairment in rats. Methods: Different neurobehavioral parameters, biochemical assays, and histopathological analyses in brain regions of rats were conducted. Results: Rats exposed to different doses of lead (lead acetate 2.5, 5.0, 7.5 mg/kg body weight p.o. for 90 days) caused a significant decrease in body weight, brain weight, and behavioral changes as compared to controls. Abnormal histopathological and increased levels of lead in blood and brain regions increased the levels of ROS, LPO, PCC and decreased the levels of GSH with concomitant reduction in SOD, CAT, and GPx activities in the brain region of rats treated with different doses of lead as compared to controls. Co-treatment of lead with omega-3 fatty acid (500 mg/kg body weight p.o. for 90 days) decreased the levels of ROS, LPO, PCC, and increased the level of GSH, also increased SOD, CAT, and GPx activity and showed improvements in behavioral as well as histopathological changes as compared to lead-treated groups. Discussion: Our results proved that omega-3 fatty acid improved behavioral deficits, altered histopathological and oxidative stress in lead-intoxicated rats. Among three different doses, 2.5 mg/kg b.wt. of lead along with omega-3 fatty acid was the most preventive dose for the neurotoxicity. This work reveals the potential of omega-fatty acid as a protective drug for lead neurotoxicity.

Pharmacological and biochemical studies on protective effects of mangiferin and its interaction with nitric oxide (NO) modulators in adjuvant-induced changes in arthritic parameters, inflammatory, and oxidative biomarkers in rats.

Current study was designed to evaluate protective effect of mangiferin and its interaction with low dose of nitric oxide (NO) modulators in complete Freund's adjuvant (CFA) inoculated rats. Male wistar rats (200-300 g, n = 8 per group) were used in the study. On day ''0'' of study arthritis was induced in rats by injecting 0.2 ml CFA in sub-planter region of right hind paw of animals. Treatment with methotrexate (5 mg/kg), mangiferin (10-30 mg/kg) alone and in combination with NO modulators was given (i.p.) from days 14 to 28. After 28 days, blood and joint synovial fluid was collected for biochemical analysis and rat paws were excised to estimate MDA and SOD in tissue (paw) homogenates. CFA inoculation significantly increases (1) arthritic index, (2) ankle diameter, (3) paw volume, and (4) serum TNF-α, IL-6, IL-1ß, and synovial TNF-α levels (p < 0.001). The serum Th1 (IFN-γ) and Th2 (IL-4) cytokine levels, MDA levels in rat paw tissue homogenates and serum NF-κB levels were also found significantly increased. Significant decrease in serum IL-10 levels and SOD activity was found after CFA inoculation. These CFA-induced arthritic changes, cytokine profile, and oxidative stress markers were significantly reversed by mangiferin (10-30 mg/kg) treatment alone and in combination with L-arginine and L-NAME nitric oxide modulators (p < 0.05). Treatment with methotrexate (5 mg/kg) also significantly reversed these adjuvant changes (p < 0.05). However, effect of methotrexate was less marked as compared to mangiferin (30 mg/kg) alone and in combination with L-NAME (10 mg/kg), but was comparable or slightly better than mangiferin (10 and 20 mg/kg). Thus, on the basis of our findings, we can suggest that interaction of mangiferin with nitric oxide modulators may have therapeutic value for chronic inflammatory disease such as RA.

Attenuation of Lead-Induced Neurotoxicity by Omega-3 Fatty Acid in Rats.

BACKGROUND: Lead is widely distributed in the environment and has been found to be associated with various health problems including neurodegenerative diseases. PURPOSE: In view of the increasing health risk caused by lead, this study has been carried out to investigate the neuroprotective effect of omega-3 fatty acid (omega-3FA) in lead-induced neurotoxicity in rats. METHODS: Biochemical parameters including oxidative stress in brain regions, lead levels in blood and brain regions and histopathological examination of brain regions of rats were carried out in the present study. RESULTS: Rats exposed to lead (lead acetate 7.5 mg/kg body weight p.o. for 14 days) caused a significant increase in the levels of lipid peroxidation, protein carbonyl content, ROS production and decreased the activities of glutathione peroxidase, superoxide dismutase and catalase in the cerebellum and cerebral cortex, respectively, as compared to controls. Abnormal histopathological changes and increase in the levels of lead in blood and brain were also observed as compared to controls. Co-treatment of lead with omega-3FA (750 mg/kg body weight p.o. for 14 days) decreased the levels of lipid peroxidation, protein carbonyl content, ROS production and increased the activities of glutathione peroxidase, superoxide dismutase and catalase and showed protection in the histopathological study as compared to rats treated with lead alone. CONCLUSIONS: The result of the present study shows that lead-induced oxidative stress and histopathological alteration in the brain region were significantly protected with co-treatment of lead and omega-3FA. This could be due to its strong antioxidant potential and metal-binding property.

Hypolipidaemic Effects of Gymnema sylvestre on High Fat Diet Induced Dyslipidaemia in Wistar Rats.

INTRODUCTION: Hyperlipidaemia is a well known risk factor for cardiovascular diseases. Lifestyle modification can be the initial step to reduce cholesterol levels. There are various drugs which are used to control dyslipidaemia. Treatment of lipid abnormalities is a lifelong battle. Moreover, the safety and effectiveness of long term lipid lowering treatment are questionable. Gymnema Sylvestre (GS) is a well known herb with various medicinal properties. AIM: To explore the hypolipidaemic activity of GS leaves extract. MATERIALS AND METHODS: Adult healthy female wistar rats, 30 in number, divided into five groups, weighing 150- 200 g were used. Dyslipidaemia was induced in rats by feeding them on high fat diet for four weeks. For the next four weeks GS extract was used as test drug while Atorvastatin was used as standard drug. Blood sample was collected for estimation of lipid profile on day 0, week 4 and week 8. Data was recorded as mean±SEM (Standard error of mean). Paired t-test and one way Analysis of Variance (ANOVA) followed by Dunnett's post hoc test was used for comparison. A p-value <0.05 was considered statistically significant. SPSS Statistics 20 (IBM software) was used for the analysis. RESULTS: Feeding rats with high fat diet for four weeks led to obesity and dyslipidaemia in rats. GS at both the doses (100mg/kg and 200mg/kg) significantly improved the lipid profile. Total Cholesterol (TC), Triglycerides (TG), Very Low Density Lipoprotein (VLDL) and Low Density Lipoprotein (LDL) values reduced significantly while that of High Density Lipoprotein (HDL) increased significantly. GS 200 mg/kg was found more effective than GS 100 mg/kg. GS improved the value of lipid profile significantly but the effect was found inferior to Atorvastatin. CONCLUSION: From the present study it can be concluded that GS possess an effective hypolipidaemic effect. Hence it can be included as an add on therapy in dyslipidaemia after further confirmatory studies.

Role of neuroinflammation and latent transcription factors in pathogenesis of Parkinson's disease.

Parkinson's disease (PD) the second most common age-associated progressive neurodegenerative disorder is characterized by loss of dopaminergic neurons, cytoplasmic inclusions of aggregated proteins (Lewy bodies), and neuroinflammation. The inflammation of neurons causes release of various inflammatory mediators (IFNs, EGF, IL5, IL6, HGF, LIF and BMP2). The hallmarks of neuroinflammation are the presence of activated microglia and reactive astrocytes in the parenchyma of the CNS and increased production of cytokines, chemokines, prostaglandins, complement cascade proteins, and reactive oxygen and nitrogen species (ROS/RNS) which in some cases can result in disruption of the blood brain barrier and direct participation of the adaptive immune system. Latent transcription factors such as NF-κB, STAT 3, AP1, and SMAD 7, Toll like receptors and FAF 1 are constitutively upregulated in activated microglia. Toll-like receptors when activated promote NF-κB signaling thus promoting a vicious cycle of neuroinflammation. These transcription factors take dopaminergic neurons to apoptotic pathway via p53 and other death domain receptors. Neuroprotective signaling pathways such as mTOR, SOCS, and TGF-ß down regulated during development of PD. YY1 signaling, which has protective effect against α-Synuclein toxicity, is significantly decreased in PD patients. In summary we can say that transcription factors promoting inflammation such as NF-κB, STAT 3, AP 1, and Toll-like receptors are constitutively upregulated in PD, while neuroprotective pathways such as mTOR, TGF-ß, and YY1 are substantially downregulated in microglia of PD patients.

Pharmacological studies on the anti-inflammatory and immunomodulatory role of pentoxifylline and its interaction with nitric oxide (NO) in experimental arthritis in rats.

AIM: Present study was designed to evaluate protective effects of pentoxifylline and its potentiation with low dose of nitric oxide (NO) modulators in adjuvant-induced experimental arthritis in rats. METHOD: Wistar rats (200-300 g, n = 8 per group) of both sexes were used in the study. On day "0" experimental arthritis was induced by injecting 0.2 ml of Complete Freund's adjuvant (CFA) in sub-planter region of right hind paw of animals. Pentoxifylline treatment alone and in combination with NO modulators was given (i.p.) from day 14 to 28. Various arthritic parameters were recorded and blood and joint synovial fluid was collected for biochemical analysis. RESULTS: CFA inoculation significantly increases (1) arthritic index (2) ankle diameter (3) paw volume (4) histopathology score (5) serum TNF-α, IL-6, IL-1ß and synovial TNF-α levels (p < 0.001) (6) serum Th1 and Th2 cytokine levels g) MDA levels in rat paw tissue homogenates (7) serum NF-κB levels. Significant decrease in serum IL-10 levels and SOD activity was observed in rats after CFA inoculation. Decrease in body weight and suppressed general quality of life of CFA inoculated rats was also observed. These CFA-induced arthritic changes were significantly reversed by pentoxifylline alone and in combination with low dose of NO modulators (p < 0.05). CONCLUSION: These results are suggestive of protective effects of pentoxifylline and its potentiation in combination with low dose of NO modulators. These results may provide new pharmacological therapy for management of rheumatoid arthritis (RA).

Attenuation of lead neurotoxicity by supplementation of polyunsaturated fatty acid in Wistar rats.

BACKGROUND: Among various types of polyunsaturated fatty acid (PUFA), omega-3 fatty acids play a crucial role in development and function of the brain. This study was undertaken to investigate the possible neuroprotective efficacy of omega-3 fatty acid on lead-induced neurotoxicity in rats. MATERIAL AND METHODS: The experiment was carried out on 32 male Wistar rats divided into four groups. The first group (control) was treated with distilled water and second group with lead acetate at the doses of 3 mg/kg b.wt. (body weight)/oral, whereas third and fourth groups were simultaneously treated with lead acetate (3 mg/kg b.wt.) plus omega-3 fatty acid (300 mg/kg b.wt./oral) and lead acetate (3 mg/kg b.wt.) plus vitamin E (100 mg/kg b.wt./oral), respectively, for a period of 90 days. Their biochemical and histopathological investigations have been carried out. RESULTS: The level of lead was markedly elevated in brain (4.71-fold) and blood (5.65-fold), also increased levels of ROS, GSH, LPO with concomitant reduction in the activities of delta-ALAD, CAT, SOD, and GPx. In addition, lead-induced brain damage was indicated by histopathological changes. Omega-3 fatty acid resulted in marked improvement in most of the biochemical parameters as well as histopathological changes in rats. The results obtained were compared with vitamin E as the standard antioxidant agents. DISCUSSION: Omega-3 fatty acid significantly (P < 0.05) decreased the effect of lead-induced brain damage as well as biochemical changes similar to that of standard drug, vitamin E. So, our result suggested that omega-3 fatty acid may play a protective role in lead-induced neurotoxicity and associated human health risk.

Effects of a standardized Ayurvedic formulation on diabetes control in newly diagnosed Type-2 diabetics; a randomized active controlled clinical study.

OBJECTIVES: The purpose of this study was to investigate the efficacy of a standardized polyherbal formulation consists of aqueous extracts from six herbs, in patients with Type-2 diabetes mellitus. DESIGN: Randomized, active control study. INTERVENTIONS: 93 patients, newly diagnosed with Type-2 diabetes mellitus were randomly allocated to group 1 (received polyherbal capsules 500 mg/day, up titrated weekly to a maximum of 3 g/day) and group 2 (received Metformin 500 mg/day, up titrated weekly to a maximum of 2 g/day). MAIN OUTCOME MEASURES: The primary endpoint was effect on the change from baseline in blood glucose (Fasting blood Glucose and Postprandial blood glucose), and glycosylated hemoglobin (HbA1c). The secondary outcome includes the effect on lipid levels, liver enzymes and renal function test. RESULTS: After 24 weeks, mean laboratory measured fasting and post prandial blood glucose showed a decrease of 25.52% and 24.22% in polyherbal formulation (PHF) treated group, compared to 31.46% and 24% decrease in Metformin treated group (estimated treatment difference -10.8; 95% CI -22.63 to 1.03 and -0.36; -12.1 to 11.38, respectively). Reduction in HbA1c was also similar for PHF and Metformin (estimated treatment difference 0.01; 95% CI -0.51 to 0.53). However, the decrease in the mean total cholesterol level was more pronounced in PHF treated group (estimated mean difference 61.3; 95% CI 55.32 to 67.28) than Metformin treated group (estimated mean difference 41.12; 95% CI 34.92 to 47.32). Also, there was statistical significance between the treatment groups in total cholesterol level at the end of six months treatment (estimated treatment difference 20.18; 95% CI 12.34 to 28.02). CONCLUSION: The study demonstrated that daily intake of this PHF decreased the glycemic level and improved lipid homeostasis, while maintaining the other serum biochemical levels to the normal, and therefore it may be useful for the patients with Type-2 diabetes. This trial is registered in the Clinical Trials Registry - India (CTRI) (CTRI/2014/03/004490).