Zilebesiran: A Promising Antihypertensive Therapy Inhibiting Angiotensinogen Synthesis.

Systemic hypertension is one of the most common noncommunicable diseases globally, with over one billion people affected. Despite the widespread use of numerous antihypertensive drugs, it is estimated that only a fifth of diagnosed patients achieve adequate blood pressure control. For this reason, the pursuit for novel antihypertensive therapies is ongoing. Zilebesiran, an siRNA designed to target the liver, is the newest potential addition to the renin-angiotensin-aldosterone system-inhibiting drugs. This subcutaneous injection post-transcriptionally silences the AGT gene responsible for the synthesis of angiotensinogen. By preventing the progenitor protein of the renin-angiotensin-aldosterone system, zilebesiran blocks the downstream production of angiotensin II, which plays multiple roles in blood pressure elevation. Phase I clinical trials have demonstrated a dose-dependent negative relationship between zilebesiran and blood pressure/serum angiotensinogen levels-with sustained effects up to 6 months. Researchers also demonstrated a promising safety profile, as most of the adverse events were mild to moderate in nature. Phase II trials assessing efficacy and optimal dosing are currently underway, with a predicted completion by 2025.

Piebaldism and chromatophore development in reptiles are linked to the tfec gene.

Reptiles display great diversity in color and pattern, yet much of what we know about vertebrate coloration comes from classic model species such as the mouse and zebrafish.1,2,3,4 Captive-bred ball pythons (Python regius) exhibit a remarkable degree of color and pattern variation. Despite the wide range of Mendelian color phenotypes available in the pet trade, ball pythons remain an overlooked species in pigmentation research. Here, we investigate the genetic basis of the recessive piebald phenotype, a pattern defect characterized by patches of unpigmented skin (leucoderma). We performed whole-genome sequencing and used a case-control approach to discover a nonsense mutation in the gene encoding the transcription factor tfec, implicating this gene in the leucodermic patches in ball pythons. We functionally validated tfec in a lizard model (Anolis sagrei) using the gene editing CRISPR/Cas9 system and TEM imaging of skin. Our findings show that reading frame mutations in tfec affect coloration and lead to a loss of iridophores in Anolis, indicating that tfec is required for chromatophore development. This study highlights the value of captive-bred ball pythons as a model species for accelerating discoveries on the genetic basis of vertebrate coloration.

Permanent Compared With Absorbable Suture in Apical Prolapse Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: To explore how permanent compared with absorbable suture affects anatomic success in native tissue vaginal suspension (uterosacral ligament suspension and sacrospinous ligament suspension) and sacrocolpopexy with mesh. DATA SOURCES: MEDLINE, EMBASE, and ClinicalTrials.gov were searched through March 29, 2022. METHODS OF STUDY SELECTION: Our population included women undergoing apical prolapse surgery (uterosacral ligament suspension and sacrospinous ligament suspension and abdominal sacrocolpopexy). Our intervention was permanent suture for apical prolapse surgery, and our comparator was absorbable suture. We determined a single anatomic success proportion per study. Adverse events collected included suture and mesh exposure, surgery for suture and mesh complication, dyspareunia, and granulation tissue. Abstracts were doubly screened, full-text articles were doubly screened, and accepted articles were doubly extracted. Quality of studies was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation) criteria. In single-arm studies using either permanent or absorbable suture, random effects meta-analyses of pooled proportions were used to assess anatomic success. In comparative studies investigating both suture types, random effects meta-analyses of pooled risk ratios were used. TABULATION, INTEGRATION, AND RESULTS: Of 4,658 abstracts screened, 398 full-text articles were assessed and 63 studies were included (24 vaginal suspension [13 uterosacral ligament suspension and 11 sacrospinous ligament suspension] and 39 sacrocolpopexy). At 2-year follow-up, there was no difference in permanent compared with absorbable suture in uterosacral ligament suspension and sacrospinous ligament suspension (proportional anatomic success rate 88% [95% CI 0.81-0.93] vs 88% [95% CI 0.82-0.92]). Similarly, at 18-month follow-up, there was no difference in permanent compared with absorbable suture in sacrocolpopexy (proportional anatomic success rate 92% [95% CI 0.88-0.95] vs 96% [95% CI 0.92-0.99]). On meta-analysis, there was no difference in relative risk (RR) of success for permanent compared with absorbable suture for uterosacral ligament suspension and sacrospinous ligament suspension (RR 1.11, 95% CI 0.93-1.33) or sacrocolpopexy (RR 1.00, 95% CI0.98-1.03). CONCLUSION: Success rates were similarly high for absorbable and permanent suture after uterosacral ligament suspension, sacrospinous ligament suspension, and sacrocolpopexy, with medium-term follow-up. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021265848.

Candida albicans and Candida dubliniensis in Periodontitis in Adolescents and Young Adults.

AIM: This study aims to evaluate the association of Candida albicans and Candida dubliniensis with periodontitis in adolescents and young adults in a Moroccan population. METHODS: 426 subjects aged between 12 and 25 years were recruited for the study. A pool of plaque sample was taken. Samples were cultured on Sabouraud Chloramphenicol medium at 37°C for 24-48 hours and then identified by the Vitek 2 YST system. Clinical data and presence of Candida albicans and Candida dubliniensis were analyzed using Jamovi (Version 1.8). RESULTS: Candida albicans was observed in 25 subjects among 68 diseased patients (37%) and in 60 subjects among 358 healthy patients (17%). It can be reported that under normal yeast conditions, there is a statistically significant difference between these two groups (P < 0.001). Candida dubliniensis was more prevalent in periodontitis than in healthy subjects (P=0.026). Regarding clinical variables, subgroups of periodontitis subjects showed significant statistical differences for periodontal probing depth, clinical attachment loss, and number of decayed teeth in advanced periodontitis in comparison with initial or mild periodontitis. The results also indicate that the presence of the two species of Candida is not related to gender or age (P > 0.05) nor related to the severity of the periodontal disease in this population. CONCLUSION: Within the limits of our study, Candida albicans is more frequently associated with periodontitis. The potential role of C. albicans in periodontitis pathogenesis is very complex. More studies on biofilm associated with different forms of periodontitis are necessary. It is also important to assess the coexistence of periodontitis and caries and the associated biofilms.

Geniposide ameliorated fluoxetine-suppressed neurite outgrowth in Neuro2a neuroblastoma cells.

AIM: Fluoxetine (FXT), a selective serotonin reuptake inhibitor (SSRI), is one of the most common psychiatric medications clinically prescribed; while over-produced serotonin may suppress neurite development. The role of major iridoids like geniposide (GPS) and genipin (GNP) from Gardenia jasminoides Ellis fruit (family Rubiaceae) in ameliorating the anti-neurite outgrowth effect of FXT is poorly understood. In this study, the effects of these iridoids on FXT-suppressed neurite outgrowth in Neuro2a neuroblastoma cells were investigated. MAIN METHODS: Neuro2a cells were treated with FXT and GPS. The effect of GPS-FXT co-treatment on neurite outgrowth was observed using inverted phase-contrast microscope imaging system, while neurite outgrowth markers - microtubule-associated protein-2 (MAP2) and growth-associated protein 43 (GAP43) were analyzed using RT-PCR, Western blot and immunofluorescence staining. The transcription factor-cAMP response element binding (CREB), and signaling pathways - mitogen-activated protein kinase (MAPK) and protein kinase B/mammalian target of rapamycin (AKT/mTOR) were also analyzed with the help of Western blot. KEY FINDINGS: The results showed that FXT decreased the neurite outgrowth in Neuro2a cells and also downregulated gene and protein expression of MAP2 and GAP43. It also downregulated the protein expression of phosphorylated-CREB, MAPK, and AKT/mTOR signaling pathways. In contrast, GPS counteracted the effects of FXT. GPS-FXT co-treatment increased the percentage of neurite-bearing cells by 3.6-fold at 200 µM as compared to FXT treatment only. SIGNIFICANCE: This study has provided the possible molecular mechanism showing how FXT exerted its detrimental side-effects on the neurite differentiation, and via the same mechanism how GPS attenuated these side effects.

Evaluation of the Inhibitory Effects of Genipin on the Fluoxetine-Induced Invasive and Metastatic Model in Human HepG2 Cells.

Metastasis of hepatocellular carcinoma (HCC) is usually unrecognized before any pathological examination, resulting in time-taking treatment and poor prognosis. As a consequence, HCC patients usually show symptoms of depression. In order to suppress such psychiatric disorders and to facilitate better treatment outcome, antidepressants are prescribed. Up to present, information about the effect of antidepressants on HCC is still lacking. Therefore, we chose fluoxetine (FXT), one of the top five psychiatric prescriptions in the United States, together with the HepG2 cell model to explore its effect on HCC. Our study found that FXT (5 µM) increased the migratory distance of HepG2 cells by a factor of nearly 1.7 compared to control. In addition, our study also investigated the effect of genipin (GNP), which is an active compound from Gardenia jasminoides Ellis fruit (family Rubiaceae), on the FXT-induced HepG2 cells. Our study found that 30 and 60 µM GNP reduced the migratory distance by 42% and 74% respectively, compared to FXT treatment alone. Furthermore, we also found that FXT upregulated matrix metalloproteinases (MMPs) genes, increased the protein expression of MMPs, urokinase-type plasminogen activator (uPA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activator protein 1 (AP-1), phosphorylated mitogen-activated protein kinase (P-p38), phosphorylated protein kinase B (P-Akt), downregulated tissue inhibitor metalloproteinases (TIMPs) genes and decreased the TIMPs proteins expression whereas, GNP fully counteracted the action of FXT. Conclusively, this study has provided valuable information regarding the possible molecular mechanisms through which FXT affects the metastatic invasiveness of HepG2 cells and evidences to support that GNP counteracts such effect via the same molecular mechanisms.

Design, synthesis and evaluation of novel benzimidazoles, benzothiazoles and benzofurans incorporating pyrazole moiety as antiangiogenic agents.

Novel benzimidazoles, benzothiazoles and benzofurans incorporating pyrazole moiety have been synthesized and screened for their antiangogenic activities, by testing their ability to inhibit human umbilical vein endothelial cell (HUVEC) proliferation, cord formation and migration in response to chemoattractant. 3 compounds 19, 23 and 26 showed antiangiogenic activities at non-cytotoxic concentrations. Compound 19 was the most active with chemotaxis activity data nearly comparable to that of the positive control, TNP-470. Compound 42 showed a significant cytotoxic effect on the tested cancer cell lines and less antiangiogenesis activity compared to compounds 19, 23 and 26. All the tested compounds, in contrary to TNP-470, interfered with the migratory function of HUVECs in response to vascular endothelial growth factor rather than the endothelial cells proliferation or cord formation. Moreover, a docked pose of compounds 19 and 26 was obtained bound to kinase insert domain receptor using Molecular Operating Environment module.

Antibacterial activity of essential oils against periodontal pathogens: a qualitative systematic review.

Periodontal diseases are among the most common infectious diseases that lead to the destruction of periodontal tissues. Anaerobic gram-negative bacteria (Aggregatibacter actinomecetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum...) isolated from periodontal lesions, have been shown to be related to the onset and progression of periodontal disease. Given the incidence of periodontitis, increased resistance of oral bacteria to antibiotics and adverse effects of some antibacterial agents currently used in dentistry, there is a need for alternative products that are safe and effective, for prevention and treatment of these diseases. Essential oils considered traditional medicines are viewed as good alternatives. In Morocco, a wide producer of essential oils, the high prevalence of aggressive periodontitis, related to virulent periodontal bacteria isolated from pockets in Moroccan adolescents and because of the reasons evoked above, the search of a new natural agent has become a necessity. In this qualitative systematic review, the virulence and increased antibiotic resistance of periopathogens, involved in periodontitis, will be exposed, justifying the use of alternative natural agents such as essential oils-based. Studies that have investigated the efficacy of such plant-derived medicines on periodontal pathogens will be described and discussed.

Gas-phase ion association provides increased selectivity and sensitivity for measuring perchlorate by mass spectrometry.

Perchlorate (ClO4-) competitively inhibits the uptake of iodide by the thyroid gland. Trace quantities of perchlorate are being increasingly detected in food and environmental samples. There is great concern that perchlorate contamination may be far more widespread than believed until now. Increasingly sensitive and unambiguous methods are needed for measuring perchlorate. We report here an ion chromatography-ion association-electrospray ionization-mass spectrometry (IC/IA-ESI-MS) method of substantially greater selectivity and sensitivity than other available single-stage MS approaches. A long chain dipositive cationic agent (D2+) is added postcolumn in low concentration. This ion associates with perchlorate, even in the gas phase. Perchlorate is, thus, detected as DClO4+ in the positive ion mode at an m/z value between 300 and 400 (depending on the choice of D2+). This results in much better S/N and selectivity, as compared to detecting 35ClO4- at m/z 99, where H34SO4- also responds. We show results for various dicationic agents which vary in their selectivity and affinity for ClO4-, typically being at least 1 order of magnitude more selective for ClO4- over HSO4-. For a 100-microL injected standard, limits of detection (LOD, S/N = 3) are as good as 25 ng/L on a single quadrupole mass spectrometer. Calibration for concentrations up to 100 microg/L displays an r2 value of > or =0.9993. We show applicability to various real samples. A number of the studied reagents are suitable for such applications.

Chemiluminometric measurement of atmospheric ozone with photoactivated chromotropic acid.

A highly sensitive, robust, fast, affordable measurement system based on interfacial gas-liquid chemiluminescence (CL) on a wetted transparent screen directly on top of a miniature photomultiplier tube provides the basis of an attractive method for ozone (O(3)). Alkaline chromotropic acid (CA, 4,5-dihydroxynaphthalene-2,7-disulfonic acid) chemiluminesces upon exposure to ozone. No light emission is observed from exposure of alkaline CA to NO(2) or H(2)O(2). However, response to ozone is highly dependent on the age and storage condition of the CA solution. As such, quantitative analysis will require frequent calibration, and the method will not be attractive. We have discovered that photoactivation plays the key role in producing (a) compound(s) from chromotropic acid that appear(s) to be the primary agent(s) responsible for the CL reaction with O(3). We thus devised a method wherein a flowing solution of CA (that is stable in neutral/acidic solutions) is rendered alkaline and then exposed for a few seconds on-line to UV radiation. The solution then reacts with ozone on a screen consisting of an "invisible" nylon stocking that provides for low liquid residence time and high light throughput and results in an LOD of 40 pptv, a determination range at least up to 230 ppbv, and 10-90% and 90-10% response times of 130 and 80 ms, respectively. Intra- and interday repeatabilities at the same concentration were 0.32 and 3.8% in relative standard deviation. On the basis of aging, CL, chromatography, and chromatography-mass spectrometry studies, we suggest that the primary CL-active species are likely dimeric semiquinone species derived from CA by a series of radical reactions.

Synthesis and biological investigations of some novel thiazolylbenzimidazoles, and benzimidazolyl-thiazolo[4,5-d]pyrimidines.

Several thiazolyl-benzimidazoles 2, 4a-c were synthesized through the reaction of 2-cyanomethyl-1 H-benzimidazole with isothiocyanates followed by cyclization of the produced intermediates 1a-b with either ethyl bormocetate or phenacyl bromides. When the cyclization was performed in alkaline medium, thiophenyl-benzimidazoles 5, 6a, b were produced. Another series of thiazolyl-benzimidazoles 8 a-d was obtained from 2,3-dihydrothiazole-2-(3 H)-thiones 7a-d and 2-cyanomethyl-1 H-benzimidazole, then cyclized to the corresponding thiazolo[4,5-d]pyrimidine 10a-d. Most of the prepared compounds were evaluated for their in-vitro antibacterial, antifungal, anti-HIV and anti-cancer activities. They showed promising antifungal activity.

Synthesis of novel thiazolo[4,5-d]pyrimidine derivatives for antimicrobial, anti-HIV and anticancer investigation.

Some novel thiazolo[4,5-d]pyrimidines containing 6-arylideneamino (3a-e). 2-dicyanomethylidene (5a), 2-(cyanoethoxy carbonyl) methylidene (5b) or 2-hydrazono (7a, b) moieties were synthesized. The prepared compounds were tested in vitro for their antibacterial, antifungal, anti-HIV and anticancer activities. Most of them showed promising antifungal activity, but only a few compounds exhibited anticancer activity.

Amplification of a novel gene, sanA, abolishes a vancomycin-sensitive defect in Escherichia coli.

We have isolated an Escherichia coli gene which, when overexpressed, is able to complement the permeability defects of a vancomycin-susceptible mutant. This gene, designated sanA, is located at min 47 of the E. coli chromosome and codes for a 20-kDa protein with a highly hydrophobic amino-terminal segment. A strain carrying a null mutation of the sanA gene, transferred to the E. coli chromosome by homologous recombination, is perfectly viable, but after two generations at high temperature (43 degrees C), the barrier function of its envelope towards vancomycin is defective.

Synthesis and biological investigations of some new thiazolylbenzimidazoles and benzimidazolylthiazolo[3,2-a]pyridines.

2-[(4-Oxo-4,5-dihydrothiazol-2-yl)methyl]-1H-benzimidazole (2) was prepared through the reaction of 2-cyanomethyl-1H-benzimidazole (1) with thioglycolic acid. The syntheses of its arylidene 3 and diazo-coupled compounds 5 and the cyclization of the aforementioned thiazolylbenzimidazole to benzimidazolylthiazolo[3,2-a]pyridines 8 were also performed. The prepared compounds were screened for their in-vitro antibacterial, antifungal, anti-HIV, and anticancer activities: they show promising antifungal activity.

Synthesis and biochemical evaluation of N-(1-substituted-cycloalkyl)-beta-(3,4-dimethoxy; or dihydroxy) phenethylamines: potential dopaminergic agents.

The design and synthesis of some hybrid-structures comprising the dopamine framework on one hand and an N-(1-substituted-cycloalkyl) moiety on the other have been elaborated. Selective members of the new series were biochemically assayed to determine their effects on the levels of dopamine and its metabolite norepinephrine in brains of Albino-rats. The brain MAO activity was also estimated. The results were compared with those displayed by apomorphine, metoclopramide and PCP.

Assessment of anti-HIV activity of some benzimidazolylthiazoles.

Benzimidazolylthiazoles 2 were synthesized by condensing 1H-benzimidazole-2-acetonitrile (1) with sulphur and isothiocyanates. The syntheses of the Schiff bases 3, thioureas 4, and thiazolopyrimido[1,6-a]benzimidazoles 5 and 6 are also described. Seven compounds were evaluated in vitro against human HIV, however, no significant activity was observed with any of these compounds.

Arabic children's pain descriptions.

A convenience sample of 60 children, aged five to 12 years, reporting to Kuwait government hospital emergency departments was studied. All were native Arabic speakers. Our aim was to compare the diagnostic usefulness of the pain information provided by children and by accompanying adults when interviewed under standard emergency department conditions. Children were asked to describe their current pain and how it had changed and to signify pain intensity using a 10-point visual analog scale (VAS). Comparable data were then collected from the accompanying adult. Senior clinicians rated these verbal and VAS descriptions for their usefulness in arriving at a diagnosis. Most children provided useful pain information. Mothers received consistently higher scores for their VAS descriptions than their children did; otherwise, the pain data provided by adults were not judged to be significantly more useful. When clinicians and teachers were asked to differentiate which data they thought had been provided by a child and which by the accompanying adult, nearly half of their decisions were wrong.

Synthesis of alkyloxybenzamide derivatives as potential antimicrobial agents.

Three series of alkyloxybenzamido derivatives have been prepared. The first comprises N1-[4-(4-alkyloxybenzamido)benzoyl]-N2-substituted alkylidene hydrazine, the second involves 1-[4-(4-alkyloxybenzamido)benzoyl]-4-alkyl, aryl, or aralkyl-3-thiosemicarbazides, and the third includes 1-substituted-5-[4-(4-alkyloxybenzamido)phenyl]-1,3,4-triazole-2-t hione. Representative samples of the prepared compounds were tested for their in-vitro antimicrobial activity.

Novel benzimidazoles with potential antimicrobial and antineoplastic activities.

The synthesis of some substituted 4-[1-(1-(1H-benzimidazol-2-yl) alkylamino]-1,5-dihydro-2H-pyrrol-2-ones and 3-[1-(1H-benzimidazol-2-yl)alkyl]-2-substituted-4(3H)-quinazolinon es is described. Five compounds displayed in vitro antibacterial and antifungal activities. Three of these compounds were tested against P-388 lymphocytic leukemia in mice and were inactive.

Syntheses and in vitro antimicrobial evaluation of some benzimidazol-2-ylmethylthioureas, benzimidazol-2-ylacetylthiosemicarbazides and products of their condensation with monochloroacetic acid.

N-Benzimidazol-2-ylacetyl-N'-[alkyl- and arylthio (carbamoyl)]hydrazines and N-benzimidazol-2-ylmethyl-N'-alkyl- and -arylthioureas were subjected to condensation with monochloroacetic acid to afford N-benzimidazol-2-ylacetyl-N'-2,3, 4,5-tetrahydro-4-oxo-3-alkyl- and -arylthiazol-2-ylidenehydrazines and 3-benzimidazol-2-ylmethyl-2-alkyl- and arylimino-2,3-dihydrothiazol-4-(5H)ones, respectively. In preliminary antimicrobial testing, some compounds turned out to have significant activity against Staphylococcus aureus.