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Cancer is one of the leading causes of death worldwide, and its incidence and mortality are increasing each year. Improved therapeutic strategies against cancer have progressed, but remain insufficient to invert this trend. Along with several other risk factors, abnormal genetic and epigenetic regulations play a critical role in the initiation of cellular transformation, as well as tumorigenesis. The epigenetic regulator UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) is a multidomain protein with oncogenic abilities overexpressed in most cancers. Through the coordination of its multiple domains and other epigenetic key players, UHRF1 regulates DNA methylation and histone modifications. This well-coordinated dialogue leads to the silencing of tumor-suppressor genes (TSGs) and facilitates tumor cells' resistance toward anticancer drugs, ultimately promoting apoptosis escape and uncontrolled proliferation. Several studies have shown that the downregulation of UHRF1 with natural compounds in tumor cells induces the reactivation of various TSGs, inhibits cell growth, and promotes apoptosis. In this review, we discuss the underlying mechanisms and the potential of various natural and synthetic compounds that can inhibit/minimize UHRF1's oncogenic activities and/or its expression. [ABSTRACT FROM AUTHOR]

The Syzygium cumini (L.) Skeels is reported to have medicinal properties, but its benefits on age-related neurological changes have not been previously explored. In the current study, after phytochemical analysis of the pulp of Syzygium cumini (L.) Skeels fruit (Sy. cmi), young BALB/c mice have been supplemented with its 5, 15, and 30% dilution for 16 months, followed by behavioral experimentation and biochemical evaluation of isolated brains. The Sy. cmi has been found enriched with phenols/flavonoids while the occurrence of nine phytocompounds has been identified through GC-MS analysis. Further, Sy. cmi supplementation has caused significant (p < 0.05) protection from anxiety-like behavior in aged mice, and they have explored open, illuminated, and exposed areas of open field, light/dark, and an elevated plus maze, respectively. Furthermore, these animals have shown improved cognitive abilities as their percent (%) spontaneous alteration and novelty preference are significantly greater in T-maze and Y-maze and familiarity/novelty recognition tests. Further, Sy. cmi-supplemented mice remember the aversive stimuli zone and escape box location in passive avoidance and Barnes maze tests, and their brains have low levels of malondialdehyde and acetylcholinesterase with elevated antioxidant enzymes. The outcomes have provided scientific insight into the beneficial effects of Sy. cmi on age-associated amnesia that might be attributed to antioxidant and anticholinergic effects exerted by phytocompounds (caryophyllene, humulene, β-Farnesene, and phytol) owned by Syzygium cumini. [ABSTRACT FROM AUTHOR]

The incidences of traumatic brain injuries (TBIs) are increasing globally because of expanding population and increased dependencies on motorized vehicles and machines. This has resulted in increased socio-economic burden on the healthcare system, as TBIs are often associated with mental and physical morbidities with lifelong dependencies, and have severely limited therapeutic options. There is an emerging need to identify the molecular mechanisms orchestrating these injuries to life-long neurodegenerative disease and a therapeutic strategy to counter them. This review highlights the dynamics and role of choline-containing phospholipids during TBIs and how they can be used to evaluate the severity of injuries and later targeted to mitigate neuro-degradation, based on clinical and preclinical studies. Choline-based phospholipids are involved in maintaining the structural integrity of the neuronal/glial cell membranes and are simultaneously the essential component of various biochemical pathways, such as cholinergic neuronal transmission in the brain. Choline or its metabolite levels increase during acute and chronic phases of TBI because of excitotoxicity, ischemia and oxidative stress; this can serve as useful biomarker to predict the severity and prognosis of TBIs. Moreover, the effect of choline-replenishing agents as a post-TBI management strategy has been reviewed in clinical and preclinical studies. Overall, this review determines the theranostic potential of choline phospholipids and provides new insights in the management of TBI. [ABSTRACT FROM AUTHOR]

Diazepam is one of the most prescribed anxiolytic and anticonvulsant that is administered through intravenous (IV), oral, intramuscular, intranasal, and rectal routes. To facilitate the clinical use of diazepam, there is a need to develop formulations that are convenient to administer in ambulatory settings. The present study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for diazepam that is capable of predicting its pharmacokinetics (PK) after IV, oral, intranasal, and rectal applications using a whole-body population-based PBPK simulator, Simcyp®. The model evaluation was carried out using visual predictive checks, observed/predicted ratios (Robs/pred), and the average fold error (AFE) of PK parameters. The Diazepam PBPK model successfully predicted diazepam PK in an adult population after doses were administered through IV, oral, intranasal, and rectal routes, as the Robs/pred of all PK parameters were within a two-fold error range. The developed model can be used for the development and optimization of novel diazepam dosage forms, and it can be extended to simulate drug response in situations where no clinical data are available (healthy and disease). [ABSTRACT FROM AUTHOR]

The current study aims to assess the beliefs of the general public in Pakistan towards conspiracy theories, acceptance, willingness to pay, and preference for the COVID-19 vaccine. A cross-sectional study was conducted through an online self-administered questionnaire during January 2021. The Chi-square test or Fisher exact test was utilized for statistical data analysis. A total of 2158 respondents completed the questionnaire, among them 1192 (55.2%) were male with 23.87 (SD: ±6.23) years as mean age. The conspiracy beliefs circulating regarding the COVID-19 vaccine were believed by 9.3% to 28.4% of the study participants. Among them, 1040 (48.2%) agreed to vaccinate on its availability while 934 (43.3%) reported the Chinese vaccine as their preference. The conspiracy beliefs of the participants were significantly associated with acceptance of the COVID-19 vaccine. The existence of conspiracy beliefs and low vaccine acceptance among the general population is a serious threat to successful COVID-19 vaccination. [ABSTRACT FROM AUTHOR]