Attenuation of Lipopolysaccharide-Induced Inflammatory Responses through Inhibition of the NF-κB Pathway and the Increased NRF2 Level by a Flavonol-Enriched n-Butanol Fraction from Uvaria alba.

Pathologic hyperreactive inflammatory responses occur when there is excessive activation of a proinflammatory NF-κB pathway and a reduced cytoprotective NRF2 cascade. The noncytotoxic, highly selective COX-2 inhibitory flavonol-enriched butanol fraction (UaB) from Uvaria alba (U. alba) was investigated for its inflammatory modulating potential by targeting NF-κB activation and NRF2 activity. Enzyme-linked immunosorbent assay was initially performed to measure levels of proinflammatory mediators [nitric oxide (NO), prostaglandin E2, and reactive oxygen species (ROS)] and cytokines [tumor necrosis factor-alpha (TNF-α), IL-1ß, and IL-6], followed by reverse transcription-polymerase chain reaction and western blotting to determine mRNA and protein expression, respectively. Using immunofluorescence staining combined with western blot analysis, the activation of NF-κB was further investigated. NRF2 activity was also measured using a luciferase reporter assay. UaB abrogated protein and mRNA expressions of inducible nitric oxide synthase (iNOS), COX-2, TNF-α, IL-1ß, and IL-6 in RAW 264.7 macrophages, thereby suppressing the production of proinflammatory mediators and cytokines. This was further validated when a concentration-dependent decrease in NO and ROS production was observed in zebrafish (Danio rerio) larvae. UaB also increased NRF2 activity in HaCaT/ARE cell line and attenuated NF-κB activation by inhibiting the nuclear translocation of transcription factor p65 in RAW 264.7 macrophages. Nontargeted LC-MS analysis of UaB revealed the presence of the flavonols quercitrin (1), quercetin (2), rutin (3), kaempferol (4), and kaempferol 3-O-rutinoside (5). Molecular docking indicates that major flavonol aglycones have high affinity toward COX-2 NSAID-binding sites, TNF-α, and TNF-α converting enzyme, while the glycosylated flavonoids showed strong binding toward iNOS and IKK-all possessing dynamic stability when performing molecular dynamics simulations at 140 ns. This is the first report to have elucidated the mechanistic anti-inflammatory potential of the Philippine endemic plant U. alba.

Age, Sex and Previous Comorbidities as Risk Factors Not Associated with SARS-CoV-2 Infection for Long COVID-19: A Systematic Review and Meta-Analysis.

Identification of predictors of long COVID-19 is essential for managing healthcare plans of patients. This systematic literature review and meta-analysis aimed to identify risk factors not associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, but rather potentially predictive of the development of long COVID-19. MEDLINE, CINAHL, PubMed, EMBASE, and Web of Science databases, as well as medRxiv and bioRxiv preprint servers were screened through 15 September 2022. Peer-reviewed studies or preprints evaluating potential pre-SARS-CoV-2 infection risk factors for the development of long-lasting symptoms were included. The methodological quality was assessed using the Quality in Prognosis Studies (QUIPSs) tool. Random-effects meta-analyses with calculation of odds ratio (OR) were performed in those risk factors where a homogenous long COVID-19 definition was used. From 1978 studies identified, 37 peer-reviewed studies and one preprint were included. Eighteen articles evaluated age, sixteen articles evaluated sex, and twelve evaluated medical comorbidities as risk factors of long COVID-19. Overall, single studies reported that old age seems to be associated with long COVID-19 symptoms (n = 18); however, the meta-analysis did not reveal an association between old age and long COVID-19 (n = 3; OR 0.86, 95% CI 0.73 to 1.03, p = 0.17). Similarly, single studies revealed that female sex was associated with long COVID-19 symptoms (n = 16); which was confirmed in the meta-analysis (n = 7; OR 1.48, 95% CI 1.17 to 1.86, p = 0.01). Finally, medical comorbidities such as pulmonary disease (n = 4), diabetes (n = 1), obesity (n = 6), and organ transplantation (n = 1) were also identified as potential risk factors for long COVID-19. The risk of bias of most studies (71%, n = 27/38) was moderate or high. In conclusion, pooled evidence did not support an association between advancing age and long COVID-19 but supported that female sex is a risk factor for long COVID-19. Long COVID-19 was also associated with some previous medical comorbidities.

Balanced electrolyte solutions versus isotonic saline in adult patients with diabetic ketoacidosis: A systematic review and meta-analysis.

BACKGROUND: Current guidelines suggest the use of isotonic saline (IS) infusion as the preferred resuscitation fluid in the management of diabetic ketoacidosis (DKA). However, balanced electrolyte solutions (BES) have been proposed as an alternative due to a lower propensity to cause hyperchloremic metabolic acidosis. Evidence regarding the use of BES in DKA remains limited. OBJECTIVES: To determine if the use of BES in fluid resuscitation leads to faster resolution of DKA compared to IS. METHODS: The study involves a comprehensive search of literature from PubMed, Cochrane CENTRAL, Google Scholar, and Science Direct of clinical trials addressing the use of BES vs IS in fluid resuscitation in DKA. The time to resolution of DKA was examined as the primary endpoint. Pooled hazard ratios (HR) and Mean Difference (MD) in hours with their 95% confidence intervals (CI) were calculated using a random-effects model. RESULTS: The literature search included 464 studies that were screened individually. A total of 9 studies were identified but 6 studies were excluded due to irrelevance in the outcome of interest and target population. The pooled hazard ratio HR significantly revealed 1.46 [1.10 to 1.94] (p = 0.009) with 12% heterogeneity while MD was -3.02 (95% CI -6.78-0.74; p = 0.12) with heterogeneity of 85%. CONCLUSION: Considering the evidence from pooled small randomized trials with moderate overall certainty of evidence, the use of BES in DKA was associated with faster rates of DKA resolution compared to IS.

MicroRNA and Other Non-Coding RNAs in Epstein-Barr Virus-Associated Cancers.

EBV is a direct causative agent in around 1.5% of all cancers. The oncogenic properties of EBV are related to its ability to activate processes needed for cellular proliferation, survival, migration, and immune evasion. The EBV latency program is required for the immortalization of infected B cells and involves the expression of non-coding RNAs (ncRNAs), including viral microRNAs. These ncRNAs have different functions that contribute to virus persistence in the asymptomatic host and to the development of EBV-associated cancers. In this review, we discuss the function and potential clinical utility of EBV microRNAs and other ncRNAs in EBV-associated malignancies. This review is not intended to be comprehensive, but rather to provide examples of the importance of ncRNAs.

pks+ Escherichia coli more prevalent in benign than malignant colorectal tumors.

BACKGROUND: Some E. coli strains that synthesize the toxin colibactin within the 54-kb pks island are being implicated in colorectal cancer (CRC) development. Here, the prevalence of pks+ E. coli in malignant and benign colorectal tumors obtained from selected Filipino patients was compared to determine the association of pks+ E. coli with CRC in this population. METHODS AND RESULTS: A realtime qPCR protocol was developed to quantify uidA, clbB, clbN, and clbA genes in formalin fixed paraffin embedded colorectal tissues. The number of malignant tumors (44/62; 71%) positive for the uidA gene was not significantly different (p = 0.3428) from benign (38/62; 61%) tumors. Significantly higher number of benign samples (p < 0.05) were positive for all three colibactin genes (clbB, clbN, and clbA) compared with malignant samples. There was also higher prevalence of pks+ E. coli among older females and in tissue samples taken from the rectum. CONCLUSION: Hence, pks+ E. coli may not be associated with CRC development among Filipinos.