Protective effect of astaxanthin on indomethacin-induced gastric ulcerations in mice.

Gastric ulcer disease remains one of the common medical burdens affecting millions worldwide due to its prevalent risk factors with the chronic usage of non-steroidal anti-inflammatory drugs at the top, reportedly through the stimulation of oxidative stress and triggering of inflammatory and apoptotic cascades in the gastric mucosa. Astaxanthin, a dietary keto-carotenoid derived from marine organisms is gaining a wide interest as a nutraceutical for its pronounced antioxidant properties. Here, we aim to examine the potential modulatory role of astaxanthin on indomethacin-induced gastric ulceration in experimental mice. Twenty-four Swiss albino mice were randomly distributed into four groups: a control group, an indomethacin group, and two groups pre-treated with either omeprazole or astaxanthin. The gastric tissues were assessed using gross morphology, ulcer scoring, gastric juice acidity, as well as reduced glutathione (GSH) and malondialdehyde (MDA) levels. Histopathological examination and immunostaining for nuclear factor-kappa B (NF-κB) and caspase-3 levels were also employed. Indomethacin group tended to show a higher number of mucosal ulcerations relative to control and pre-treated groups. The indomethacin group also showed significantly lower GSH levels and higher MDA levels relative to control. Immunostaining of gastric tissue sections showed a higher reactivity to NF-κB and caspase-3 in indomethacin group. Astaxanthin pre-treatment significantly elevated gastric juice pH, normalized GSH levels, and lowered the indomethacin-induced elevations in MDA, NF-κB, and caspase-3 levels. These results indicate that astaxanthin exhibits a comparable protective effect to omeprazole, against indomethacin-induced gastric ulceration. This anti-ulcerogenic effect could be mediated through its antioxidant, anti-inflammatory, and anti-apoptotic modulatory activities.

Prefrontal coding of learned and inferred knowledge during REM and NREM sleep.

Idling brain activity has been proposed to facilitate inference, insight, and innovative problem-solving. However, it remains unclear how and when the idling brain can create novel ideas. Here, we show that cortical offline activity is both necessary and sufficient for building unlearned inferential knowledge from previously acquired information. In a transitive inference paradigm, male C57BL/6J mice gained the inference 1 day after, but not shortly after, complete training. Inhibiting the neuronal computations in the anterior cingulate cortex (ACC) during post-learning either non-rapid eye movement (NREM) or rapid eye movement (REM) sleep, but not wakefulness, disrupted the inference without affecting the learned knowledge. In vivo Ca2+ imaging suggests that NREM sleep organizes the scattered learned knowledge in a complete hierarchy, while REM sleep computes the inferential information from the organized hierarchy. Furthermore, after insufficient learning, artificial activation of medial entorhinal cortex-ACC dialog during only REM sleep created inferential knowledge. Collectively, our study provides a mechanistic insight on NREM and REM coordination in weaving inferential knowledge, thus highlighting the power of idling brain in cognitive flexibility.

Apigenin protects from hepatorenal damage caused by lead acetate in rats.

Exposure to lead (Pb) is associated with serious health problems including hepatorenal toxicity. Apigenin is a natural-sourced flavonoid with promising antioxidant and anti-inflammatory effects. In this research, we investigated the potential protective role of apigenin against lead acetate (PbAc)-induced hepatorenal damage. Thus, this experiment studied the exposure of male Wistar Albino rats to apigenin and/or PbAc and their effects in comparison to the control rats. Apigenin administration decreased the levels of Pb and prevented the histopathological deformations in liver and kidney tissues following PbAc exposure. This was confirmed by the normalized levels of liver and kidney function markers. Additionally, apigenin inhibited significantly oxidative reactions through upregulating Nrf2 and HO-1, and activating their downstreamed antioxidants accompanied by a marked depletion of pro-oxidants. Moreover, apigenin decreased the elevated pro-inflammatory cytokines and inhibited cell loss in liver and kidney tissues in response to PbAc intoxication in both tissues. The obtained results demonstrated that apigenin could be used to attenuate the molecular, biochemical, and histological alterations associated with Pb exposure due to its potent antioxidant, anti-inflammatory, and antiapoptotic effects.

Selective engram coreactivation in idling brain inspires implicit learning.

Passive priming of prior knowledge to assimilate ongoing experiences underlies advanced cognitive processing. However, the necessary neural dynamics of memory assimilation remains elusive. Uninstructed brain could also show boosted creativity, particularly after idling states, yet it remains unclear whether the idling brain can spontaneously spark relevant knowledge assimilations. We established a paradigm that links/separates context-dependent memories according to geometrical similarities. Mice exploring one of four contexts 1 d before undergoing contextual fear conditioning in a square context showed a gradual fear transfer to preexposed geometrically relevant contexts the next day, but not after 15 min. Anterior cingulate cortex neurons representing relevant, rather than distinct, memories were significantly coreactivated during postconditioning sleep only, before their selective integration the next day during testing. Disrupting sleep coreactivations prevented assimilation while preserving recent memory consolidation. Thus, assimilating pertinent memories during sleep through coreactivation of their respective engrams represents the neural underpinnings of sleep-triggered implicit cortical learning.

Seroprevalence of neutralizing antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among healthcare workers in Makkah, Saudi Arabia.

OBJECTIVE: The new coronavirus disease 2019 (COVID-19) is a major health problem worldwide. The surveillance of seropositive individuals serves as an indicator to the extent of infection spread and provides an estimation of herd immunity status among population. Reports from different countries investigated this issue among healthcare workers (HCWs) who are "at risk" and "sources of risk" for COVID-19. This study aims to investigate the seroprevalence of COVID-19 among HCWs in one of the COVID-19 referral centers in Makkah, Saudi Arabia using three different serological methods. METHODS: In-house developed enzyme-linked immunoassay (ELISA), commercially available electro-chemiluminescence immunoassay (ECLIA), and microneutralization (MN) assay were utilized to determine the seroprevalence rate among the study population. 204 HCWs participated in the study. Both physicians and nurses working in the COVID-19 and non COVID-19 areas were included. Twelve out of 204 were confirmed cases of COVID-19 with variable disease severity. Samples from recovered HCWs were collected four weeks post diagnosis. RESULTS: The overall seroprevalence rate was 6.3% (13 out of 204) using the in-house ELISA and MN assay and it was 5.8% (12 out of 204) using the commercial ECLIA. Among HCWs undiagnosed with COVID-19, the seroprevalence was 2% (4 out 192). Notably, neutralizing antibodies were not detected in 3 (25%) out 12 confirmed cases of COVID-19. CONCLUSIONS: Our study, similar to the recent national multi-center study, showed a low seroprevalence of SARS-Cov-2 antibodies among HCWs. Concordance of results between the commercial electro-chemiluminescence immunoassay (ECLIA), in-house ELISA and MN assay was observed. The in-house ELISA is a promising tool for the serological diagnosis of SARS-CoV-2 infection. However, seroprevalence studies may underestimate the extent of COVID-19 infection as some cases with mild disease did not have detectable antibody responses.

Indicators of Critical Illness and Predictors of Mortality in COVID-19 Patients.

COVID-19 is an emerging disease all over the world and spreading at an unpredicted rate, resulting in significant influences on global economies and public health. Clinical, laboratory, and imaging characteristics have been partially described in some observational studies. Not enough systematic reviews on predictors of critical illness and mortality in COVID 19 have been published to date. In this review, we had illustrated the prognostic predictors of COVID-19 by gathering published information on the risk factors related to the outcomes of SARS-CoV-2 infections.

Spontaneous spondylodiscitis: review, incidence, management, and clinical outcome in 44 patients.

OBJECTIVESpontaneous spondylodiscitis remains uncommon but is a serious complication of the vertebral column. Risk factors include diabetes, hemodialysis, intravenous drug abuse, and chronic steroid use, and pain is the most common presenting symptom. This study aims to review the literature and report on the incidence, management, and clinical outcome of spontaneous spondylodiscitis in 44 patients.METHODSThis is a prospective study including 44 patients with spontaneous spondylodiscitis managed in the neurosurgery department of Cairo University Hospitals during the period between January 2012 and October 2017. All patients had a full clinical assessment, laboratory tests, radiological studies in the form of MRI with and without contrast, and a postoperative follow-up of up to 12 months.RESULTSTwelve cases underwent conservative treatment in the form of complete bed rest, intravenous antibiotics, and a spinal brace. Ten cases underwent surgical intervention in the form of laminectomy, debridement, and open biopsy. Twenty-two cases underwent laminectomy and surgical stabilization with fusion. There were 15 cases of tuberculous spondylodiscitis, 6 cases of brucellosis, 6 cases of pyogenic infection, and 17 cases in which no organism could be detected.CONCLUSIONSOnce the primary diagnosis is confirmed, early and adequately prolonged antibiotic therapy is recommended for spontaneous spondylodiscitis. Some cases can be successfully treated with conservative treatment alone, whereas surgery may be needed in other cases such as severe destruction of endplates, spinal abscess formation, mechanical instability, neurological deficits, and severe pain that have failed to respond to conservative treatment.

Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents.

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 µM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 µM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).

Synthesis and Cytotoxic Activity of Biphenylurea Derivatives Containing Indolin-2-one Moieties.

In our endeavor towards the development of potent anticancer agents, two different sets of biphenylurea-indolinone conjugates, 5a-s and 8a,b were synthesized. The in vitro cytotoxicity of the synthesized compounds was examined in two human cancer cell lines, namely MCF-7 breast cancer and PC-3 prostate cancer cells using the sulforhodamine B (SRB) colorimetric assay. In particular, the MCF-7 cancer cell line was more susceptible to the synthesized compounds. Compound 5o (IC50 = 1.04 ± 0.10 µM) emerged as the most active member in this study against MCF-7, with 7-fold increased activity compared to the reference drug, doxorubicin (IC50 = 7.30 ± 0.84 µM). Compounds 5l, 5q and 8b also exhibited superior cytotoxic activity against MCF-7 with IC50 values of 1.93 ± 0.17, 3.87 ± 0.31 and 4.66 ± 0.42 µM, respectively. All of the tested compounds were filtered according to the Lipinski and Veber rules and all of them passed the filters. Additionally, several ADME descriptors for the synthesized compounds 5a-s and 8a,b were predicted via a theoretical kinetic study performed using the Discovery Studio 2.5 software.

Bis-isatin hydrazones with novel linkers: Synthesis and biological evaluation as cytotoxic agents.

Many bis-isatins and isatins with hydrazide extension were reported to have a potential anti-proliferative effects against different cancer cell lines and cancer targets. In this study, four series of bis-isatins with hydrazide linkers were synthesized. These compounds were investigated for their antitumor activity by assessing their cytotoxic potency against HepG2, MCF-7 and HCT-116 cancer cell lines. Compound 21c possessed significant cytotoxic activity against MCF-7 (IC50 = 1.84 µM) and HCT-116 (IC50 = 3.31 µM) that surpasses the activity of doxorubicin against both cell lines (MCF-7; IC50 = 2.57 µM and HCT-116; IC50 = 3.70 µM). Cell cycle analysis and annexin V-FITC staining of MCF-7 cells treated with 21c suggested that the cytotoxic effect of the compound could be attributed to its pro-apoptotic activity.

Indoline ureas as potential anti-hepatocellular carcinoma agents targeting VEGFR-2: Synthesis, in vitro biological evaluation and molecular docking.

In our effort to develop potent and effective agents with anti-proliferative activity towards HepG2 hepatocellular carcinoma cells with potential inhibitory activity against VEGFR-2, a novel series of 1-(4-((2-oxoindolin-3-ylidene)amino)phenyl)-3-arylureas was designed and synthesized. All the newly prepared ureas 9a-x were evaluated in vitro for their anti-proliferative activity against HepG2 hepatocellular carcinoma cell line. Compounds 9a-c, 9e, 9f, 9j, 9m-o, 9t-v and 9x exhibited good activity against HepG2 cancer cells (IC50 = 1.22 ± 0.11-8.37 ± 0.85 µM) comparable to that of doxorubicin and sorafinib (IC50 = 2.90 ± 0.36 and 3.40 ± 0.25 µM, respectively). These thirteen compounds were further evaluated for their inhibitory activity against VEGFR-2. Compound 9x emerged as the most active counterpart against VEGFR-2 with IC50 value of 0.31 ± 0.04 µM. Furthermore, a molecular docking of the tested compounds was carried out in order to investigate their binding pattern with the prospective target, VEGFR-2 (PDB-code: 4ASD).

Design, synthesis and in vitro antiproliferative activity of novel isatin-quinazoline hybrids.

Using a molecular hybridization approach, a new series of isatin-quinazoline hybrids 15a-o was designed and synthesized via two different synthetic routes. The target compounds 15a-o were prepared by the reaction of quinazoline hydrazines 12a-e with indoline-2,3-diones 13a-c or by treating 4-chloroquinazoline derivatives 11a-e with isatin hydrazones 14a-c. The in vitro anticancer activity of the newly synthesized hybrids was evaluated against the liver HepG2, breast MCF-7 and colon HT-29 cancer cell lines. A distinctive selective growth inhibitory effect was observed towards the HepG2 cancer cell line. Compounds 15b, 15g and 15l displayed the highest potency, with IC50 values ranging from 1.0 ± 0.2 to 2.4 ± 0.4 µM, and they were able to induce apoptosis in HepG2 cells, as evidenced by enhanced expression of the pro-apoptotic protein Bax and reduced expression of the anti-apoptotic protein Bcl-2, in addition to increased caspase-3 levels.