Inhibition of Uridine 5'-diphospho-glucuronosyltransferases A10 and B7 by vitamins: insights from in silico and in vitro studies.

Uridine 5'-diphospho-glucuronosyltransferases (UGTs) have been considered as a family of enzymes responsible for the glucuronidation process, a crucial phase II detoxification reaction. Among the various UGT isoforms, UGTs A10 and B7 have garnered significant attention due to their broad substrate specificity and involvement in the metabolism of numerous compounds. Recent studies have suggested that certain vitamins may exert inhibitory effects on UGT activity, thereby influencing the metabolism of drugs, environmental toxins, and endogenous substances, ultimately impacting their biological activities. In the present study, the inhibition potential of vitamins (A, B1, B2, B3, B5, B6, B7, B9, D3, E, and C) on UGT1A10 and UGT2B7 was determined using in silico and in vitro approaches. A 3-dimensional model of UGT1A10 and UGT2B7 enzymes was built using Swiss Model, ITASSER, and ROSETTA and verified using Ramachandran plot and SAVES tools. Molecular docking studies revealed that vitamins interact with UGT1A10 and UGT2B7 enzymes by binding within the active site pocket and interacting with residues. Among all vitamins, the highest binding affinity predicted by molecular docking was - 8.61 kcal/mol with vitamin B1. The in vitro studies results demonstrated the inhibition of the glucuronidation activity of UGTs by vitamins A, B1, B2, B6, B9, C, D, and E, with IC50 values of 3.28 ± 1.07 µg/mL, 24.21 ± 1.11 µg/mL, 3.69 ± 1.02 µg/mL, 23.60 ± 1.08 µg/mL, 6.77 ± 1.08 µg/mL, 83.95 ± 1.09 µg/ml, 3.27 ± 1.13 µg/mL and 3.89 ± 1.12 µg/mL, respectively. These studies provided the valuable insights into the mechanisms underlying drug-vitamins interactions and have the potential to guide personalized medicine approaches, optimizing therapeutic outcomes, and ensuring patient safety. Indeed, further research in the area of UGT (UDP-glucuronosyltransferase) inhibition by vitamins is essential to fully understand the clinical relevance and implications of these interactions. UGTs play a crucial role in the metabolism and elimination of various drugs, toxins, and endogenous compounds in the body. Therefore, any factors that can modulate UGT activity, including vitamins, can have implications for drug metabolism, drug-drug interactions, and overall health. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-023-00182-0.

An Update on Strategies to Deliver Protein and Peptide Drugs to the Eye.

In the past few decades, advancements in protein engineering, biotechnology, and structural biochemistry have resulted in the discovery of various techniques that enhanced the production yield of proteins, targetability, circulating half-life, product purity, and functionality of proteins and peptides. As a result, the utilization of proteins and peptides has increased in the treatment of many conditions, including ocular diseases. Ocular delivery of large molecules poses several challenges due to their high molecular weight, hydrophilicity, unstable nature, and poor permeation through cellular and enzymatic barriers. The use of novel strategies for delivering protein and peptides such as glycoengineering, PEGylation, Fc-fusion, chitosan nanoparticles, and liposomes have improved the efficacy, safety, and stability, which consequently expanded the therapeutic potential of proteins. This review article highlights various proteins and peptides that are useful in ocular disorders, challenges in their delivery to the eye, and strategies to enhance ocular bioavailability using novel delivery approaches. In addition, a few futuristic approaches that will assist in the ocular delivery of proteins and peptides were also discussed.

Nanocarriers for the Delivery of Neuroprotective Agents in the Treatment of Ocular Neurodegenerative Diseases.

Retinal neurodegeneration is considered an early event in the pathogenesis of several ocular diseases, such as diabetic retinopathy, age-related macular degeneration, and glaucoma. At present, there is no definitive treatment to prevent the progression or reversal of vision loss caused by photoreceptor degeneration and the death of retinal ganglion cells. Neuroprotective approaches are being developed to increase the life expectancy of neurons by maintaining their shape/function and thus prevent the loss of vision and blindness. A successful neuroprotective approach could prolong patients' vision functioning and quality of life. Conventional pharmaceutical technologies have been investigated for delivering ocular medications; however, the distinctive structural characteristics of the eye and the physiological ocular barriers restrict the efficient delivery of drugs. Recent developments in bio-adhesive in situ gelling systems and nanotechnology-based targeted/sustained drug delivery systems are receiving a lot of attention. This review summarizes the putative mechanism, pharmacokinetics, and mode of administration of neuroprotective drugs used to treat ocular disorders. Additionally, this review focuses on cutting-edge nanocarriers that demonstrated promising results in treating ocular neurodegenerative diseases.

Amelioration of intracerebroventricular streptozotocin-induced cognitive dysfunction by Ocimum sanctum L. through the modulation of inflammation and GLP-1 levels.

DPP-4 inhibitors have been shown to reverse amyloid deposition in Alzheimer's disease (AD) patients with cognitive impairment. Ocimum sanctum L. leaves reported the presence of important phytoconstituents which are reported to have DPP-4 inhibitory activity. To investigate the effects of petroleum ether extract of Ocimum sanctum L. (PEOS) in Intracerebroventricular streptozotocin (ICV-STZ) induced AD rats. ICV-STZ (3 mg/kg) was injected bilaterally into male Wistar rats, while sham animals received the artificial CSF. The ICV-STZ-induced rats were administered with three doses of PEOS (100, 200, and 400 mg/kg, p.o.) for thirty days. All experimental rats were subjected to behaviour parameters (radial arm maze task and novel object recognition test), neurochemical parameters such as GLP-1, Aß42, and TNF-α levels, and histopathological examination (Congo red staining) of the left brain hemisphere. PEOS significantly reversed the spatial learning and memory deficit exhibited by ICV-STZ-induced rats. Furthermore, PEOS also shows promising results in retreating Aß deposition, TNF α, and increasing GLP-1 levels. The histopathological study also showed a significant dose-dependent reduction in amyloid plaque formation and dense granule in PEOS -treated rats as compared to the ICV-STZ induced rats (Negative control). The results show that extract of Ocimum sanctum L. attenuated ICV-STZ-induced learning and memory deficits in rats and has the potential to be employed in the therapy of AD.

Therapeutic Approaches to Amyotrophic Lateral Sclerosis from the Lab to the Clinic.

Amyotrophic Lateral Sclerosis (ALS) is a terminal neuro-degenerative disorder that is clinically recognized as a gradual degeneration of the upper and lower motor neurons, with an average duration of 3 to 5 years from initial of symptoms to death. The mechanisms underlying the pathogenesis and progression of the disease are multifactorial. Therefore, to find effective treatments, it is necessary to understand the heterogeneity underlying the progression of ALS. Recent developments in gene therapy have opened a new avenue to treat this condition, especially for the characterized genetic types. Gene therapy methods have been studied in various pre-clinical settings and clinical trials, and they may be a promising path for developing an effective and safe ALS cure. A growing body of evidence demonstrates abnormalities in metabolic energy at the cellular and whole-body level in animal models and people living with ALS. Using and incorporatig high-throughput "omics" methods have radically transformed our thoughts about ALS, strengthened our understanding of the disease's dynamic molecular architecture, differentiated distinct patient subtypes, and created a reasonable basis for identifying biomarkers and novel individualised treatments. Future clinical and laboratory trials would also focus on the diverse relationships between metabolism and ALS to address the issue of whether targeting poor metabolism in ALS is an effective way to change disease progression. In this review, we focus on the detailed pathogenesis of ALS and highlight principal genes, i.e., SOD1, TDP-43, C9orf72, and FUS, as well as targeted ALS therapies. An attempt is made to provide up-to-date clinical outcomes, including various biomarkers that are thought to be important players in early ALS detection.

Potentiation of anti-Alzheimer activity of curcumin by probiotic Lactobacillus rhamnosus UBLR-58 against scopolamine-induced memory impairment in mice.

Curcumin, a major component of Indian saffron through clinical studies, revealed its neuroprotective effect in neurodegenerative diseases. However, it has not been utilized alone orally due to its low bioavailability. There are certain strategies to overcome the drawbacks such as poor absorption and low aqueous solubility. Many strategies are utilized to increase the systemic availability of curcumin. Among them, the steady intestinal and liver metabolism of curcumin by a curcumin adjuvant (enzyme inhibitor/inducer) is an important and less engrossed strategy for improving the overall systemic bioavailability of curcumin. Here, we assess the effect of probiotic Lactobacillus rhamnosus as a curcumin adjuvant (potentiate the effect of curcumin) in scopolamine-induced dementia in mice. To induce amnesia, scopolamine was used in a mouse model (1 mg/kg, daily for 10 days i.p.). After execution of behavioural tests (Morris water maze test), brains and liver were isolated for further neurochemical and histopathology examination. Our results showed a significant increase in antioxidant enzyme levels in curcumin with a probiotic group compared with curcumin alone. Besides, histopathology study results showed less neuronal damage of curcumin with probiotics as compared with the curcumin and scopolamine alone groups. Additionally, curcumin with probiotics improved memory and cognitive functions in the behavioural study with the significance of p ≤ 0.0001. In conclusion, curcumin with probiotics has greater activity as compared with curcumin alone and reverses the hallmarks of Alzheimer's disease (AD).

The use of real-time PCR and species-specific primers for the identification and monitoring of Paecilomyces lilacinus.

The Paecilomyces lilacinus is the most widely tested fungus for the control of root-knot and cyst nematodes. The fungus has also been implicated in a number of human and animal infections, difficulties in diagnosis often result in misdiagnosis or delays in identification leading to a delay in treatment. Here, we report the development of species-specific primers for the identification of P. lilacinus based on sequence information from the ITS gene, and their use in identifying P. lilacinus isolates, including clinical isolates of the fungus. The primer set generated a single PCR fragment of 130 bp in length that was specific to P. lilacinus and was also used to detect the presence of P. lilacinus from soil, roots and nematode eggs. Real-time PCR primers and a TaqMan probe were also developed and provided quantitative data on the population size of the fungus in two field sites. PCR, bait and culture methods were combined to investigate the presence and abundance of the fungus from two field sites in the United Kingdom where potato cyst nematode populations were naturally declining, and results demonstrated the importance of using a combination of methods to investigate population size and activity of fungi.