Pomegranate polyphenol punicalin ameliorates lipopolysaccharide-induced memory impairment, behavioral disorders, oxidative stress, and neuroinflammation via inhibition of TLR4-NF-кB pathway.

Neuroinflammation may play an important role in the development of Alzheimer's disease (AD). Previous studies have reported that lipopolysaccharide (LPS)-induced neuroinflammation causes memory impairments and behavioral disorders. We investigated the potential preventive effects of punicalin (PUN), a polyphenolic component of pomegranate, on LPS-induced memory deficiency and anxiety- and depression-like behaviors, along with the underlying mechanisms. LPS-treated cultured microglial BV2 cells and BV2 cell/Neuro-2a (N2a) cell coculture system were investigated for anti-neuroinflammatory effects of PUN in vitro. The in vivo experiments involved mice administered a 4-week course of oral gavage with 1500 mg/kg/d PUN before intraperitoneal LPS (250 mg/kg daily 7 times) injections. The in vitro results demonstrated that PUN inhibited the LPS-induced inflammatory cytokine (IL-18, IL-1ß, TNF-ɑ, and IL-6) production in BV2 cells and protected N2a cells from synaptic damage mediated by BV2 microglia-induced neuroinflammation. In in vivo studies, it was observed that PUN improved memory impairment and anxiety- and depression-like behaviors caused by LPS and reduced the expression of inflammatory proteins such as iNOS, COX-2, IL-1ß, IL-2, IL-6, and TNF-α. Furthermore, PUN inhibited the LPS-induced production of MDA; increased the activities of CAT, SOD, and GSH-Px, and inhibited LPS-induced Aß1-42 generation through down-regulation of APP and BACE1 expression. Moreover, PUN also suppressed the expression of TLR4, IRAK4, TRAF6, IKK-ß, NF-κB, p65, and HMGB1 in LPS-treated mouse brain and cultured microglial BV-2 cells. These results suggest that PUN inhibits LPS-induced memory impairment via anti-inflammatory and anti-amylogenic mechanisms through inhibition of TLR4-NF-kB activation.

Methylated urolithin A, mitigates cognitive impairment by inhibiting NLRP3 inflammasome and ameliorating mitochondrial dysfunction in aging mice.

Effective therapeutic interventions for elderly patients are lacking, despite advances in pharmacotherapy. Methylated urolithin A (mUro A), a modified ellagitannin (ET)-derived metabolite, exhibits anti-inflammatory, antioxidative, and anti-apoptotic effects. Current research has primarily investigated the neuroprotective effects of mUroA in aging mice and explored the underlying mechanisms. Our study used an in vivo aging model induced by d-galactose (D-gal) to show that mUro A notably improved learning and memory, prevented synaptic impairments by enhancing synaptic protein expression and increasing EPSCs, and reduced oxidative damage in aging mice. mUro A alleviated the activation of the NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome, leading to reduced glial cell activity and neuroinflammation in both accelerated aging and naturally senescent mouse models. Moreover, mUroA enhanced the activity of TCA cycle enzymes (PDH, CS, and OGDH), decreased 8-OHdG levels, and raised ATP and NAD+ levels within the mitochondria. At the molecular level, mUro A decreased phosphorylated p53 levels and increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), thus enhancing mitochondrial function. In conclusion, mUro A alleviates cognitive impairment in aging mice by suppressing neuroinflammation through NLRP3 inflammasome inhibition and restoring mitochondrial function via the p53-PGC-1α pathway. This suggests its potential therapeutic agent for brain aging and aging-related diseases.

Recent advancement in bioeffect, metabolism, stability, and delivery systems of apigenin, a natural flavonoid compound: challenges and perspectives.

Apigenin is a bioflavonoid compound that is widely present in dietary plant foods and possesses biological activities that protect against immune, cardiovascular, and neurodegenerative diseases and cancer. Therefore, apigenin is widely used in food and medicine, and increasing attention has been drawn to developing new delivery systems for apigenin. This review highlights the biological effects, metabolism, stability, and bioactivity of apigenin. In addition, we summarized advancements in the delivery of apigenin, which provides some references for its widespread use in food and medicine. Better stability of apigenin may enhance digestion and absorption and provide health benefits. Constructing delivery systems (such as emulsions, nanostructured lipid carriers, hydrogels, and liposomes) for apigenin is an effective strategy to improve its bioavailability, but more animal and cell experiments are needed to verify these findings. Developing apigenin delivery systems for food commercialization is still challenging, and further research is needed to promote their in-depth development and utilization.

Pomegranate polyphenol punicalagin improves learning memory deficits, redox homeostasis, and neuroinflammation in aging mice.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder characterized by loss of memory and cognitive dysfunction in the aged. Despite remarkable advances in drug therapy, effective pharmacological interventions are rare. Punicalagin (PU) is an active antioxidant polyphenol found in pomegranates, raspberries, blueberries, and chestnuts that has attracted considerable attention owing to its strong antioxidant and anti-inflammatory properties. The current study focused on the neuroprotective effect of PU on aging mice and its potential mechanisms. In this study, we first evaluated the protective effect of PU on neuro-2a (N2a) cell damage mediated by BV2 microglia-induced neuroinflammation. The in vivo D-galactose (D-gal)-induced brain aging model demonstrated that PU ameliorated deficits in learning and memory and prevented neuroinflammation, which was evident from the decrease in microglial activation and astrocytosis. Furthermore, PU reduced the levels of malondialdehyde (MDA) and reactive oxygen species (ROS) and inhibited NLRP3 inflammasome activation, reducing the levels of inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a), interleukin-18 (IL-18), and interleukin-1 beta (IL-1ß) in both accelerated aging and naturally senescent mouse models. PU effectively improved neuroinflammation, learning and memory deficits, and redox homeostasis in aging mice, and it could be a potential therapeutic agent for AD.

Correction: Gut microbial metabolite urolithin B attenuates intestinal immunity function in vivo in aging mice and in vitro in HT29 cells by regulating oxidative stress and inflammatory signalling.

Correction for 'Gut microbial metabolite urolithin B attenuates intestinal immunity function in vivo in aging mice and in vitro in HT29 cells by regulating oxidative stress and inflammatory signalling' by Peng Chen et al., Food Funct., 2021, 12, 11938-11955, DOI: 10.1039/D1FO02440J.

The Gut Microbiota Metabolite Urolithin B Improves Cognitive Deficits by Inhibiting Cyt C-Mediated Apoptosis and Promoting the Survival of Neurons Through the PI3K Pathway in Aging Mice.

Background: Despite considerable advances in pharmacotherapy, more effective therapeutic interventions for aging-related neurodegenerative disorders (NDs), such as Alzheimer's disease (AD), remain limited. Urolithin B (UB), one of the major subcategories of urolithins (microbiota metabolites) found in various tissues after ellagitannin consumption, has been shown to possess antioxidant, anti-inflammatory, and antiapoptotic effects. However, the neuroprotective effect of UB on brain aging in mice and its potential mechanisms were still unknown. Methods: In the current research, we first assessed the ameliorative effects of UB on oxidative injury and apoptosis induced by H2O2 in neuro-2a cells. Then a subcutaneous injection of D-galactose in mice for 8 weeks was used to establish the aging model to evaluate the protective effects of UB. The capacity of memory and learning, alterations of hippocampus histology and corresponding molecular mechanisms were all evaluated. Results: The D-gal-induced accelerated aging model in vivo demonstrated that UB could significantly ameliorate deficits in learning and memory by inhibiting the accumulation of advanced glycation end products (AGEs) and elevating the expression and activity of Cu, Zn-SOD and CAT. Furthermore, UB downregulated the c-Jun N-terminal kinase (JNK) signaling pathway and prevented cytochrome c release from isolated mitochondria, thereby inhibiting neuronal apoptosis during the aging process. More importantly, UB stimulation of aging mice activated ERK and phosphoinositide 3-kinase (PI3K), leading to neuronal survival along with Akt and p44/42 mitogen-activated protein kinase (MAPK) phosphorylation and activation. Conclusion: In summary, UB effectively alleviated cognitive deficits and ameliorated brain aging-related conditions and could be considered a healthcare product to prevent aging-associated NDs such as AD.

Gut microbial metabolite urolithin B attenuates intestinal immunity function in vivo in aging mice and in vitro in HT29 cells by regulating oxidative stress and inflammatory signalling.

Urolithin B (Uro B), one of the major subcategories of urolithins (microbial metabolites) found in various tissues after ellagitannin consumption, has been demonstrated to possess antioxidant and anti-inflammatory effects. The current research mainly focused on the ameliorative effect of Uro B on intestinal immunity function and exploring the potential mechanisms of its protective role in aging mice induced by D-galactose (D-gal). In the current research, we assessed the ameliorative effects of Uro B on inflammatory injury induced by lipopolysaccharides in HT29 cells. The D-gal-induced accelerated aging model in vivo demonstrated that Uro B could elevate the activities of superoxide dismutase, catalase, glutathione peroxidase, and total anti-oxidation capability, decrease malondialdehyde content, regulate the levels of inflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-4, and IL-1ß) in the small intestine, and reshape the composition of gut microbiota and decrease the intestinal barrier injury in aging mice. Furthermore, Uro B inhibited the expression of TLR4, IRAK4, TRAF6, IKK-ß, NF-κB p65, and HMGB1 in the small intestine. Therefore, these findings indicated that Uro B effectively weakened the injury to the small intestine and ameliorated intestinal immunity function through the downregulation of the HMGB1-TLR4-NF-κB pathway in aging mice. Uro B could be considered a healthcare product to prevent diseases associated with an aging immune system.

Physical Compatibility and Chemical Stability of Fentanyl and Naloxone Hydrochloride in 0.9% Sodium Chloride Injection Solution for Patient-Controlled Analgesia Administration.

BACKGROUND AND OBJECTIVE: The combination of naloxone hydrochloride (NH) and fentanyl citrate (FC) in patient-controlled analgesia (PCA) is examined to reduce the risk of opioid-induced nausea and vomiting. However, there are no such commercially available drug mixtures, and there is also no published evidence on the compatibility and stability of NH and FC. Thus, the primary purpose of the current research is to investigate the physical compatibility and chemical stability of NH when mixed with FC over a 72-h period in a 0.9% sodium chloride injection solution for PCA administration under storage at 4°C and 25°C. METHODS: Test solutions of 20 µg/mL FC and 4 µg/mL NH were prepared and stored in polyvinyl chloride (PVC) bags or glass bottles with a 0.9% sodium chloride injection solution as the diluent. During the 72-h storage period at 4°C or 25°C without light protection, the concentrations of the test drugs were assayed via high-performance liquid chromatography (HPLC), and the physical compatibility was determined with the naked eye. Furthermore, pH measurement of each sample was also performed with a pH meter. RESULTS: The percentages of the initial concentrations of FC and NH in the various solutions were maintained at a minimum of 98% over the 72-h study period. All of the mixtures remained clear and colourless throughout the observation period, and no precipitation or turbidity was observed in any of the batches. CONCLUSION: The 20 µg/mL FC test solution was physically compatible and chemically stable with the 4 µg/mL NH test solution when stored at 4°C or 25°C in PVC bags or glass bottles containing the 0.9% sodium chloride injection solution.

Clinical outcomes of continuous vs intermittent meropenem infusion for the treatment of sepsis: A systematic review and meta-analysis.

The antibiotic meropenem is commonly administered to patients with sepsis and septic shock. The aim of this study was to conduct a meta-analysis to evaluate the clinical efficacy and safety of continuous compared to intermittent meropenem infusion for the treatment of sepsis. Electronic databases such as PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI) were researched to collect clinical trials comparing continuous and intermittent infusion of meropenem in patients with sepsis. After data extraction and quality assessment of the included studies, Stata v. 12.0 software (Stata Corporation LLC, College Station, USA) was used for a meta-analysis of mortality, clinical cure, microbiological eradication, and safety. Seven studies with a total of 1,191 participants met the inclusion criteria and were included in the meta-analysis. The meta-analysis showed that continuous meropenem infusion was superior to intermittent infusion in terms of mortality (combined risk ratio (RR) = 0.66, 95% confidence interval (95% CI) = 0.46-0.98, p = 0.03), clinical cure rate (combined RR = 1.15, 95% CI = 1.02-1.30, p = 0.026) and microbiological eradication (combined RR = 1.20, 95% CI = 1.01-1.42, p = 0.04), although it may increase the incidence of some adverse events (AEs). Compared with intermittent dosing, administration of meropenem antibiotics through continuous infusion in patients with sepsis is associated with decreased hospital mortality, increased clinical cure rates and greater microbiological eradication. Further high-quality studies should be conducted to confirm our findings.

Experiences and perceptions risk of health-care workers from coronavirus: A protocol for systematic review.

BACKGROUND: Healthcare workers (HCWs) were at the frontline during the battle against coronavirus. Understanding and managing their fears and anxieties may hold lessons for handling future outbreaks. However, the experiences and perceptions risk of HCWs from coronavirus still remains to be controversial. Thus, the objective of this review is to identify, appraise, and synthesize available evidence related to the experiences and perceptions of risk of HCWs from coronavirus. METHODS: The studies were gathered from PubMed, Cochrane Library, EMBASE, CBMdisc, CNKI, WKSP, CSJFT, Google Scholar, and PsycINFO, along with several sources of gray literature. The retrieval of full-text studies, data extraction, and quality assessment of the included studies will be independently conducted by 2 reviewers. The meta-aggregative will be used for findings pooling and a summary of ConQual findings tables will be presented in future. RESULTS: This study will be submitted to a peer-reviewed journal for publication. CONCLUSION: The literature will provide a high-quality analysis of the current evidence to assess the experiences and perceptions risk of health-care workers from coronavirus. REGISTRATION INFORMATION: CRD42020170388.

Compatible stability of methylprednisolone sodium succinate and tropisetron in 0.9% sodium chloride injection.

Background: A combination of methylprednisolone sodium succinate and tropisetron hydrochloride is commonly used to treat the nausea and vomiting associated with antineoplastic therapy. The objective of this study was to investigate the stability of tropisetron hydrochloride and methylprednisolone sodium succinate in 0.9% sodium chloride injection for up to 48 hours. Methods: Commercial solutions of methylprednisolone sodium succinate and tropisetron hydrochloride were obtained and further diluted with 0.9% sodium chloride injection to final concentrations of either 0.4 or 0.8 mg/mL (methylprednisolone sodium succinate) and 0.05 mg/mL (tropisetron). The admixtures were assessed for periods of up to 48 hours after storage at 4°C with protection from light and at 25°C without protection from light. Physical compatibility was determined visually, and the chemical compatibility was measured with high-performance liquid chromatography (HPLC) and by measurement of pH values. Results: HPLC analysis demonstrated that methylprednisolone sodium succinate and tropisetron hydrochloride in the various solutions were maintained at 97% of the initial concentrations or higher during the testing period. There were no changes observed by physical precipitation or pH in any of the prepared solutions. Conclusions: Tropisetron hydrochloride injection and methylprednisolone sodium succinate injection in 0.9% sodium chloride injection are stable for up to 48 hours at 4°C and 25°C.

Efficacy and safety of dexmedetomidine combined with tramadol for patient-controlled intravenous analgesia in Chinese surgical patients: A systematic review and meta-analysis.

BACKGROUND: Patient-controlled intravenous analgesia (PCIA) has been suggested as an effective method of pain relief. There are several randomized controlled trials (RCTs) of dexmedetomidine (DEX) combined with tramadol for PCIA in Chinese surgical patients. The purpose of this study was to perform a systematic review and meta-analysis to evaluate the efficacy and safety of DEX combined with tramadol for PCIA in Chinese surgical patients from current data. METHODS: The RCTs of DEX combined with tramadol for PCIA were gathered from the PubMed, Excerpta Medica Database, Cochrane Library, Cochrane Library, China National Knowledge Infrastructure database, and VIP databases. After data extraction and quality assessment of the included RCTs, RevMan 5.3 software was employed for the meta-analysis of visual analog scale (VAS) scores, Ramsay sedation scores, effective pressure times for PCIA, tramadol consumption, and safety. RESULTS: Fourteen RCTs were included. Compared with tramadol alone, postoperative intravenous tramadol-DEX combination PCA led to lower VAS scores (weighted mean differences [WMD]12h = 0.14, 95% confidence interval [CI] v1.50 to 1.79; WMD24h = 0.78, 95% CI -0.92 to -0.62; WMD48h = 0.51, 95% CI -0.66 to -0.38; all P < .05), lower Ramsay sedation scores (WMD24h = 0.08, 95% CI -0.14 to -0.02; WMD48h = 0.09, 95% CI -0.11 to -0.07; all P < .05), and less postoperative tramadol consumption (WMD0-24h = -102.59 mg, 95% CI -149.68 to -55.49; WMD0-48h = -152.91 mg, 95% CI -259.93 to -45.89; all P < .05). With regard to safety, there was a significant difference between DEX-tramadol and tramadol for PCIA in terms of the incidence of postoperative nausea and vomiting, dizziness, chills, and restlessness (all P < .05). CONCLUSION: According to the domestic evidence, this systematic review and meta-analysis suggests that DEX-tramadol PCIA is superior to tramadol in terms of analgesic efficacy and safety for Chinese surgical patients. However, because of some clear limitations (sample size and heterogeneity), these results should be interpreted with caution. Further large-scale and well-designed studies are needed to summarize and analyze the data to draw a more convincing conclusion.

Ameliorative effect of urolithin A on d-gal-induced liver and kidney damage in aging mice via its antioxidative, anti-inflammatory and antiapoptotic properties.

Urolithin A, a metabolite produced by human colon microflora from ellagic acid and related compounds, has been reported to have antioxidant, anti-inflammatory and antiapoptotic properties. The present study investigates the protective effects of urolithin A (Uro A) on d-galactose (d-gal)-induced liver and kidney injury and the possible mechanisms in mice. In this study, we first investigated the antioxidant ability of Uro A in vitro. Then mice were treated with d-gal subcutaneously (150 mg kg-1 d-1), followed by Uro A at different dosages (50, 100, 150 mg kg-1 d-1, administered orally) for 8 weeks. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN) and creatinine (Cr) in the serum were tested. Histopathological features were assessed by hematoxylin and eosin (HE) staining followed by an assessment of the antioxidant and anti-inflammatory activities. Furthermore, we also evaluated the expression levels of the genes Bax, Bcl-2 and cleaved caspase-3 in the liver and kidney. The results showed that Uro A treatment obviously attenuated d-gal-induced liver and kidney damage. The beneficial effects of Uro A were accompanied by a decline in malondialdehyde (MDA) levels and a rise in the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC) activity in the liver and kidney and downregulation of the levels of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1ß) and interleukin-6 (IL-6), in serum. Moreover, Uro A could modulate the expression of Bax, Bcl-2 and cleaved caspase-3 in the livers and kidneys of aging mice. These findings suggested that Uro A ameliorated d-gal-induced liver and kidney injury through attenuating oxidative stress, inflammatory responses and apoptosis.

Activation of the miR-34a-Mediated SIRT1/mTOR Signaling Pathway by Urolithin A Attenuates D-Galactose-Induced Brain Aging in Mice.

Despite tremendous advances in modern medicine, effective prevention or therapeutic strategies for age-related neurodegenerative diseases such as Alzheimer's disease (AD) remain limited. Currently, accumulating evidence has demonstrated that microRNAs (miRNAs) are increasingly associated with age-related diseases and are emerging as promising therapeutic targets. Urolithin A, a metabolite compound resulting from the transformation of ellagitannins by gut bacteria, has been reported to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The present study primarily focused on the ameliorative effect of urolithin A on aging mice and on the exploration of the potential mechanisms of such an ameliorative effect on cognitive impairment and brain aging. In this study, we first tested the neuroprotective effect of urolithin A using an in vitro H2O2-induced PC12 cell oxidative damage model. The in vivoD-gal-induced brain aging model showed that urolithin A significantly suppressed the upregulation of miR-34a induced by D-gal. Moreover, target genes associated with miR-34a were also examined. Urolithin A supplementation ameliorated apoptosis induced by D-gal and rescued miR-34a overexpression-induced impaired autophagy in brain aging mice after a 2-month administration. Furthermore, urolithin A activated autophagy by upregulating the SIRT1 signaling pathway and downregulating the mTOR signaling pathway. In conclusion, urolithin A may exert neuroprotective effects and may aid in preventing D-gal-induced brain aging through activation of the miR-34a-mediated SIRT1/mTOR signaling pathway.

Curative effectiveness and safety of osimertinib in the treatment for non-small-cell lung cancer: a meta-analysis of the experimental evidence.

BACKGROUND: Osimertinib is an EGFR-TKI that is selective for both EGFR-TKI-sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer (NSCLC). The purpose of this study was conducting a meta-analysis to evaluate the clinical efficacy and safety of osimertinib in the treatment for NSCLC. METHODS: Using "osimertinib" as a keyword combined with "non-small-cell lung cancer" and "randomized controlled trial" as medical subject headings, the following electronic databases were searched: PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure. After data extraction and quality assessment of the included randomized controlled trials, the RevMan 5.3 software and R meta package were applied for meta-analysis of objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Ten studies met our criteria and were included in the meta-analysis, with a total of 3,260 participants. The meta-analysis showed that osimertinib therapy was superior to the control therapy alone in ORR (combined RR=1.53, 95% CI: 0.87-2.71, P=0.14), DCR (combined RR=1.07, 95% CI: 0.79-1.44, P=0.66), PFS (combined RR=0.32, 95% CI: 0.24-0.44, P<0.00001), and OS (combined RR=0.57, 95% CI: 0.47-0.70, P<0.00001). In addition, osimertinib led to some toxicities, and the overall prevalence of all-grade diarrhea was 40% (95% CI: 33-47), paronychia 26% (95% CI: 20-33), rash 40% (95% CI: 34-47), dry skin 28% (95% CI: 23-33), and stomatitis 15% (95% CI: 9-23). CONCLUSION: Our study showed that osimertinib demonstrated a significant improvement in the ORR, DCR, PFS, and OS with tolerable adverse effects for NSCLC patients. However, because of some clear limitations (heterogeneity and publication bias), these results should be interpreted with caution.