Herpes simplex viral encephalitis with acute memory impairment and low cellular cerebrospinal fluid: A case report with systematic review literature.

Herpes simplex encephalitis (HSVE) is a potentially fatal infectious central nervous system (CNS) disorder. Thus, early detection is critical in determining the case's fate. Clinical history and examination, brain computed tomography, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and lumbar puncture have been used to establish a diagnosis. This report describes a case of HSVE with hypocellular cerebrospinal fluid (CSF) and an uncommon form of memory impairment. However, MRI results were consistent with HSVE, and CSF PCR tested positive for HSV-1 DNA that responded to treatment. We routinely advise patients to begin antiviral therapy as soon as possible to avoid complications.

Dietary chamomile flowers extract improved performance and mitigated aflatoxin B1 toxicity in rabbits.

Aflatoxin B1 (AFB1) is among the poisonous mycotoxins that contaminate food and feed. Limited studies are available on the efficacy of chamomile (Cha) against oxidative stress, liver damage and pro-inflammatory response induced by AFB1. The present study aims to evaluate the effects of Cha on the performance and protective effects against AFB1 in growing rabbits. The experimental rabbits were divided into four different groups, including Cha (70 mg kg day-1), AFB1 (AF; 30 µg kg day-1), AFB1+Cha (AFLCha) and control (CON). The results indicated that the AFB1 treatment had lower values of performance, and carcass parameters compared to the Cha and AFLCha treatments. Furthermore, the Cha and AFLCha groups had lower values of liver and kidney function activities compared to the AFB1 treatment. The higher values of antioxidant enzymes were observed in Cha and AFLCha treatments than in the AFB1 treatment. AFB1 treatments had higher levels of malondialdehyde and liver functions with lower levels of antioxidant enzymes (glutathione and superoxide dismutase) compared to Cha and CON groups. In conclusion, dietary Cha could mitigate the oxidative stress of AFB1-induced liver deterioration.

Evaluation of Sechium edule fruit attenuation impact on the cardiomyopathy of the STZ-induced diabetic rats.

Sechium edule, commonly known as chayote is known for its low glycemic index, high fiber content, and rich nutritional profile, which suggests it may be beneficial for individuals with diabetes. While research specifically examining the impact of chayote on diabetes is limited, this study screened its biological impacts by using different biomarkers on streptozotocin-induced diabetic (STZ-ID) rats. The ethanolic extract of the Sechium edule fruits was assessed for different phytochemical, biochemical, and anti-diabetic properties. In the results, chayote extract had high phenolic and flavonoid contents respectively (39.25 ± 0.65 mg/mL and 12.16 ± 0.50 mg/mL). These high phenolic and flavonoid contents showed high implications on STZ-ID rats. Altogether 200 and 400 mg/kg of the extract considerably reduced the blood sugar level and enhanced the lipid profile of the STZ-ID rats. Additionally, they have decreased blood urea and serum creatinine levels. Besides, the levels of SGOT, SGPT, LDH, sodium, and potassium ions were significantly lowered after the administration period. More importantly, the electrocardiogram (ECG) parameters such as QT, RR, and QTc which were prolonged in the diabetic rats were downregulated after 35 days of administration of S. edule extract (400 mg/kg). And, the histological examination of the pancreas and kidney showed marked improvement in structural features of 200 and 400 mg/kg groups when compared to the diabetic control group. Where the increase in the glucose levels was positively correlated with QT, RR, and QTc (r2 = 0.76, r2 = 0.76, and r2 = 0.43) which means that ECG could significantly reflect the diabetes glucose levels. In conclusion, our findings showed that the fruit extract exerts a high potential to reduce artifacts secondary to diabetes which can be strongly suggested for diabetic candidates. However, there is a need to study the molecular mechanisms of the extract in combating artifacts secondary to diabetes in experimental animals.

Lipid nanoparticles of quercetin (QU-Lip) alleviated pancreatic microenvironment in diabetic male rats: The interplay between oxidative stress - unfolded protein response (UPR) - autophagy, and their regulatory miRNA.

BACKGROUND: Autophagy is a well-preserved mechanism essential in minimizing endoplasmic reticulum stress (ER)-related cell death. Defects in ß-cell autophagy have been linked to type 1 diabetes, particularly deficits in the secretion of insulin, boosting ER stress sensitivity and possibly promoting pancreatic ß-cell death. Quercetin (QU) is a potent antioxidant and anti-diabetic flavonoid with low bioavailability, and the precise mechanism of its anti-diabetic activity is still unknown. Aim This study aimed to design an improved bioavailable form of QU (liposomes) and examine the impact of its treatment on the alleviation of type 1 diabetes induced by STZ in rats. METHODS: Seventy SD rats were allocated into seven equal groups 10 rats of each: control, STZ, STZ + 3-MA, STZ + QU-Lip, and STZ + 3-MA + QU-Lip. Fasting blood glucose, insulin, c-peptide, serum IL-6, TNF-α, pancreatic oxidative stress, TRAF-6, autophagy, endoplasmic reticulum stress (ER stress) markers expression and their regulatory microRNA (miRNA) were performed. As well as, docking analysis for the quercetin, ER stress, and autophagy were done. Finally, the histopathological and immunohistochemical analysis were conducted. SIGNIFICANCE: QU-Lip significantly decreased glucose levels, oxidative, and inflammatory markers in the pancreas. It also significantly downregulated the expression of ER stress and upregulated autophagic-related markers. Furthermore, QU-Lip significantly ameliorated the expression of several MicroRNAs, which both control autophagy and ER stress signaling pathways. However, the improvement of STZ-diabetic rats was abolished upon combination with an autophagy inhibitor (3-MA). The findings suggest that QU-Lip has therapeutic promise in treating type 1 diabetes by modulating ER stress and autophagy via an epigenetic mechanism.

Optical Control of Cell-Surface and Endomembrane-Exclusive ß-Adrenergic Receptor Signaling.

Beta-adrenergic receptors (ßARs) are G protein-coupled receptors (GPCRs) that mediate catecholamine-induced stress responses, such as heart rate increase and bronchodilation. In addition to signals from the cell surface, ßARs also broadcast non-canonical signaling activities from the cell interior membranes (endomembranes). Dysregulation of these receptor pathways underlies severe pathological conditions. Excessive ßAR stimulation is linked to cardiac hypertrophy, leading to heart failure, while impaired stimulation causes compromised fight or flight stress responses and homeostasis. In addition to plasma membrane ßAR, emerging evidence indicates potential pathological implications of deeper endomembrane ßARs, such as inducing cardiomyocyte hypertrophy and apoptosis, underlying heart failure. However, the lack of approaches to control their signaling in subcellular compartments exclusively has impeded linking endomembrane ßAR signaling with pathology. Informed by the ß1AR-catecholamine interactions, we engineered an efficiently photo-labile, protected hydroxy ß1AR pro-ligand (OptoIso) to trigger ßAR signaling at the cell surface, as well as exclusive endomembrane regions upon blue light stimulation. Not only does OptoIso undergo blue light deprotection in seconds, but it also efficiently enters cells and allows examination of G protein heterotrimer activation exclusively at endomembranes. In addition to its application in the optical interrogation of ßARs in unmodified cells, given its ability to control deep organelle ßAR signaling, OptoIso will be a valuable experimental tool.

Intravenous fluid rate of 250 mL/h versus 125 mL/h in nulliparous women: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Evidence regarding the type and rate of intravenous (IV) fluid administration during labor is still inconclusive and the studies assessing the impact of IV fluids had mixed results. OBJECTIVES: To evaluate the effects of IV fluids at an infusion rate of 250 mL/h as compared with 125 mL/h on labor outcomes in nulliparous women. SEARCH STRATEGY: We searched six databases for relevant studies through a search strategy containing the relevant keywords "IV hydration", "IV fluids", and "labor" from the inception of these databases to May 1, 2023, without any applied restrictions. SELECTION CRITERIA: Search results were imported to Covidence for screening of eligible articles for this review. Randomized controlled trials (RCTs) assessing the impact of IV fluids at 250 mL/h on the outcomes of labor in nulliparous women at term (>37 weeks) as compared with 125 mL/h were included only. DATA COLLECTION AND ANALYSIS: Data regarding the characteristics of included studies, participant's baseline characteristics, and concerned outcomes were collected in an Excel spreadsheet and all the concerned outcomes were pooled as risk ratios (RR) or mean difference (MD) with 95% confidence interval (CI) in the meta-analysis models using RevMan 5.4. MAIN RESULTS: Pooled data from 11 RCTs with 1815 patients showed that 250 mL/h infusion rate had a significant reduction in cesarean section rate (RR 0.70, 95% CI 0.56-0.88, P = 0.002), the first stage of labor duration (MD -46.97, 95% CI -81.79 to -12.14, P = 0.008), the second stage of labor duration (MD -2.69, 95% CI -4.34 to -1.05, P = 0.001), prolonged labor incidence (RR 0.72, 95% CI 0.58-0.89, P = 0.003), as compared with 125 mL/h. Also, the vaginal delivery rate (RR 1.07, 95% CI 1.02-1.12, P = 0.009) was higher with a 250 mL/h infusion rate. CONCLUSION: IV fluids at an infusion rate of 250 mL/h during labor in nulliparous women decreased the cesarean delivery rate, increased the vaginal delivery rate, shortened the first and second-stage labor duration, decreased the incidence of prolonged labor as compared with 125 mL/h. These findings suggest enhanced labor progression and a lower risk of labor complications with higher infusion rates. However, future research involving a more diverse population and exploring the potential benefits of combining IV infusion rates with other interventions, such as adding dextrose or less restrictive oral intake during labor, is needed.

Synergy between Interleukin-1ß, Interferon-γ, and Glucocorticoids to Induce TLR2 Expression Involves NF-κB, STAT1, and the Glucocorticoid Receptor.

Glucocorticoids act via the glucocorticoid receptor (GR; NR3C1) to downregulate inflammatory gene expression and are effective treatments for mild to moderate asthma. However, in severe asthma and virus-induced exacerbations, glucocorticoid therapies are less efficacious, possibly due to reduced repressive ability and/or the increased expression of proinflammatory genes. In human A549 epithelial and primary human bronchial epithelial cells, toll-like receptor (TLR)-2 mRNA and protein were supra-additively induced by interleukin-1ß (IL-1ß) plus dexamethasone (IL-1ß+Dex), interferon-γ (IFN-γ) plus dexamethasone (IFN-γ+Dex), and IL-1ß plus IFN-γ plus dexamethasone (IL-1ß+IFN-γ+Dex). Indeed, ∼34- to 2100-fold increases were apparent at 24 hours for IL-1ß+IFN-γ+Dex, and this was greater than for any single or dual treatment. Using the A549 cell model, TLR2 induction by IL-1ß+IFN-γ+Dex was antagonized by Org34517, a competitive GR antagonist. Further, when combined with IL-1ß, IFN-γ, or IL-1ß+IFN-γ, the enhancements by dexamethasone on TLR2 expression required GR. Likewise, inhibitor of κB kinase 2 inhibitors reduced IL-1ß+IFN-γ+Dex-induced TLR2 expression, and TLR2 expression induced by IL-1ß+Dex, with or without IFN-γ, required the nuclear factor (NF)-κB subunit, p65. Similarly, signal transducer and activator of transcription (STAT)-1 phosphorylation and γ-interferon-activated sequence-dependent transcription were induced by IFN-γ These, along with IL-1ß+IFN-γ+Dex-induced TLR2 expression, were inhibited by Janus kinase (JAK) inhibitors. As IL-1ß+IFN-γ+Dex-induced TLR2 expression also required STAT1, this study reveals cooperation between JAK-STAT1, NF-κB, and GR to upregulate TLR2 expression. Since TLR2 agonism elicits inflammatory responses, we propose that synergies involving TLR2 may occur within the cytokine milieu present in the immunopathology of glucocorticoid-resistant disease, and this could promote glucocorticoid resistance. SIGNIFICANCE STATEMENT: This study highlights that in human pulmonary epithelial cells, glucocorticoids, when combined with the inflammatory cytokines interleukin-1ß (IL-1ß) and interferon-γ (IFN-γ), can synergistically induce the expression of inflammatory genes, such as TLR2. This effect involved positive combinatorial interactions between NF-κB/p65, glucocorticoid receptor, and JAK-STAT1 signaling to synergistically upregulate TLR2 expression. Thus, synergies involving glucocorticoid enhancement of TLR2 expression may occur in the immunopathology of glucocorticoid-resistant inflammatory diseases, including severe asthma.

Management strategy and outcomes of sacrococcygeal teratoma - an Egyptian multicenter experience.

OBJECTIVES: Nationwide criteria regarding patients with sacrococcygeal teratoma (SCT) are still lacking in Egypt. We aimed to present a multicenter study regarding the management and outcomes of this tumor to evaluate our national treatment strategy. METHODS: A retrospective analysis including all patients with SCT who were managed at four major Egyptian centers between 2013 and 2023. Clinical data, surgical approaches, and short- and long-term outcomes were discussed. RESULTS: The study included 95 patients (74 were females). Antenatal diagnosis was reported in 25% of patients. Seventy-one patients (74.7%) were classified as Altman type I/II. Surgery was performed via a perineal approach in 75 patients, whereas the remaining 20 underwent a combined abdominoperineal approach. Vertical elliptical incision with midline closure was conducted in 51.5% of patients, followed by classic or modified chevron incisions. Benign mature teratoma was detected in 82% of patients. At a median follow-up of 57 months, eight patients (8.5%) had relapsed. The 5-year overall survival (OS) and event-free survival (EFS) of all patients were 94% and 91%, respectively. In the after-care monitoring, 19 patients (20%) had urinary or bowel dysfunctions. Nine of them were managed using medications. Clean intermittent catheterization was practiced in another five patients. The remaining five underwent further surgical interventions. CONCLUSION: Favorable outcomes were achieved in our country during the last decade. Diverse perineal incisions were performed for resection, and vertical elliptical with midline closure was the commonest. During follow-up, 20% of patients developed urological or bowel dysfunctions that required medical and surgical treatment modalities to improve their quality of life.

De-epithelialized overlap flap to secure urethroplasty in second stage hypospadias repair: revisiting the Smith technique.

BACKGROUND: The application of a second layer between the neourethra and skin was a major contribution, which has improved the outcome of hypospadias repair. Here, we report our experience of revisiting the original Smith technique using a de-epithelialized overlap flap to support the urethroplasty in staged hypospadias repair. METHODS: The study included primary cases of proximal hypospadias with significant chordee who underwent two-stage repair during the period 2016 through 2021. The ventral curvature was corrected at first stage by excision of the urethral plate, followed by covering the ventral shaft by skin flaps or inner preputial graft. The second stage (Thiersch -Duplay urethroplasty) was performed six months later. The de-epithelialized overlap flap (double breasting) technique was used to cover the neo-urethra in all cases, which was combined with a dartos scrotal flap to cover the proximal neourethra when indicated. RESULTS: The study included 17 boys with proximal hypospadias who underwent two-stage repair. Follow up period after the second stage ranged between 6 and 30 months (mean 19.7; median 18.5). Post-operative complications were detected in 7 cases (41%). Most complications were related to distal/glanular disruptions whether partial or complete (5 cases). One case developed a penoscrotal fistula that was closed surgically. Another case (belonging to the group which used preputial graft in the 1st stage) presented 21 months after the second stage with urethral stricture (penoscrotal). CONCLUSION: Applying the de-epithelialized double-breasting skin closure can offer alternative second layer coverage for the neourethra along the penile shaft in staged repair of proximal hypospadias.

Use of N-(4-aminophenyl)piperidine derivatization to improve organic acid detection with supercritical fluid chromatography-mass spectrometry.

The analysis of organic acids in complex mixtures by LC-MS can often prove challenging, especially due to the poor sensitivity of negative ionization mode required for detection of these compounds in their native (i.e., underivatized or untagged) form. These compounds have also been difficult to measure using supercritical fluid chromatography (SFC)-MS, a technique of growing importance for metabolomic analysis, with similar limitations based on negative ionization. In this report, the use of a high proton affinity N-(4-aminophenyl)piperidine derivatization tag is explored for the improvement of organic acid detection by SFC-MS. Four organic acids (lactic, succinic, malic, and citric acids) with varying numbers of carboxylate groups were derivatized with N-(4-aminophenyl)piperidine to achieve detection limits down to 0.5 ppb, with overall improvements in detection limit ranging from 25-to-2100-fold. The effect of the derivatization group on sensitivity, which increased by at least 200-fold for compounds that were detectable in their native form, and mass spectrometric detection are also described. Preliminary investigations into the separation of these derivatized compounds identified multiple stationary phases that could be used for complete separation of all four compounds by SFC. This derivatization technique provides an improved approach for the analysis of organic acids by SFC-MS, especially for those that are undetectable in their native form.

The Potential Effects of Quercetin-Loaded Nanoliposomes on Amoxicillin/Clavulanate-Induced Hepatic Damage: Targeting the SIRT1/Nrf2/NF-κB Signaling Pathway and Microbiota Modulation.

Amoxicillin/clavulanate (Co-Amox), a commonly used antibiotic for the treatment of bacterial infections, has been associated with drug-induced liver damage. Quercetin (QR), a naturally occurring flavonoid with pleiotropic biological activities, has poor water solubility and low bioavailability. The objective of this work was to produce a more bioavailable formulation of QR (liposomes) and to determine the effect of its intraperitoneal pretreatment on the amelioration of Co-Amox-induced liver damage in male rats. Four groups of rats were defined: control, QR liposomes (QR-lipo), Co-Amox, and Co-Amox and QR-lipo. Liver injury severity in rats was evaluated for all groups through measurement of serum liver enzymes, liver antioxidant status, proinflammatory mediators, and microbiota modulation. The results revealed that QR-lipo reduced the severity of Co-Amox-induced hepatic damage in rats, as indicated by a reduction in serum liver enzymes and total liver antioxidant capacity. In addition, QR-lipo upregulated antioxidant transcription factors SIRT1 and Nrf2 and downregulated liver proinflammatory signatures, including IL-6, IL-1ß, TNF-α, NF-κB, and iNOS, with upregulation in the anti-inflammatory one, IL10. QR-lipo also prevented Co-Amox-induced gut dysbiosis by favoring the colonization of Lactobacillus, Bifidobacterium, and Bacteroides over Clostridium and Enterobacteriaceae. These results suggested that QR-lipo ameliorates Co-Amox-induced liver damage by targeting SIRT1/Nrf2/NF-κB and modulating the microbiota.

Enhancement of biochemical and genomic pathways through lycopene-loaded nano-liposomes: Alleviating insulin resistance, hepatic steatosis, and autophagy in obese rats with non-alcoholic fatty liver disease: Involvement of SMO, GLI-1, and PTCH-1 genes.

Non-alcoholic fatty liver (NAFL) is a prevalent hepatic disorder of global significance that can give rise to severe complications. This research endeavor delves into the potential of nano-liposomal formulated Lycopene (Lip-Lyco) in averting the development of obesity and insulin resistance, both of which are major underlying factors contributing to NAFL. The investigation further scrutinizes the impact of Lip-Lyco on intricate cellular pathways within the liver tissue of rats induced with NAFL, specifically focusing on the progression of steatosis and fibrosis. To establish an obesity-NAFL model, twenty rats were subjected to a high-fat diet (HFD) for a duration of twelve weeks, after which they received an oral treatment of Lip-Lyco (10mg/kg) for an additional eight weeks. Another group of sixteen non-obese rats were subjected to treatment with or without Lip-Lyco, serving as a control for comparison. Results: The rats on a hypercaloric diet had high body mass index (BMI) and insulin resistance, reflected in disturbed serum adipokines and lipid profiles. Oxidative stress, inflammation, and apoptosis were evident in hepatic tissue, and the autophagic process in hepatocytes was inhibited. Additionally, the hedgehog pathway was activated in the liver tissue of NAFL group. Lip-Lyco was found to counteract all these aspects of NAFL pathogenesis. Lip-Lyco exhibited antioxidant, anti-inflammatory, hypoglycemic, antiapoptotic, autophagy-inducing, and Hedgehog signaling inhibitory effects. This study concludes that Lip-Lyco, a natural compound, has promising therapeutic potential in combating NAFLdisease. However, more experimental and clinical studies are required to confirm the effectiveness of lycopene in treating NAFLdisease.

Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells.

Roles for the baculoviral inhibitor of apoptosis repeat-containing (BIRC) genes, BIRC2 and BIRC3, may include signaling to the inflammatory transcription factor, nuclear factor-κB (NF-κB) and protection from cell death. However, distinct functions for each BIRC are not well-delineated. Given roles for the epithelium in barrier function and host defence, BIRC2 and BIRC3 expression was characterized in pulmonary epithelial cell lines and primary human bronchial epithelial cells (pHBECs) grown as undifferentiated cells in submersion culture (SC) or as highly differentiated cells at air-liquid interface (ALI). In A549 cells, interleukin-1ß (IL1B) and tumor necrosis factor α (TNF) induced BIRC3 mRNA (~20-50-fold), with maximal protein expression from 6-24 h. Similar effects occurred in BEAS-2B and Calu-3 cells, as well as SC and ALI pHBECs. BIRC2 protein was readily detected in unstimulated cells, but was not markedly modulated by IL1B or TNF. Glucocorticoids (dexamethasone, budesonide) modestly increased BIRC3 mRNA and protein, but showed little effect on BIRC2 expression. In A549 cells, BIRC3 mRNA induced by IL1B was unchanged by glucocorticoids and showed supra-additivity with TNF-plus-glucocorticoid. Supra-additivity was also evident for IL1B-plus-budesonide induced-BIRC3 in SC and ALI pHBECs. Using A549 cells, IL1B- and TNF-induced BIRC3 expression, and to a lesser extent, BIRC2, was prevented by NF-κB inhibition. Glucocorticoid-induced BIRC3 expression was prevented by silencing and antagonism of the glucocorticoid receptor. Whereas TNF, but not IL1B, induced degradation of basal BIRC2 and BIRC3 protein, IL1B- and TNF-induced BIRC3 protein remained stable. Differential regulation by cytokines and glucocorticoids shows BIRC2 protein expression to be consistent with roles in rapid signaling events, whereas cytokine-induced BIRC3 may be more important in later effects. While TNF-induced degradation of both BIRCs may restrict their activity, cytokine-enhanced BIRC3 expression could prime for its function. Finally, shielding from glucocorticoid repression, or further enhancement by glucocorticoid, may indicate a key protective role for BIRC3.

Perforated gallbladder in neonates with review of literature.

INTRODUCTION: Neonatal perforated gallbladder is a rare and implausible surgical emergency. Pneumoperitonium and neonatal intestinal obstruction are the main clinical presentations. Many cases of neonatal perforated gallbladder had no clear pathology. Most proper treatment is cholecystectomy during formal exploration. CASE PRESENTATION: We reported a case of male neonate in his first days of life, presented with abdominal distention and pneumoperitonium and so, surgical exploration revealed perforated gallbladder for which cholecystectomy done. CLINICAL DISCUSSION: Idiopathic gallbladder perforation is seldom condition and is hard to discover before exploration. Besides, pathogenesis remains unknown. In our presented case, the real cause of perforation was unknown and main presentation was pneumoperitonium. CONCLUSION: Although perforated gallbladder is a rare entity and in most of cases does not cause pneumoperitonium, but perforated gallbladder should be taken in account of all cases of pneumoperitonium.

Liposome-Encapsulated Berberine Alleviates Liver Injury in Type 2 Diabetes via Promoting AMPK/mTOR-Mediated Autophagy and Reducing ER Stress: Morphometric and Immunohistochemical Scoring.

In the advanced stages of type 2 diabetes mellitus (T2DM), diabetic liver damage is a common complication that can devastate a patient's quality of life. The present study investigated the ability of liposomal berberine (Lip-BBR) to aid in ameliorating hepatic damage and steatosis, insulin homeostasis, and regulating lipid metabolism in type 2 diabetes (T2DM) and the possible pathways by which it does so. Liver tissue microarchitectures and immunohistochemical staining were applied during the study. The rats were divided into a control non-diabetic group and four diabetic groups, which are the T2DM, T2DM-Lip-BBR (10 mg/kg b.wt), T2DM-Vildagliptin (Vild) (10 mg/kg b.wt), and T2DM-BBR-Vild (10 mg/kg b.wt + Vild (5 mg/kg b.wt) groups. The findings demonstrated that Lip-BBR treatment could restore liver tissue microarchitectures, reduce steatosis and liver function, and regulate lipid metabolism. Moreover, Lip-BBR treatment promoted autophagy via the activation of LC3-II and Bclin-1 proteins and activated the AMPK/mTOR pathway in the liver tissue of T2DM rats. Lip-BBR also activated the GLP-1 expression, which stimulated insulin biosynthesis. It decreased the endoplasmic reticulum stress by limiting the CHOP, JNK expression, oxidative stress, and inflammation. Collectively, Lip-BBR ameliorated diabetic liver injury in a T2DM rat model with its promotion activity of AMPK/mTOR-mediated autophagy and limiting ER stress.

Recent Advances of Ocular Drug Delivery Systems: Prominence of Ocular Implants for Chronic Eye Diseases.

Chronic ocular diseases can seriously impact the eyes and could potentially result in blindness or serious vision loss. According to the most recent data from the WHO, there are more than 2 billion visually impaired people in the world. Therefore, it is pivotal to develop more sophisticated, long-acting drug delivery systems/devices to treat chronic eye conditions. This review covers several drug delivery nanocarriers that can control chronic eye disorders non-invasively. However, most of the developed nanocarriers are still in preclinical or clinical stages. Long-acting drug delivery systems, such as inserts and implants, constitute the majority of the clinically used methods for the treatment of chronic eye diseases due to their steady state release, persistent therapeutic activity, and ability to bypass most ocular barriers. However, implants are considered invasive drug delivery technologies, especially those that are nonbiodegradable. Furthermore, in vitro characterization approaches, although useful, are limited in mimicking or truly representing the in vivo environment. This review focuses on long-acting drug delivery systems (LADDS), particularly implantable drug delivery systems (IDDS), their formulation, methods of characterization, and clinical application for the treatment of eye diseases.

Isolation and identification of novel selective antitumor constituents, sidrin and sidroside, from Zizyphus spina-christi.

Background: The leaves of Zizyphus spina-christi (L.) Willd contain several compounds exhibiting different pharmacologic activities. However, studies on the cytotoxic activity of these compounds are limited. Objectives: We aimed to investigate and isolate cytotoxic compounds with selective antitumor effects from the leaves of Z. spina-christi using bioassay-guided fractionation of methanol extract. Methods: Powdered, dried leaves were subjected to methanol extraction and fractionated using n-hexane, chloroform, ethyl acetate, and n-butanol. Fractions with positive cytotoxicity against HeLa and THP-1 cell lines were further fractionated and eluted using various concentrations of organic solvents. Active compounds were isolated using different chromatographic methods and their chemical structures were determined using extensive spectroscopic methods, such as 1D NMR (1H NMR, 13C NMR, and DEPT), 2D NMR (COSY, HMBC, and HMQC), HRFAB-MS, and IR. Furthermore, the cytotoxic effects of the isolated compounds were evaluated against 62 tumor cell lines (including HeLa and THP-1) in addition to normal bone marrow cells. Results: The chloroform and aqueous methanol fractions of the leaves showed cytotoxic activity. Two compounds were successfully isolated and named "sidrin" (13-ß-hydroxy-lup-20(30)-ene-2,3-ß-epoxy-28-carboxylate) and "sidroside" (3-O-ß-D-glucopyranosyl-(1-3)-α-L-arabinopyranosyl-jujubogenin-20-O-α-L-rhamnopyranoside). Sidrin exhibited cytotoxic activity against the human leukemia (Hl-60, RPMI-8226), lung cancer (A549, EKVX), breast cancer (BT-549, MDA-MB-231/ATCC), colon cancer (KM12), melanoma (M14, SK-MEL-5), and central nervous system (CNS) cancer (SF-295) cell lines, and selectivity was observed against the Hl-60, EKVX, BT-549, KM12, and SF-295 cell lines. In addition, sidrin was more active than sidroside and doxorubicin against the Hl-60 and EKVX cell lines. In contrast, sidrin had a similar effect to doxorubicin against the BT-549 and renal cancer (UO-31) cell lines. Sidroside was more selective against the leukemia (CCRF-CEM, MOLT-4), lung cancer (HOP-92, NCI-H322M), breast cancer (MDA-MB-468), melanoma (LOX IMVI), CNS cancer (SNB-19), ovarian cancer (OVCAR-8), renal cancer (UO-31, RXF 393), and prostate cancer (PC-3) cell lines. Both compounds exhibited similar activity against the breast cancer (MDA-MB-231, T-47D), colon cancer (HCC-2998, HCT-116), ovarian cancer (OVCAR-3), renal cancer (UO-31, 786-0, and SN 12C) cell lines. Normal bone marrow cells were unaffected at the same concentrations of sidrin and sidroside applied to tumor cells. Conclusions: These results suggest tumor-selective cytotoxicity of sidrin and sidroside.

Overexpression of Krüppel-Like Factor 9 Enhances the Antitumor Properties of Paclitaxel in Malignant Melanoma-Derived Cell Lines.

Over the past decade, the treatment of metastatic melanoma has improved significantly due to the development of innovative therapies, such as drugs that target the BRAF/MAPK kinase pathway and the PD-1 pathway. However, these therapies do not work for all patients, highlighting the need for additional research on the pathophysiology of melanoma. Paclitaxel is a chemotherapeutic agent used when first-line treatments are unsuccessful; however, its efficacy is limited. Since Krüppel-like factor 9 (KLF9) (antioxidant repressor) is downregulated in melanoma, we propose that restoring KLF9 levels may sensitize malignant melanoma to chemotherapeutic agents, such as paclitaxel. We used adenovirus overexpression and siRNA technologies to assess the role of KLF9 in mediating the response of malignant melanoma-derived cell lines RPMI-7951 and A375 to paclitaxel treatment. We found that increasing KLF9 levels potentiates the effectiveness of paclitaxel, as shown by apoptotic parameters such as decreased cell viability, pro-caspase-3 activation, increased number of annexin V-positive cells, and reduction in nuclear proliferation marker (KI67). These results suggest that KLF9 may be a potential target for improving chemotherapeutic response in melanoma.

Supercritical Fluid Nanospray Mass Spectrometry: II. Effects on Ionization.

Nanospraying supercritical fluids coupled to a mass spectrometer (nSF-MS) using a 90% supercritical fluid CO2 carrier (sCO2) has shown an enhanced desolvation compared to traditional liquid eluents. Capillaries of 25, 50, and 75 µm internal diameter (i.d.) with pulled emitter tips provided high MS detection sensitivity. Presented here is an evaluation of the effect of proton affinity, hydrophobicity, and nanoemitter tip size on the nSF-MS signal. This was done using a set of primary, secondary, tertiary, and quaternary amines with butyl, hexyl, octyl, and decyl chains as analytes. Each amine class was analyzed individually to evaluate hydrophobicity and proton affinity effects on signal intensity. The system has shown a mass sensitive detection on a linear dynamic range of 0.1-100 µM. Results indicate that hydrophobicity has a larger effect on the signal response than proton affinity. Nanospraying a mixture of all amine classes using the 75 µm emitter has shown a quaternary amine signal not suppressed by competing analytes. Competing ionization was observed for primary, secondary, and tertiary amines. The 75 and 50 µm emitters demonstrated increased signal with increasing hydrophobicity. Surprisingly, the 25 µm i.d. emitter yielded a signal decrease as the alkyl chain length increased, contrary to conventional understanding. Nanospraying the evaporative fluid in a sub-500 nm emitter likely resulted in differences in the ionization mechanism. Results suggest that 90% sCO2 with 9.99% methanol and 0.01% formic acid yielded fast desolvation, high ionization efficiency, and low matrix effect, which could benefit complex biological matrix analysis.

Ginkgo biloba leaves extract's cosmeceutical evaluation: a preliminary assessments on human volunteers towards achieving improved skin condition and rejuvenation.

BACKGROUND: Ginkgo biloba (GB) leaves extract is known to possess potent antioxidants and other bioactivities such as improved skin conditions and rejuvenation. OBJECTIVE: This study aimed to develop a cosmeceutical preparation to utilize the strong antioxidant potential of GB leaves as part of the skincare formulation. METHODS: Cream incorporated GB (GBC) was prepared by mixing the obtained extract with stearic acid-sodium hydroxide components in an emulsion format. The obtained GBC was characterized for GB contents, uniformity, pH, compatibility, stability, and skin's human application. RESULTS: A homogeneous, physically, and chemically stable, with pH near the skin pH and shiny cream, was obtained. The prepared cream was easy to rub and pearly in appearance. It was effective and safe during the two-week trial conducted on human volunteers according to clinical trial registry protocols. The cream scavenged free radicals in DPPH assay tests. The cream incorporated GB made the skin more spirited and tauter. Furthermore, the wrinkles were reduced and the skin was renewed vigor. CONCLUSION: The GBC worked at the topical level and provided benefits when applied daily for the trial duration. The formulation also provided visually observable anti-wrinkle effects on the skin, with visible improvements in the skin's shape and texture. The prepared cream can be used to rejuvenate the skin.