E-cigarette use among university students in Palestine: Prevalence, knowledge, and determinant factors.

BACKGROUND: Recent reports indicated accelerated rates of e-cigarette use, especially among youth in various Middle Eastern countries, including Palestine. Nevertheless, little is known about knowledge, attitudes, and perceptions regarding this topic in Palestine. This study aimed to assess the prevalence of e-cigarette use among Palestinian university students, along with their knowledge, attitudes, and perceptions about e-cigarette use. METHODS: An observational cross-sectional study, utilizing an online self-administered questionnaire, was conducted on Palestinian students from five universities between 17/04/2023 and 04/11/2023. RESULTS: A total of 1002 Palestinian university students completed the questionnaire. The prevalence of e-cigarette use among students was 18.1%. The mean knowledge score about e-cigarettes was significantly lower among the users of e-cigarettes compared to non-users. E-cigarette use was significantly associated with the participants' smoking status. Among e-cigarette users, 43.6% were also current traditional cigarette users, and 66.9% were current waterpipe users. E-cigarette use was significantly associated with having a friend who is a smoker and/ or a smoking mother. Binary logistic regression revealed a significant positive effect between the participant's smoking status, the mother's smoking status, knowledge about e-cigarettes, and the use of e-cigarettes (p-value < 0.05). Among e-cigarette users, 18.8% used them in indoor places at the university, and 25% reported using them daily in the past month. Affordability of e-cigarettes was the most reported reason for their use (47.5%). CONCLUSION: This study concluded that e-cigarette use is prevalent and rapidly rising among university students in Palestine. This is worrisome as it is significantly associated with insufficient knowledge about the adverse health effects of E-cigarette use, and its addictive nature. These findings focus on the importance of improving the students' knowledge about e-cigarette use by implementing educational campaigns and considering age regulations on e-cigarette availability and use.

Evaluation of knowledge and attitudes regarding Alzheimer's disease and related dementia among medical students in Palestine: A cross-sectional study.

INTRODUCTION: Dementia, a major global health concern, is an acquired disorder that causes a progressive decline in cognitive abilities, affecting learning and memory, language, executive function, complex attention, perceptual-motor skills, and social cognition. Our study aims to evaluate the knowledge and attitudes regarding dementia and Alzheimer's disease among medical students. METHODS: This cross-sectional study was conducted among 393 medical students in Palestine from August 2023 to November 2023. The assessment of knowledge and attitude toward dementia was measured using the Alzheimer's Disease Knowledge Scale (ADKS) and Dementia Attitude Scale (DAS). The data were analyzed using SPSS version 26, and the Mann-Whitney U-test and the Kruskal-Wallis test were used to compare the mean between the groups with a 5% significance level. RESULTS: The overall mean score of the student's knowledge of dementia measured by the ADKS was 18.91 (±3.32 SD) out of 30. The mean score of the student's attitude toward dementia measured by the DAS was 91.68 (±3.32 SD). Clinical students had higher ADKS scores than pre-clinical students (p-value < 0.001). No significant differences in the knowledge and attitudes toward dementia were found between males and females. The medical students' knowledge and attitude scores were positively correlated (ρ = 0.227, p-value <0.001). CONCLUSION: Palestinian medical student's knowledge about Alzheimer's disease and dementia is insufficient, with students in the clinical phase showing better understanding than pre-clinical students. The findings highlight a necessity for enhancing the dementia curriculum and conducting further studies to evaluate training's impact on students' knowledge and attitudes.

Total phenolic contents, cytotoxic, free radicals, porcine pancreatic α-amylase, and lipase suppressant activities of Artemisia dracunculus plant from Palestine.

Artemisia dracunculus: L. (A. dracunculus) is a popular vegetable and spice cultivated across many Middle Eastern countries. The herb's aqueous extract has significant folkloric medicinal importance for treating various disorders. Hence, the present investigation aimed to investigate A. dracunculus hydrophilic extract phytochemical constituents and pleiotropic biological potentials, as no previous studies have investigated the antilipase and anti-α-amylase effects of the A. dracunculus plant. Total phenol content and phytochemical screening assays were performed utilizing standard analytical methods. While the α-amylase inhibition, free radical-scavenging, antilipase, and cytotoxic activities were determined using dinitrosalicylic acid (DNSA), DPPH, p-nitrophenyl butyrate (PNPB), and MTS assays, respectively. The standard phytochemical analysis of A. dracunculus aqueous extract shows that this extract contains only a phenolic group. The total phenol content was 0.146 ± 0.012 mg GAE/g of the plant dry extract. The A. dracunculus aqueous extract exhibited potent DPPH free radical inhibitory (IC50 dose of 10.71 ± 0.01 µg/mL) and anti-lipase activities (IC50 dose of 60.25 ± 0.33 µg/mL) compared with Trolox (IC50 = 5.7 ± 0.92 µg/mL) and Orlistat (IC50 = 12.3 ± 0.35 µg/mL), respectively. However, it showed a weak anti-α-amylase effect (IC50 value > 1,000 µg/mL) compared with Acarbose (IC50 = 28.18 ± 1.27 µg/mL). A. dracunculus has a cytotoxic effect against the HeLa cancer cell line compared with the chemotherapeutic agent Doxorubicin. The extract has the same percent of inhibition as Doxorubicin (99.9%) at 10 mg/mL. Overall, these results pointed out for the first time the importance of considering A. dracunculus effects as a favorite candidate for preventing and treating metabolic disorders. Also, our results confirm the findings of previous reports on the role of A. dracunculus in the management of cancer and disorders resulting from the accumulation of harmful free radicals. On the contrary, the current study concluded that the antidiabetic role of A. dracunculus could be minimal. Further in-depth investigations are urgently warranted to explore the importance of A. dracunculus in pharmaceutical production.

Factor VII Deficiency in an End-Stage Renal Disease Patient With Recurrent Thrombosis: A Case Report.

Congenital factor VII deficiency is a rare bleeding disorder with variable presentations. Thromboembolism is a well-established complication of this heterogeneous disease. As it is a rare disease, there is no information regarding its treatment when it is present with other comorbidities such as end-stage renal disease. This study describes a 47-year-old male with multiple comorbidities who was recently diagnosed with end-stage renal disease. He had recurrent admissions to the hospital due to thrombotic arteriovenous access failure as well as acute coronary syndrome, despite a high international normalized ratio that was resistant to replacement therapy. Eventually, apixaban became his main treatment regimen. This case needs to be reported because it is rare in terms of including a factor VII deficiency patient with end-stage renal disease, as well as to emphasize the unclear recommendations available for patients with factor VII deficiency and end-stage renal disease. International collaboration may be the best course of action to study enough patients and come up with effective recommendations.

Assessment of Perceptions and Predictors Towards Consanguinity: A Cross-Sectional Study from Palestine.

Background/Aim: Consanguinity represents a biological relationship between two individuals. In clinical genetics, it specifically refers to the marriage between individuals who are second cousins or closer. The aim of the study is to assess perceptions and their predictors among the Palestinian population towards consanguinity. Methods: A survey-based cross-sectional study was conducted. The sample was collected using convenience and snowball sampling methods, yielding a sample of 1008 participants. The perceptions towards consanguinity and its predictors were assessed using Chi-square test. Results: The prevalence of consanguinity among married participants was 18.7% (N = 81/432), while it was 28.8% among their parents. Consanguinity rate was significantly low among the young age group (ie, <47 years old) and among participants whose mothers have undergraduate educational levels (P < 0.05). Other factors like parental consanguinity, educational level of participants, their father's educational level, and residency place showed no significant associations (P > 0.05). Rejection of consanguinity was significantly noted among young age participants, absence of parental consanguinity, the presence of children or family members with genetic disorders and female gender (P < 0.001). Furthermore, participants who indicated that they are governmental employees, those with 2000-5000 ILS monthly income, those who are married (P < 0.01), and those who indicated that their mothers are holders of postgraduate degree were significantly more likely to reject the idea of consanguinity (P < 0.05). Also, medical and/or scientific reasons were significantly associated with rejecting the idea of consanguinity (P < 0.001). Conclusion: Consanguinity prevalence has decreased among recent generations in Palestine, but it remains a significant challenge in Palestine. Therefore, educational and awareness programs about consanguinity and its health effects are effective strategies for reducing the consanguinity rate, especially for persons who are at the age of marriage.

Weaker SARS-CoV-2 vaccine responses in nonalcoholic fatty liver disease with advanced liver fibrosis.

Background: SARS-CoV-2 vaccine responses that could harbor potential risks to chronic liver diseased patients. Aims: To assess immune response following Pfizer's SARS-CoV-2 vaccine in patients with different liver fibrosis severities of nonalcoholic fatty liver disease (NAFLD). Methods: Clinical and histological (NAS-score and fibrosis stage) characteristics of NAFLD patients before vaccine were correlated with serologic vaccine responses of two doses of the BNT162b2. Serum SARS-CoV-2 spike immunoglobulins (anti-S) were assessed on day seven following immunization (Liaison assay). Results: The mean-age of patients (n = 157) was 56.9 ± 13.2 years (46.5 % males). 94.8 % had a positive response (anti-S levels ≥ 19 AU/ml). The anti-S cutoff of 200 AU/ml used to separate strong vs. weak responses. A strong response (anti-S titers ≥ 200 AU/ml) was observed in 93/157 (59.2 %) patients with a mean-age of 53.1 ± 13.8 years (45.2 % males). A weak response (anti-S titers < 200 AU/ml) was observed in 64/157 (40.8 %) cases with a mean-age of 62.3 ± 10.2 years (p < 0.0001). The strong response subgroup had lower metabolic comorbidities, including glucose hemostasis, hypertension, and dyslipidemia (p < 0.04). Moreover, the strong response subgroup had fibrosis stages F0-F2 (75.3 % vs. 56.3 %) and lower rates of advanced stages F3-F4 (24.7 % vs. 43.8 %). The F0-F2 subgroups had significantly higher rates of strong responses than the F3-F4 stages. The anti-S ≥ 200 and anti-S ≥ 400 AU/ml response achieved in 66 % and 36.8 % of the F0-F2 population was significantly higher than the 45.1 % (p = 0.006) and 23.5 % (p = 0.05) in the F3-F4 population, respectively. The Fib-4 calculations and Fibroscan evaluations were consistent with histologic fibrosis assessment. Conclusion: Advanced liver fibrosis (assessed by histology, Fib-4, or Fibroscan) is a risk factor for lower response to Pfizer's BNT162b2 vaccine, and patients should be prioritized for the vaccine booster against SARS-CoV-2.

The immune and metabolic treatment approach of using testosterone on mice models of liver injury.

Background: Natural killer (NK) cells showed an anti-fibrotic effect; however, their function is thought to be impaired in advanced liver injury. In the current study, we aimed to assess the immune and metabolic impact of testosterone on mice models of liver injury. Methods: Carbon-tetrachloride induced liver fibrosis male mice models was i.p injected for 2 weeks (acute) and 4 weeks (chronic) (n = 36). Testosterone (4 mg/kg mouse body weight) was injected i.p. following the first week of the acute model of CCl4 and following the second week of the chronic model of CCl4. At the end of the experiments, mice were sacrificed, and serum was collected for assessing liver enzymes of ALT and AST, as well as inflammatory markers of IL-6, metabolic makers of C-peptide levels, and lipid and glucose profiles. Livers were harvested and used for histological assessments for inflammation and fibrosis. Fibrosis profiles from liver extracts, αSMA and Collagen III, were assessed by RT-PCR. Moreover, liver tissue-resident NK cells were isolated and evaluated for their activity by assessing INF-γ and IL-6 receptors using ELISA and flow cytometry, respectively. Results: Serum ALT, AST, and IL-6, as well as metabolic assessments of cholesterol, triglyceride, C-peptide, fasting blood sugar, and fibrotic profiles, were linearly correlated with disease progressions. Histological characterization of the liver was worsened in the chronic model of liver injury. Testosterone-treated mice exhibit a significant reduction in collagen depositions with less dense fibrosis tissue associated with reduced liver injury enzymes and metabolic markers in both the acute and chronic CCl4 mice models in favor of the latter one (p < 0.05). Moreover, testosterone treatments displayed a significant decrease in serum IL-6 of 2.4-fold (p = 0.0001) and 2.3-fold (p = 0.0003) in the acute and chronic models, respectively (p = 0.002), and data showed an increase in INF-γ release from NK associated with a reduction in their IL-6 receptor expressions (p < 0.05). Conclusion: Our results indicated effects of testosterone on mediating a decreased expressions of NK IL-6 receptors and consequently inducing their activation; which in part, could explain the amelioration of liver injury. Our data suggest an anti-inflammatory and anti-fibrotic treatment approach of using testosterone for delaying disease progressions.

Arum palaestinum delays hepatocellular carcinoma proliferation through the PI3K-AKT-mTOR signaling pathway and exhibits anticoagulant effects with antimicrobial properties.

Background: Arum palaestinum Boiss (AP) is a wild plant in Palestine whose leaves have a long history as food and medicine in Middle Eastern countries. The current study aimed to evaluate the biological characteristics of AP flower extract, including its antimicrobial and coagulation cascade activities and its effects on anticancer molecular pathways. Methods: The antimicrobial activity of the aqueous extract of AP flowers was assessed using a microdilution assay against eight pathogens. The coagulation properties were assessed by prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time (TT) tests using standard hematological methods. The biological effects of AP on hepatocellular carcinoma were measured by assessing the impact of AP on cell cycle, proliferation (CFSE), apoptosis (annexin-v+/PI), and tumorigenicity (αFP and HBsAg), as well as its effects on the PI3K-AKT-mTOR molecular signaling pathway. Results: The antimicrobial screening results revealed that the aqueous extract of AP had potent antibacterial effects against P. vulgaris and E. faecium compared to ampicillin, with MIC values of 6.25, 6.25, and 18 µg/mL, respectively. Moreover, the AP aqueous extract exerted anticoagulant activity, with significant prolonged results in the aPTT and TT tests (25 µg/mL and 50 µg/mL, respectively) and slightly prolonged results in the PT test (50 µg/mL). The anticancer results indicated a delay in the cell cycle through decreased cell proliferation rates following incubation with AP fractions. The effect of the aqueous fraction was most evident in a delay in the S phase. The aqueous and DMSO fractions maintained the cells in the G2-M phase, similar to the DOX, while the flower extract in methanol accelerated the cells in the G2-M phase, suggesting that AF flower extracts may have anti-cancer properties. The aqueous extract of AP 1) reduced secretions of HCC αFP by 1.55-fold and 3.3-fold at the 50 and 100 µg/mL concentrations, respectively (p = 0.0008); 2) decreased phosphorylation in the PI3K-AKT-mTOR signaling pathway (p < 0.05); and 3) shifted cells from necrosis to apoptosis by 50% and 70% at the 50 and 100 µg/mL concentrations, respectively (p < 0.05). Conclusion: The results of this study showed the activities of the bioactive components for the treatment of infectious diseases and blood coagulation disorders, which could also be a potential therapeutic approach for delaying HCC tumorigenicity.

CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis.

ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.

Alleviation of Hepatic Steatosis by Alpha-Defensin Is Associated with Enhanced Lipolysis.

Background and Objectives: The neutrophilic peptide, alpha-defensin, is considered an evolving risk factor intimately linked with lipid mobilization. It was previously linked to augmented liver fibrosis. Here, we assess a potential association between alpha-defensin and fatty liver. Materials and Methods: A cohort of transgenic C57BL/6JDef+/+ male mice that overexpress the human neutrophil-derived alpha-defensin in their polymorphonuclear neutrophils (PMNs) were assessed for liver steatosis and fibrosis development. Wild type (C57BL/6JDef.Wt) and transgenic (C57BL/6JDef+/+) mice were maintained on a standard rodent chow diet for 8.5 months. At the termination of the experiment, systemic metabolic indices and hepatic immunological cell profiling were assessed. Results: The Def+/+ transgenic mice exhibited lower body and liver weights, lower serum fasting glucose and cholesterol, and significantly lower liver fat content. These results were associated with impaired liver lymphocytes count and function (lower CD8, NK cells, and killing marker CD107a). The metabolic cage demonstrated dominant fat utilization with a comparable food intake in the Def+/+ mice. Conclusions: Chronic physiological expression of alpha-defensin induces favorable blood metabolic profile, increased systemic lipolysis, and decreased hepatic fat accumulation. Further studies are needed to characterize the defensin net liver effect.

SARS-CoV-2 vaccine alleviates disease burden and severity in liver transplant recipients even with low antibody titers.

BACKGROUND AND AIMS: We retrospectively assessed the clinical Pfizer's mRNA SARS-CoV-2 BNT162b2 vaccination outcomes and the serologic impact on liver transplant (LT) recipients. PATIENTS AND METHODS: One hundred and sixty-seven LT cases followed between March 1, 2020 and September 25, 2021, and were stratified into two groups: (1) 37 LT recipients after SARS-CoV-2 infection before vaccine era and (2) 130 LT recipients vaccinated with 2 doses without earlier SARS-CoV-2 exposure. Serum SARS-CoV-2 spike immunoglobulins (anti-S) were assessed 7 days following vaccination (Liaison assay). RESULTS: In addition to the 37 nonvaccinated cases (22.2% of total group) who experienced SARS-CoV-2 infection (34 symptomatic and 3 asymptomatic), another 8 vaccinated symptomatic recipients (4.8%) were infected (5 from the third and three from the fourth waves). Three of the 45 infected cases died (6.7%) before the vaccine program. Vaccinated group: of the 130 LT vaccinated recipients, 8 (6.2%) got infected postvaccination (added to the infected group) and were defined as clinical vaccine failure; 38 (29.2%) were serological vaccine failure (total failure 35.4%), and 64.6% cases were serological vaccine responders (anti-S≥19 AU/mL). Longer post-LT interval and lower consumption of immunosuppressants (steroids, FK506, and mycophenolate mofetil) correlated with favorable SARS-CoV-2 vaccine response. Mammalian target of rapamycin inhibitors improved vaccine outcomes associated with lower FK506 dosages and serum levels. Patients with anti-S levels <100 AU/mL risked losing serologic response or being infected with SARS-CoV-2. A booster dose achieved an effective serologic response in a third of failures and most responders, securing better and possibly longer protection. CONCLUSION: Pfizer's BNT162b2 vaccine seems to lessen SARS-CoV-2 morbidity and mortality of LT recipients even with weak serological immunogenicity. Switching mycophenolate mofetil to mammalian target of rapamycin inhibitors might be effective before boosters in vaccine failure cases. A booster vaccine should be considered for nonresponders and low-responders after the second dose.

Gundelia tournefortii inhibits hepatocellular carcinoma progression by lowering gene expression of the cell cycle and hepatocyte proliferation in immunodeficient mice.

Gundelia (G.) tournefortii has antibacterial, anti-inflammatory, and hypolipemic effects. We evaluated the anticancer effect of G. tournefortii in an hepatocellular carcinoma (HCC) mouse model of an HCC cell line (Hep3B) injected into NOD.CB17-Prkdc-SCID/NCrHsD male mice. Tumorigenicity was assessed by tumor size, histology, serum α-fetoprotein (αFP), and glypican 3 (GPC3). HCC-related gene expression of the cell cycle (Cyclin-dependent kinase inhibitor 2A (CDNK2A)), proliferation (MKI67), and platelet-derived growth factor receptor α (PDGFA) were measured. HCC cell cycle alterations, apoptosis, and antioxidant markers in serum and liver following treatment with G. tournefortii were determined. Signaling pathways of liver p53 and phosphorylated PI3K, AKT, and mTOR were also evaluated. Results indicate a significant increase in tumor size in HCC animals associated with elevated αFP, GPC3, and MKI67. Tumor markers of p53 and phosphorylated AKT/PI3K/mTOR signaling pathway were diminished, with less proliferating cells and reduced PDGFRA gene expression following G. tournefortii infection. H&E staining showed a remarkable reduction in inflammatory lesions in HCC mice treated with G. tournefortii. This result was in line with a significant delay in the G2/M phase of HCC-primary hepatocytes by 1.39- to 2.4-fold and reduced HCC necrosis associated with inhibited CDNK2A gene expression. Antioxidant activity was significantly lower in the HCC mice than in the control group. Moreover, G. tournefortii inhibited the HCC formation of 3D MCTS spheroids. G. tournefortii treatment markedly restored antioxidant levels and displayed anticancer and antiproliferative effects and could be a promising cancer therapy.

A Retrospective Study Using Mentzer Index for Prevalence of Iron Deficiency Anemia among Infants Visiting Maternal Centers at the Age of One Year.

Anemia, defined as a hemoglobin level two standard deviations below the mean for age, is prevalent in infants and children worldwide. Characterizing anemia as microcytic and normocytic depends on the mean corpuscular volume (MCV), which is an important parameter in differentiating many types of anemia. Microcytic anemia due to iron deficiency is the most common type of anemia in children. In this study, we aimed to assess the Mentzer index used by the Ministry of Health (MOH) in Palestine as a useful tool in differentiating between iron deficiency anemia (IDA) and thalassemia. We assessed for the prevalence of IDA among infants at the age of one year visiting the mother centers from seven West Bank provinces in Palestine. Medical records and hematology laboratory data of 3262 infants were retrospectively analyzed from the years of 2018 to 2020. The Mentzer index applied to all population by dividing mean corpuscular volume (MCV, in fL) by the red blood cell count (RBC, in millions per microliter). A corrected Mentzer index was further calculated among anemic infants to include only microcytic (MCV with less than 72 fl) and hypochromic (mean corpuscular hemoglobin concentration (MCHC) with less than 32 g/L) indices. Mentzer index calculations for the whole population showed that 29.1% were anemic (hemoglobin (HGB) less than 11 g/dl): 21.1% had mild anemia, 7.6% had moderate anemia, while 0.2% had severe anemia. The corrected Mentzer index calculations showed a prevalence of 5.9% and 3.2% among IDA and thalassemia infants, respectively. Severity of anemia was correlated with low body weight and infants born through cesarean mother birth with no interference with gender influence. CBC indices of RBC count, HGB, MCV, and mean corpuscular hemoglobin (MCH) showed a significant difference (p values < 0.05) between IDA and thalassemia infants' populations following the corrected Mentzer index. With the corrected Mentzer index, we introduced a new CBC index among infants at the age of 1 year in Palestine. These lab references could aid in differentiating IDA and thalassemia among the population and improve initial diagnosis screenings. The Mentzer index calculation for the whole population did not necessarily include cases of IDA, and therefore, it is recommended to comprise microcytic and hypochromic anemia indices prior to performing the Mentzer index.

Ecballium elaterium improved stimulatory effects of tissue-resident NK cells and ameliorated liver fibrosis in a thioacetamide mice model.

Ecballium elaterium (EE), widely used plant in Mediterranean medicine, showed anticancer activity. This study aimed to investigate EE effects on liver fibrosis in an animal model of thioacetamide (TAA). Intraperitoneal administration of TAA was performed twice weekly for four weeks in C57BL6J mice. Livers were extracted and serum were evaluated for inflammatory markers (H&E staining, ALT, AST, ALP), pro-inflammatory cytokines, fibrosis (Sirius red staining, Masson's trichrome, α-smooth muscle actin and collagen III), and metabolic (cholesterol, triglyceride, C-peptide, and fasting-blood-sugar) profiles. Glutathione, glutathione peroxidase, and catalase liver antioxidant markers were assessed. Tissue-resident NK cells from mice livers were functionally assessed for activating receptors and cytotoxicity. Compared to vehicle-treated mice, the TAA-induced liver injury showed attenuation in the histopathology outcome following EE treatment. In addition, EE-treated mice resulted in decreased serum levels of ALT, AST, and ALP, associated with a decrease in IL-20, TGF-ß, IL-17, IL-22 and MCP-1 concentrations. Moreover, EE-treated mice exhibited improved lipid profile of cholesterol, triglycerides, C-peptide, and FBS. EE treatment maintained GSH, GPX, and CAT liver antioxidant activity and led to elevated counts of tissue-resident NK (trNK) cells in the TAA-mice. Consequently, trNK demonstrated an increase in CD107a and IFN-γ with improved potentials to kill activated hepatic-stellate cells in an in vitro assay. EE exhibited antifibrotic and antioxidative effects, increased the number of trNK cells, and improved metabolic outcomes. This plant extract could be a targeted therapy for patients with advanced liver injury.

Advanced Liver Fibrosis Correlates With Impaired Efficacy of Pfizer-BioNTech COVID-19 Vaccine in Medical Employees.

The Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine has been offered to nonallergic ≥16-year-old Israeli adults since December 19, 2020. Data regarding factors associated with vaccine ineffectiveness are limited. The aim of this study is to assess the impact of hepatic fibrosis on the efficacy of the BioNTech vaccine. Serum severe acute respiratory syndrome coronavirus 2 spike immunoglobulins (S IgG) obtained at least 7 days following vaccination completion was correlated with the prevaccine calculated Fibrosis-4 (FIB-4) score among 719 employees in the Hadassah Medical Center, Jerusalem. Positive vaccine response (S IgG levels ≥ 19 AU/mL) was found in 708 of 719 individuals (98.5%). Vaccine failure (S IgG levels < 19) was found in 11 (1.5%); of these, 7 were immunosuppressed. Mean FIB-4 available in 501 of 708 vaccine responders was 1.13 ± 0.66, mean age 51.4 ± 12.4 years (29.3% males), and mean S IgG titers 239.7 ± 86.1 AU/mL. Similar to the general population, 70.5% had normal FIB-4 (<1.3), 26.8% undetermined FIB-4 (1.3-2.67), and 2.7% advanced FIB-4 (>2.67). When divided into response subgroups, 158 of 501 individuals (30.1%) with IgG titers 19-100 AU/mL had a mean FIB-4 of 1.48 ± 0.82; 198 (39.5%) with IgG titers 101-200 AU/mL had mean FIB-4 of 1.22 ± 0.76; 83 (16.6%) with titers 201-300 AU/mL had mean FIB-4 of 1.04 ± 0.48; 38 (7.6%) individuals with IgG titers 301-400 AU/ml had a mean FIB-4 of 1.08 ± 0.63; and 121 (24.2%) with IgG titers >400 AU/mL had mean FIB-4 of 1.18 ± 0.87. Increased FIB-4, age, and male gender significantly correlated with lower postvaccine IgG titers (P < 0.001). FIB-4 results were confirmed using FibroScan data displaying advanced fibrosis impact on weakened COVID-19 vaccine response. Conclusion: Immune suppression, older age, male gender, and advanced chronic liver disease are risk factors for lower vaccine response. The FIB-4 provides a simple tool to prioritize candidates for third-dose vaccine booster.

Sodium+/taurocholate cotransporting polypeptide as target therapy for liver fibrosis.

OBJECTIVE: Sodium+/ taurocholate cotransporting polypeptide (NTCP) is a membrane transporter affecting the enterohepatic circulation of bile acids (BAs). We aimed to evaluate NTCP's roles in humans and animal models of liver fibrosis (LF). DESIGN: Primary hepatic stellate cells (pHSCs) isolated from livers biopsies of patients with LF with different fibrosis grading were stained for NTCP. NTCP gene silencing, taurocholic acid (TCA), obeticholic acid (OCA), epigallocatechin gallate (EGCG) and HA-100 dihydrochloride (HA-100) were used as tools to modulate NTCP expression on human HSC line (LX2). BA trafficking/uptake were assessed extracellularly (LX2 culture medium) and intracellularly following treatment with/without NTCP neutralizing antibody. LF models of C57/BL6 mice of carbon tetrachloride (CCl4) and leptin-deficient (Ob/Ob) fed with high-fat diet (Ob/Ob HFD ) were evaluated for pHSCs-NTCP expressions, metabolic and LF profiles following intraperitoneal injections of NTCP neutralizing antibody. RESULTS: pHSCs from F3/F4-scored patients of LF exhibit threefold increased NTCP expressions compared with F0-scored patients (p<0.0001). Sorted-activated HSCs (LX2αSMA+) showed high expressions of NTCP and high TCA uptake in vitro and triggered a further increase in their activations. This phenomenon was inhibited with NTCP small interfering RNA and the NTCP neutralizing antibody. Sorted LX2NTCP+ (high alpha smooth muscle actin (αSMA)/high NTCP) cells showed high phosphorylated pathways of AKT/mTOR and protein kinase C (PKC) accompanied with a decrease in farnesoid X receptor expression. Moreover, LX2NTCP+ cells treated with EGCG, OCA and PKC inhibitor HA-100 significantly decreased NTCP and αSMA. NTCP neutralizing antibody inhibited NTCP (less TCA uptake); it attenuated LF in both CCl4 and Ob/Ob HFD animal models with ameliorated metabolic profile. CONCLUSION: NTCP expression is linearly correlated with fibrosis severity. Modulated BA trafficking could be an important step in LF pathogenesis. Antagonising BA uptake may suggest a therapeutic strategy for preventing disease progression.

The impact of filtered water-pipe smoke on healthy versus cancer cells and their neurodegenerative role on AMPA receptor.

Water pipe smoking is highly prevalent in developing countries, especially in Eastern Mediterranean regions. Research finds that more than 100 million people smoke a water pipe. Furthermore, tobacco smoking is one of the leading behavioral factors related to an increased risk of cancer, a leading cause of death globally. We aim to introduce a novel filtration system for water-pipe smoking and evaluate cytotoxic effects of common water pipe condensed smoke in comparison with our novel filtration system on normal (HEK293t) and cancer cell lines (Hep3B and MCF7) by MTS assay, alpha-fetoprotein (aFP), and apoptosis/necrosis effects. More so, the smoke substituents' neurotoxicity effect was evaluated by analyzing the depressive property on AMPA receptors (AMPARs). Our results showed that the silica filtration system was more effective than the water filtration system. The number of toxic compounds was reduced from 145 mg in distilled water extract (DWE) to 57.5 mg in silica solution extract (SSE). The SSE method also showed lower toxicity impacts on normal and cancerous cell lines (HEK293t, Hep3B, and MCF7) with CC50 values 149.9, 10.14, and 8.9 µg/ml, relative to the DWE method (CC50 values 77.1, 3.1, and 5.24 µg/ml, respectively). SSE extraction also reduced the α-FP (tumor marker test) to 2273.3 ng/ml which was closer in value to untreated cells (4066.7 ng/ml) in comparison with DWE which reduced it greatly to 1658.7 ng/ml, and the biophysical properties of AMPAR subunits demonstrate a reduced effect on desensitization rates of GluA2 homomer and GluA1/2 heteromer, using SSE relative to DWE. In conclusion, the condensed smoke of ordinary water pipe (DWE) has cytotoxic and neurotoxic impacts on various cell lines, while our newly developed system (SSE) was less toxic.

Anticancer, Free Radicals, and Digestive Enzyme Inhibitory Activities of Rubus sanctus Schreb Root Four Solvent Fractions.

BACKGROUND: Humankind used herbal products as a source of medicines since they understood their therapeutic benefits from ancient times. Therefore, the current research aimed to determine the anticancer, antioxidant, and metabolic enzyme inhibitory activities of Rubus sanctus (RS) root four solvent fractions for the first time. METHODS: The antioxidant, antilipase, and anti-α-amylase potentials of (RS) four solvent fractions were evaluated using standard biomedical assays. Moreover, the DNA cell cycle of liver cancer was assessed using a propidium iodide (PI) assay. At the same time, the apoptosis activity was estimated utilizing flow the cytometry method. RESULTS: The methanol and acetone (RS) fractions showed the highest antioxidant activity with IC50 values of 0.078 ± 0.22 and 0.67 ± 0.25 µg/ml, respectively, compared with Trolox, which has an antioxidant IC50 value of 2.039 ± 0.52 µg/ml. Moreover, the methanol (RS) fraction has the highest anti-α-amylase activity with an IC50 value of 20.12 ± 0.34 µg/ml compared with acarbose, which has an IC50 value of 6.565 ± 0.3 µg/ml. Also, the acetone (RS) fraction revealed the highest antilipase activity with an IC50 value of 6.03 ± 1.23 µg/ml compared with the positive control orlistat which has an IC50 value of 0.39 ± 0.45 µg/ml. The aqueous, methanol, acetone, and hexane fractions of the (RS) roots decreased the secretion of the α-fetoprotein in the liver cancer cells. The acetone fraction was the most potent α-fetoprotein inhibitor with an average of 237 ± 12.5% compared with the average of the untreated cells, which was 4066.6 ± 202%. The hexane fraction was the most effective in diminishing apoptosis with an average of 14.5 ± 1.6%, compared with 49% ± 2 untreated cells' average. In inhibiting cell cycle progression, it was recognized that methanol fraction seems to be the most powerful amplifier of the (RS) effect, as it increased the proportion of the cells with an average of 24.5 ± 2.2%, compared with 7.4 ± 1.8% in the doxorubicin (DOX). Data indicated a decrease in cell proliferation rate by prolonging the G2-M phase and thus slowing cancer progression. Our results suggest that (RS) roots four solvent fractions have potential anticancer activity. CONCLUSION: The (RS) roots four solvent fractions have potential anticancer, antioxidant, antilipase, and α-amylase inhibitory activities. It could be a promising source for applications in the functional food, nutraceutical, and pharmaceutical industries.

Efficacy of Birth Dose Vaccination in Preventing Mother-to-Child Transmission of Hepatitis B: A Randomized Controlled Trial Comparing Engerix-B and Sci-B-Vac.

Background and aims: Peripartum transmission of hepatitis B virus (HBV) from an infected mother to the child can be prevented in most but not all cases by immediate vaccination of the newborn. The aim of this study was to compare the efficacy of two licensed hepatitis B vaccines, Engerix-B versus Sci-B-Vac, in preventing peripartum HBV transmission. Methods: A prospective multicenter randomized controlled study in 4 delivery centers was performed from 2009 to 2014. HBsAg positive pregnant women and their newborns were recruited at the delivery rooms. All newborns received Hepatitis B Immune Globulin within 10 h after birth, as well as active HBV vaccination at 0, 1 and 6 months of age. Maternal assessment at delivery included transaminases, blood count, international normalized ratio and viral status. Infants were tested for HBsAg, anti-HBc and anti-HBs at 12 months of age. Results: In the intention to treat (ITT), 171 infant and mother pairs fulfilled the study enrollment criteria and completed follow up, 82 received Engerix-B and 89 Sci-B-Vac. Maternal parameters and viral status were similar in both groups. At 12 months of age, the Sci-B-Vac group had lower HBsAg carriage rates (1/89, 1.1%) than the Engerix-B group (5/82, 6.1%) with borderline significance (risk difference of -0.05, 95% CI -0.11-0.007, t-test = 0.05), and borderline significance lower vaccine failure rates with anti-HBs < 10 mIU/mL in the Sci-B-Vac (2/89, 2.2%) than in the Engerix-B (8/82, 9.8%, p = 0.05). Higher seroprotection rates were found in the Sci-B-Vac group with all anti-HBs titer stratifications of >10 mIU/mL (p = 0.05), >100 mIU/mL (p = 0.05) and >1000 mIU/mL (p = 0.01). Active/passive vaccination was effective in 10/13 cases with maternal HBV DNA levels > 7 log10 IU/mL up to 9.5 log10 IU/mL, but failed in 3 cases for unknown reasons. Conclusion: Sci-B-Vac was superior to Engerix-B in preventing peripartum HBV transmission in neonates from HBsAg+ mothers and induces significantly higher anti-HBs levels. NIH registration number: NCT01133184.

Synthesis and Biological Evaluation of Novel Isoxazole-Amide Analogues as Anticancer and Antioxidant Agents.

Cancer now is one of the leading causes of mortality in the world. There has been a lot of effort to discover new anticarcinogenic agents that allow treatment with fewer side effects. A series of isoxazole-carboxamide derivatives (2a-2g) were synthesised and evaluated for their cytotoxic activity against breast (MCF-7), cervical (HeLa), and liver (Hep3B) cancer cell lines and their antioxidant activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The results showed that 2d and 2e were the most active compounds against Hep3B cells, with a half-maximal inhibitory concentration (IC50) of around 23 µg/ml; 2d showed the highest activity against HeLa cells, with an IC50 15.48 µg/ml. However, 2a had the lowest IC50 (39.80 µg/ml) against MCF-7 cells. By contrast, compound 2g was inactive against all cancer cell lines, with IC50 values >400 µg/ml. Both 2d and 2e reduced Hep3B secretion of alpha-fetoprotein (to 1829.33 ± 65.91 ng/ml and 1758.66 ± 54.04 ng/ml, respectively). Furthermore, in cell cycle analysis, 2d and 2e induced a delay in the G2/M phase of 18.07%, which is similar to the doxorubicin positive control. Moreover, 2d and 2e reduced the necrosis rate of Hep3B threefold and instead shifted the cells to apoptosis. Our results indicate that 2d and 2e have potent and promising anticancer activity. However, compound 2a was the most active as antioxidant agent (IC50 = 7.8 ± 1.21 µg/ml) compared with Trolox as a positive control (IC50 2.75 µg/ml).