Role of APOC3 3238C/G polymorphism in HIV-associated neurocognitive disorder.

Apolipoprotein not only have a role in cholesterol metabolism but also play a role in normal brain function. Apolipoprotein gene polymorphisms are known risk factors for a number of mental and neurological disorders. The expression of brain apolipoproteins is significantly altered in several brain disorders. Therefore, we assed ApoC33238 C/G polymorphism in a total of 248 patient infected with HIV (45 with HAND, 89 without HAND, 114 without ART) and 134 healthy controls using PCR-RFLP. ApoC3 3238CG, 3238 GG genotypes and 3238G allele showed a non-significant increased risk for severity of HAND (P = 0.16, OR = 1.83; P = 0.32, OR = 2.78; P = 0.10, OR = 1.65) while comparing individuals with and without HAND. ApoC3 3238 GG genotype and 3238G allele revealed an increased risk for disease progression when compared between HIV patients with and without ART (P = 0.55, OR = 1.76; P = 0.65, OR = 1.12) though risk could not reach statistical significance. ApoC3 3238 GG genotype and 3238G allele were associated with the reduced risk of acquiring HIV infection when comparing HIV patients who are not on ART with healthy controls (P = 0.05, OR = 0.29; P = 0.04, OR = 0.66). In HIV patients on ART,ApoC3 3238 GG genotype showed an increased susceptibility to development of HAND (P = 0.48, OR = 2.24) when comparing alcohol drinkers and non-drinkers however risk could not reach statistical significance. In conclusion, the genotype ApoC33238GG displayed an inclination of risk for the severity of HAND and HIV disease progression. The polymorphism of APOC3 3238C/G may have a role to reduce the risk for acquisition of HIV infection. ApoC33238GG genotype in presence of alcohol may increase susceptibility to development of HAND.

Methotrexate, an anti-inflammatory drug, inhibits Hepatitis E viral replication.

Hepatitis E Virus (HEV) is a positively oriented RNA virus having a 7.2 kb genome. HEV consists of three open reading frames (ORF1-3). Of these, ORF1 codes for the enzymes Methyltransferase (Mtase), Papain-like cysteine protease (PCP), RNA helicase, and RNA-dependent RNA polymerase (RdRp). Unavailability of a vaccine or effective drug against HEV and considering the side effects associated with the off-label use of ribavirin (RBV) and pegylated interferons, an alternative approach is required by the modulation of specific enzymes to prevent the infection. HEV helicase is involved in unwinding the double-stranded RNA, RNA processing, transcriptional regulation, and pre-mRNA processing. Therefore, we screened FDA-approved compounds from the ZINC15 database against the modelled 3D structure of HEV helicase and found that methotrexate and compound A (Pubchem ID BTB07890) inhibit the NTPase and dsRNA unwinding activity leading to inhibition of HEV RNA replication. This may be further authenticated by in vivo study.

Higher sensitivity and accuracy of synovial next-generation sequencing in comparison to culture in diagnosing periprosthetic joint infection: a systematic review and meta-analysis.

PURPOSE: The purpose of this meta-analysis was to compare the diagnostic parameters of synovial next-generation sequencing (NGS) and cultures in diagnosing periprosthetic joint infections (PJI). METHODS: PubMed, Web of Science, Cochrane, and Google Scholar were searched from inception until 8 Jan 2022 for literature investigating the role of NGS in comparison to culture in the diagnosis of PJI. The studies were included if they investigated the diagnostic value of culture and NGS in diagnosing PJIs against the Musculoskeletal Infection Society (MSIS) criteria. Diagnostic parameters, such as sensitivity, specificity, positive predictive value, negative predictive value, positive-likelihood ratio, negative-likelihood ratio, accuracy, and area under the curve (AUC), were calculated for the included studies to evaluate the performance of NGS in comparison to culture in PJI diagnosis. RESULTS: The total number of the included patients was 341 from seven articles. The pooled sensitivity, specificity, and diagnostic odds ratio of NGS were 94% (95% CI 91-97%), 89% (95% CI 82-95%), and 138.5 (95% CI 49.1-390.5), respectively. NGS has positive- and negative-likelihood ratios of 7.9 (95% CI 3.99-15.6) and 0.1 (95% CI 0.0-0.1), respectively. On the other hand, the pooled sensitivity, specificity, and diagnostic odds ratio of culture were 70% (95% CI 61-79%), 94% (95% CI 88-98%), and 28.0 (95% CI 12.6-62.2), respectively. The SROC curve for NGS showed that the accuracy (AUC) was 91.9%, and that the positive and negative predictive values were 8.6 (95% CI 5.0-19.5) and 0.1 (95% CI 0.0-0.1), respectively. While, culture SROC curve demonstrated that the accuracy (AUC) was 80.5% and the positive- and negative-likelihood ratio were 12.1 (95% CI 4.5-49.6) and 0.3 (95% CI 0.2-0.4). CONCLUSIONS: NGS has a potential role in diagnosing hip and knee PJIs due to its high sensitivity, specificity, and accuracy. However, the sensitivity and specificity reported by the studies varied according to the time of synovial sampling (preoperative, postoperative, or mixed).

Reinventing Patient Support and Continuity of Care Using Innovative Physician-staffed Hotline: More than 60,000 Patients Served Across 15 Medical and Surgical Specialties During the First Wave of COVID-19 Lockdown in Qatar.

Rising disease prevalence early during the COVID-19 pandemic in the State of Qatar led to stoppage of all non-emergency health care services. To maintain continuity of care and information exchanges for non-emergency patients, a physician-operated telephone hotline was set up that involved triage followed by immediate consultation with a specialized physician. We describe the initiation and evaluate the operations of the Urgent Consultation Centre (UCC) hotline manned by 150 physicians and aimed at urgent non-life-threatening consultations at Hamad Medical Corporation, the public health provider in Qatar. UCC established a hotline to triage inbound patient calls related to 15 medical and surgical specialties. For calls between April-August 2020, we describe call volume, distribution by specialty, outcomes, performance of UCC team, as well as demographics of callers. During the study period, UCC received 60229 calls (average 394 calls/day) from Qatari nationals (38%) and expatriates (62%). Maximum total daily calls peaked at 1670 calls on June 14, 2020. Call volumes were the highest from 9 AM to 2 PM. Response rate varied from 89% to 100%. After an initial telephone triage, calls were most often related to and thus directed to internal medicine (24.61%) and geriatrics (11.97%), while the least percentage of calls were for pain management and oncology/hematology (around 2% for each). By outcome of consultation, repeat prescriptions were provided for 60% of calls, new prescriptions (15%), while referrals were to outpatient department (17%), emergency department/pediatric emergency center (5%), and primary health care centres (3%). We conclude that during a pandemic, physician-staffed telephone hotline is feasible and can be employed in innovative ways to conserve medical resources, maintain continuity of care, and serve patients requiring urgent care.

Deep-sea fungal metabolites as potential inhibitors of glucose-regulatory enzymes: In silico structure-activity analysis.

Chronic diabetes mellites related hyperglycemia is a major cause of mortality and morbidity due to further complications like retinopathy, hypertension and cardiovascular diseases. Though several synthetic anti-diabetes drugs specifically targeting glucose-metabolism enzymes are available, they have their own limitations, including adverse side-effects. Unlike other natural or marine-derived pharmacologically important molecules, deep-sea fungi metabolites still remain under-explored for their anti-diabetes potential. We performed structure-based virtual screening of deep-sea fungal compounds selected by their physiochemical properties, targeting crucial enzymes viz., α -amylase, α -glucosidase, pancreatic-lipoprotein lipase, hexokinase-II and protein tyrosine phosphatase-1B involved in glucose-metabolism pathway. Following molecular docking scores and MD simulation analyses, the selected top ten compounds for each enzyme, were subjected to pharmacokinetics prediction based on their AdmetSAR- and pharmacophore-based features. Of these, cladosporol C, tenellone F, ozazino-cyclo-(2,3-dihydroxyl-trp-tyr), penicillactam and circumdatin G were identified as potential inhibitors of α -amylase, α -glucosidase, pancreatic-lipoprotein lipase, hexokinase-II and protein tyrosine phosphatase-1B, respectively. Our in silico data therefore, warrants further experimental and pharmacological studies to validate their anti-diabetes therapeutic potential.

Isolation and Characterization of Two Chalcone Derivatives with Anti-Hepatitis B Virus Activity from the Endemic Socotraen Dracaena cinnabari (Dragon's Blood Tree).

Hepatitis B virus (HBV) infection is prevalent and continues to be a global health concern. In this study, we determined the anti-hepatitis B virus (HBV) potential of the Socotra-endemic medicinal plant Dracaena cinnabari and isolated and characterized the responsible constituents. A bioassay-guided fractionation using different chromatographic techniques of the methanolic extract of D. cinnabari led to the isolation of two chalcone derivatives. Using a variety of spectroscopic techniques, including 1H-, 13C-, and 2D-NMR, these derivatives were identified as 2,4'-dihydroxy-4-methoxydihydrochalcone (compound 1) and 2,4'-dihydroxy-4-methoxyhydrochalcone (compound 2). Both compounds were isolated for the first time from the red resin (dragon's blood) of D. cinnabari. The compounds were first evaluated for cytotoxicity on HepG2.2.15 cells and 50% cytotoxicity concentration (CC50) values were determined. They were then evaluated for anti-HBV activity against HepG2.2.15 cells by assessing the suppression of HBsAg and HBeAg production in the culture supernatants and their half maximum inhibitory concentration (IC50) and therapeutic index (TI) values were determined. Compounds 1 and 2 indicated inhibition of HBsAg production in a dose- and time-dependent manner with IC50 values of 20.56 and 6.36 µg/mL, respectively.

The anti-hepatitis B virus and anti-hepatotoxic efficacies of solanopubamine, a rare alkaloid from Solanum schimperianum.

Chronic liver disease caused by hepatitis B virus (HBV) remains an important health issue. Though there are effective HBV-polymerase inhibitors (e.g., lamivudine), their prolonged use leads to emergence of drug-resistant (polymerase mutant) strains. Several herbal formulations and phytochemicals have been therefore, reported as potential anti-HBV agents with no sign of resistance in experimental and clinical settings. In this study, we assessed the anti-HBV as well as hepatoprotective salutations of solanopubamine, a rare alkaloid isolated from S. schimperianum. In cultured HepG2.2.15 cells, solanopubamine showed marked anti-HBV activity in a time and dose-dependent manner. Solanopubamine (30 µM) efficiently inhibited HBsAg and HBeAg expressions by 66.5%, 70.5%, respectively as compared to 82.5% and 86.5% respective inhibition by lamivudine (2 µM) at day 5. Molecular docking analyses of solanopubamine revealed formations of stable complexes with lamivudine-sensitive as well as lamivudine-resistant polymerase through interactions of catalytic 'YMDD/YIDD' motif residues. Moreover, solanopubamine attenuated DCFH-induced oxidative and apoptotic damage and restored HepG2 cell viability by 28.5%, and downregulated caspase-3/7 activations by 33%. Further docking analyses of solanopubamine showed formation of stable complexes with caspase-3/7. Taken together, our data demonstrates promising anti-HBV and anti-hepatotoxic therapeutic potential of solanopubamine, and warrants further molecular and pharmacological studies.

Mobile-bearing versus fixed-bearing total knee arthroplasty: a meta-analysis of randomized controlled trials.

OBJECTIVE: The purpose of this study was to perform a meta-analysis comparing mobile-bearing with fixed-bearing total knee arthroplasty (TKA) in terms of all-cause revision rates, aspetic loosening, knee functional scores, range of motion and radiographic lucent lines and osteolysis. METHODS: PubMed, Cochrane Library, Google Scholar and Web of Science were searched up to January 2020. Randomized controlled trials that compared primary mobile-bearing with fixed-bearing TKA, reporting at least one of the outcomes of interest, at a minimum follow-up of 12 months were included. All outcomes of interest were pooled at short-term (< 5 years), mid-term (5 to 9 years) and long-term (> = 10 years) follow-up intervals. RESULTS: A total of 70 eligible articles were included in the qualitative and statistical analyses. There was no difference between mobile-bearing or fixed-bearing TKA at short-term, mid-term and long-term follow-ups in all outcome measures including all-cause revision rate, aseptic loosening, oxford knee score, knee society score, Hospital for Special Surgery score, maximum knee flexion, radiographic lucent lines and radiographic osteolysis. CONCLUSION: The current level of evidence demonstrated that both mobile-bearing and fixed-bearing designs achieved excellent outcomes, yet it does not prove the theoretical advantages of the mobile-bearing insert over its fixed-bearing counterpart. The use of either design could therefore be supported based on the outcomes assessed in this study. LEVEL OF EVIDENCE: Level II, Therapeutic.

Structural exploration of Y-domain reveals its essentiality in HEV pathogenesis.

Hepatitis E virus (HEV) is a major causative agent of hepatitis E infections across the globe. Although the essentiality of HEV nonstructural polyprotein (pORF1) putative Y-domain (Yd) has been established in viral pathogenesis, its structural-functional role remains elusive. The current research discusses the novel exploration on Yd protein expression, purification, biophysical characterization and structure-based docking analysis. The codon optimized synthetic gene and optimized expression parameters i.e., 5 h induction with 0.25 mM IPTG at 37 °C, resulted in efficient production of Yd protein (~40 kDa) in E. coli BL21(DE3) cells. Majority of the recombinant Yd (rYd) protein expressed as inclusion bodies was solubilized in 0.5% N-lauroylsarcosine and purified using Ni-NTA chromatography. Circular dichroism (CD) and UV visible absorption spectroscopic studies on Yd revealed both secondary and tertiary structure stability in alkaline range (pH 8.0-10.0), suggesting correlation with its physiological activity. Thus, loss in structure at low pH perhaps play crucial role in cytoplasmic-membrane interaction. The biophysical data were in good agreement with insilico structural analyses, which suggested mixed α/ß fold, non-random and basic nature of Yd protein. Furthermore, due to Yd protein essentiality in HEV replication and pathogenesis, it was considered as a template for docking and drug-likeness analyses. The 3D modeling of Yd protein and structure-based screening and drug-likeness of inhibitory compounds, including established antiviral drugs led to the identification of top nine promising candidates. Nonetheless, in vitro studies on the predicted interaction of Yd with intracellular-membrane towards establishing replication-complexes as well as validations of the proposed therapeutic agents are warranted.

The outcomes of stand alone polyetheretherketone cages in anterior cervical discectomy and fusion.

The procedure of anterior cervical discectomy and fusion is considered as the treatment of choice in degenerative disc disease, which material provides the best clinical and radiological fusion and other outcomes remains heavily debated. Materials that augment the process of fusion consist of bone grafting, titanium, polyetheretherketone (PEEK), or carbon cages. The application of PEEK cages has been recommended as it is radiolucent, and it has a modulus of elasticity that is similar to cortical bone. PEEK cages can be either filled with various materials or unfilled cages. Filled PEEK cages can include bone autografts, bone allografts, demineralized bone matrix, and other materials that facilitate fusion. This narrative review highlights that standalone filled PEEK cages were likely to have better radiological outcomes and satisfactory clinical outcomes for myelopathy when compared with standalone unfilled PEEK cages.

The safety of outpatient total shoulder arthroplasty: a systematic review and meta-analysis.

PURPOSE: To meet the increasing demands of total shoulder arthroplasty (TSA) while reducing its financial burden, there has been a shift toward outpatient surgery. This systematic review and meta-analysis aimed to evaluate the safety of outpatient TSA. METHODS: The primary objective was to compare re-admission rates and postoperative complications in outpatient versus inpatient TSA. The secondary objectives were functional outcomes and costs. PubMed, Google Scholar, and Web of Science were searched until March 28, 2020. The inclusion criteria were studies reporting at least complications or readmission rates within a period of 30 days or more. RESULTS: Ten level III retrospective studies were included with 7637 (3.8%) and 192,025 (96.2%) patients underwent outpatient and inpatient TSA, respectively. Outpatient TSA had relatively younger and healthier patients. There were no differences between outpatient and inpatient arthroplasty for 30- and 90-day readmissions. Furthermore, unadjusted comparisons demonstrated significantly less total and major surgical complications, less total, major, and minor medical complications in favour of outpatient TSA. However, subgroup analyses demonstrated that there were no significant differences in all complication if the studies had matched controls and regardless of data source (database or nondatabase studies). The revision rates were similar between both groups at a 12-24 months follow-up. Two studies reported a significant reduction in costs in favour of outpatient TSA. CONCLUSION: This study highlights that outpatient TSA could be a safe and effective alternative to inpatient TSA in appropriately selected patients. It was evident that outpatient TSA does not lead to increased readmissions, complications, or revision rates. A potential additional benefit of outpatient TSA was cost reduction.

Corrigendum to "New terpenic and phenolic compounds from Suaeda monoica reverse oxidative and apoptotic damages in human endothelial cells". [Saudi Pharm. J. 29(10) (2021) 1102-1111].

[This corrects the article DOI: 10.1016/j.jsps.2021.08.007.].

New terpenic and phenolic compounds from Suaeda monoica reverse oxidative and apoptotic damages in human endothelial cells.

Elevation in hyperglycemia-associated methylglyoxal level can trigger vascular endothelial cells oxidative stress and apoptosis. The present work assesses the cell proliferative, anti-oxidative and anti-apoptotic potential of Suaeda monoica derived four new terpenes: a norsesquaterpenol (normonisesquaterpenol), a monocyclic triterpenoid (suaedanortriterpene dione), an aromatic monoterpenic ester and a labdane-type norditerpenic xyloside as well as two new phenols: an alkylated ß-naphthol and a ß-methoxy naphthalene in cultured human umbilical vein endothelial cells (HUVEC). Of these, suaedanortriterpenedione (53.7%), normonisesquaterpenol (51.4%) and norditerpenic xyloside (48%) showed the most promising cell proliferative activities compared to others. Moreover, normonisesquaterpenol, norditerpenic xyloside and suaedanortriterpenedione efficiently reversed the oxidative and apoptotic cell damage via downregulation of capase-3/7 by 44.3%, 42.2% and 39.4%, respectively against dichlorofluorescin, whereas by 46.2%, 43.5% and 42.5%, respectively against methylglyoxal. Aminoguanidine, the reference drug inhibited caspase-3/7 activity by 56.2% and 54.7% through attenuation of dichlorofluorescin and methylglyoxal, respectively. Further in silico molecular docking analysis revealed formation of stable complexes between the tested compounds and caspase-3/7. Conclusively, we for the first time demonstrate the growth stimulatory, anti-oxidative and anti-apoptotic salutations of S. monoica derived novel compounds in human endothelial cells. This warrants their further assessment as vascular cell protective and rejuvenating therapeutics, especially in hyperglycemic conditions.

Novel polycyclic pyrroloquinazoline alkaloids from Anisotes trisulcus and their biological activity.

Two new polycyclic pyrroloquinazoline alkaloids with unprecedented skeleton, anisulcusines A (1) and B (2), along with four known compounds (3-6), were identified from the aerial parts of Anisotes trisulcus (Forssk.) Nees. To our knowledge, anisulcusines A and B are the first polycyclic pyrroloquinazoline alkaloids that possess a unique N-methyl-1,2-dihydro-1'H-spiro[benzo[d][1,3]oxazine moiety. The chemical structures of the new compounds were elucidated through extensive spectroscopic analyses and high-resolution mass spectroscopy. Anisulcusine B (2) exerted moderate cytotoxic effect on cultured human hepatoma (HuH7) cells, whereas compounds 1 and 3-5 exhibited mild cell proliferative or growth stimulatory activity. HIGHLIGHTS Two new polycyclic pyrroloquinazoline alkaloids from Anisotes trisulcus. Structures were elucidated on the basis of 1D- and 2D-NMR and HR-ESI-MS spectra. Compound (2) exerted moderate cytotoxic effect against human hepatoma (HuH7) cells. Compounds (1, 3-5) exhibited mild cell proliferative or growth stimulatory activity.

Bioassay-guided isolation of anti-hepatitis B virus flavonoid myricetin-3-O-rhamnoside along with quercetin from Guiera senegalensis leaves.

Recently, we have shown in vitro anti-hepatitis B virus (HBV) activity of G. senegalensis J.F. Gmel leaves, and Identified quercetin and other flavonoids by HPTLC. Here we report bioassay-directed fractionation of G. senegalensis leaves using column chromatography and isolation of two flavonoinds from the n-butanol fraction, their structure determination (1H NMR, 13C NMR and 2D-NMR) and assessment of antiviral activities (HBsAg and HBeAg assay) in HBV-reporter HepG2.2.2.15 cells. Further molecular docking was performed against HBV polymerase (Pol/RT) and capsid (Core) proteins as well as host-receptor sodium taurocholate co-transporting polypeptide (NTCP). The two isolated bioactive compounds were identified as quercetin and myricetin-3-O-rhamnoside. Quercetin significantly inhibited synthesis of HBsAg and HBeAg by about 60% and 62%, respectively as compared to myricetin-3-O-rhamnoside by 44% and 35%, respectively. Molecular docking of the two anti-HBV flavonoids revealed their higher binding affinities towards Pol/RT than Core and NTCP. In conclusion, this is the first report on anti-HBV active myricetin-3-O-rhamnoside along with quercetin isolated from G. senegalensis leaves. Their possible mode of anti-HBV activities are suggested through binding with viral Pol/RT and Core as well as host NTCP proteins.

Oncoglabrinol C, a new flavan from Oncocalyx glabratus protects endothelial cells against oxidative stress and apoptosis, and modulates hepatic CYP3A4 activity.

Active herbal or natural compounds have high chemical diversity and specificity than synthetic drugs. Recently, we have validated the hypoglycemic salutation of Oncocalyx glabratus in rodent model, and demonstrated the activation of PPARα/γ by its newly ioslated flavan derivative Oncoglabrinol C (5,3'-Dihydroxyflavan 7-4'-O-digallate) in liver cells (HepG2). Here we evaluated the potential of Oncoglabrinol C against Dichlorofluorescin (DCFH) and Methylglyoxal (MGO) induced endothelial cells (HUVEC) oxidative and apoptotic damage, including activation of PXR-mediated hepatic CYP3A4. Our MTT assay showed protection of ~57% and ~63.5% HUVEC cells by 10 and 20 µg/ml doses of Oncoglabrinol C, respectively through attenuating DCFH triggered free-radicals. Also, the two doses effectively protected ~53% and ~65.5% cells, respectively by reversing MGO toxicity. In DCFH and MGO treated cells, Oncoglabrinol C (20 µg/ml) effectively downregulated caspase 3/7 activity by ~33% and ~43.5%, respectively. Moreover, in reporter gene (dual-luciferase) assay, Oncoglabrinol C (20 µg/ml) moderately activated hepatic CYP3A4. Molecular docking of Oncoglabrinol C indicated its strong interactions with cellular caspase 3/7, PPARα/γ and PXR proteins, which supported its anti-apoptotic (antagonistic) as well as pro-hypoglycemic and PXR/CYP activating (agonistic) activities. Taken together, our findings demonstrated the potential of Oncoglabrinol C in reversing the endothelial oxidative and apoptotic damage as well as in the activation of hepatic CYP3A4. This warrants further evaluations of Oncoglabrinol C and related compounds towards developing effective and safe drugs against diabetes associated cardiovascular disorders.

Cell proliferation activity delineated by molecular docking of four new compounds isolated from the aerial parts of Suaeda monoica Forssk. ex. J.F. Gmel.

Using different chromatographic methods, four new compounds were isolated from the aerial parts of Suaeda monoica (Chenopodiaceae) along with 2-hydroxy-1-naphthoic acid (SCM-3). The structures of the new compounds were established as 6'-hydroxy-10'-geranilanyl naphtha-1-oate (SMC-1), 4,4,8ß,10ß-Tetramethyl-9ß-isobutanyl decalin-13-ol-13-O-ß-D-xylopyranoside (SCM-2), 6'-(2-hydroxynaphthalen-3-yl) hexanoic acid (SCM-4) and 1'-(2-Methoxy-3-naphthyl)-4'-(2''-methylbenzoyl)-n-butane (SMC-5) by IR, EIMS and NMR (1 & 2D) analyses. All compounds (50 µg/mL) were tested for cell proliferative potential on cultured human liver cell HepG2 cells by MTT assay. The results revealed a marked cell proliferative potential of all compounds (1.42-1.48 fold) as compared to untreated control. The results of molecular docking and binding with specific proteins such as PTEN (Phosphatase and Tensin homolog) and p53 also justify the cell proliferative potential of the isolated compounds. Glide program with Schrodinger suit 2018 was used to evaluate the binding between SMC compounds and proteins (PTEN and p53). The binding affinity of all compounds was in order of 104-105 M-1 towards both PTEN and p53. All the SMC compounds have been found to bind at the active site of PTEN, thereby may prevent the binding of phosphatidylinositiol 3,4,5-triphosphate (PI3P). In the locked position, PTEN would not be able to hydrolyze PI3P and hence the PI3P regulated signaling pathway remains active. Similarly, SMC molecules were found to interact with the amino acid residues (Ser99, Thr170, Gly199, and Asp224) which are critically involved in the formation of tetrameric p53. The blockage of p53 to attain its active conformation thus may prevent the recruitment of p53 on DNA and hence may promote cell proliferation.

Hepatoprotective effect of Solanum surattense leaf extract against chemical- induced oxidative and apoptotic injury in rats.

BACKGROUND: Of over 35 Saudi plants traditionally used to treat liver disorders, majority still lack scientific validations. We therefore, evaluated the anti-oxidative, anti-apoptotic and hepatoprotective potential of Solanum surattense leaves total ethanol-extract (SSEE). METHODS: The cytoprotective (4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide/ MTT assay) and anti-apoptotic (caspase-3/7) potential of SSEE (25-200 µg/mL) were assessed in cultured HepG2 cells against dichlorofluorescein (DCFH)-induced toxicity. The hepatoprotective salutation of SSEE (100 and 200 mg/kg.bw/day) in carbon tetrachloride (CCl4)-intoxicated rats was evaluated by serum biochemistry and histopathology. The anti-oxidative activity of SSEE (31.25-500 µg/mL) was tested by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging and linoleic acid bleaching assays. Also, SSEE was subjected to qualitative phytochemical analysis, and standardized by validated high-performance liquid chromatography (HPTLC). RESULTS: SSEE at doses 50, 100 and 200 µg/mL showed HepG2 cell proliferative and protective potential by about 61.0, 67.2 and 95%, respectively through inhibition of caspase-3/7 against DCFH-toxicity. In CCl4-injured rats, SSEE (200 mg/kg) significantly (P < 0.001) normalized serum transaminases, alkaline phosphatase, bilirubin, cholesterol, triglycerides, and total protein, including tissue malondialdehyde and nonprotein sulfhydryls levels, supported by the liver histopathology. SSEE further showed strong in vitro anti-oxidative and anti-lipid peroxidative activities, evidenced by the presence of alkaloids, flavonoids, tannins, sterols and saponins. Identification of ß-sitosterol (3.46 µg/mg) strongly supported the anti-oxidative and hepatoprotective salutation of SSEE. CONCLUSION: Our findings suggest the therapeutic potential of S. surattense against chemical-induced oxidative stress and liver damage. However, isolation of the active principles and elucidation of mechanism of action remain to be addressed.

The anti-hepatitis B virus therapeutic potential of anthraquinones derived from Aloe vera.

Although the approved hepatitis B virus (HBV)-polymerase inhibitors (e.g., lamivudine) often lead to drug-resistance, several natural products have shown promising efficacies. Though Aloe vera (AV) gel and its constituents are shown inhibitors of many viruses, their anti-HBV activity still remains elusive. We therefore, tested the anti-HBV potential of AV extract and its anthraquinones in hepatoma cells, including molecular docking, high-performance thin layer chromatography (HPTLC), and cytochrome P450 (CYP3A4) activation analyses. Our anti-HBV assays (HBsAg/HBeAg Elisa) showed maximal inhibition of viral antigens production by aloe-emodin (~83%) > chrysophanol (~62%) > aloin B (~61%) > AV extract (~37%) in HepG2.2.15 cells. Interestingly, the effect of aloe-emodin was comparable with lamivudine (~86%). Moreover, sequential treatment with lamivudine (pulse) followed by aloe-emodin (chase) enhanced the efficacy of monotherapy by ~12%. Docking (AutoDock Vina) of the anthraquinones indicated strong interactions with HBV-polymerase residues that formed stable complexes with high Gibbs's free energy. Further, identification of aloe-emodin and aloin B by validated HPTLC in AV extract strongly endorsed its anti-HBV potential. In addition, our luciferase-reporter gene assay of transfected HepG2 cells showed moderate induction of CYP3A4 by aloe-emodin. In conclusion, this is the first report on anti-HBV potential of AV-derived anthraquinones, possibly via HBV-polymerase inhibition. Of these, although aloin B exhibits novel antiviral effect, aloe-emodin appears as the most promising anti-HBV natural drug with CYP3A4 activating property towards its enhanced therapeutic efficacy.

The in vitro and in vivo anti-hepatotoxic, anti-hepatitis B virus and hepatic CYP450 modulating potential of Cyperus rotundus.

In the present study we investigated the hepatotoprotective, hepatitis B virus (HBV) inhibitory and hepatic CYP450 enzyme (CYP3A4) modulatory potential of Cyperus rotundus rhizome fractions. The crude ethanol-extract, including different organic and aqueous fractions were tested for in vitro cytoprotection on HepG2 cells (MTT assay), followed by in vivo evaluation in Wistar rats (serum biochemistry and lipid profile). The in vitro anti-HBV activity was tested on HepG2.2.15 cells (HBsAg and HBeAg Elisa). Of these, the n-butanol and aqueous fractions showed the most promising, dose-dependent hepatoprotection in DCFH-injured HepG2 cells. Further, in CCl4-injured rats, oral administration of C. rotundus (100 and 200 mg/kg·bw/day) significantly normalized serum markers of healthy liver function (SGOT, SGPT, GGT, ALP and bilirubin) and lipid profile (cholesterol, HDL, LDL, VLDL, TG and MDA), including tissue NP-SH and TP levels. Compared to other fractions, the ethyl acetate, n-butanol and aqueous fractions exhibited the best inhibitory effects on viral HBsAg and HBeAg secretions in dose- and time-dependent manner. In addition, reporter gene assay (Dual-luciferase) of transfected HepG2 cells showed mild activation of nuclear PXR-mediated CYP3A4 gene by the three active fractions. Taken together, C. rotundus showed very promising hepatoprotective and anti-HBV potential in experimental settings. In addition, this is the first report on modulation of CYP3A4 by C. rotundus that suggests its safe consumption in relation to drug metabolism and efficacy. Our data could therefore, provide the basis for the ethnobotanical medicinal use of C. rotundus in metabolic liver disorder and hepatitis B patients.