共查询到20条相似文献,搜索用时 15 毫秒
1.
《Bioorganic & medicinal chemistry》2020,28(2):115227
Aberrant hedgehog (Hh) pathway signaling is implicated in multiple cancer types and targeting the Smoothened (SMO) receptor, a key protein of the Hh pathway, has proven effective in treating metastasized basal cell carcinoma. Our lead optimization effort focused on a series of heteroarylamides. We observed that a methyl substitution ortho to the heteroaryl groups on an aniline core significantly improved the potency of this series of compounds. These findings predated the availability of SMO crystal structure in 2013. Here we retrospectively applied quantum mechanics calculations to demonstrate the o-Me substitution favors the bioactive conformation by inducing a dihedral twist between the heteroaryl rings and the core aniline. The o-Me also makes favorable hydrophobic interactions with key residue side chains in the binding pocket. From this effort, two compounds (AZD8542 and AZD7254) showed excellent pharmacokinetics across multiple preclinical species and demonstrated in vivo activity in abrogating the Hh paracrine pathway as well as anti- tumor effects. 相似文献
2.
《Saudi Journal of Biological Sciences》2023,30(8):103736
Poultry production has been developing in Vietnam with challenges of disease. Thus, feed additive should be investigated not only growth but also health enhancement. Here, we aimed to determine the effects of Saccharomyces cerevisiae-fermented rice (FR) and β-glucan on turkey’s growth performance, carcass characteristics, immune and fatty acid (FA) profiles. A total of 180 turkey chicks aged 1–56 days were randomly assigned to five sextuplicate groups and the birds had ad libitum feed and water access throughout the experiment. The five treatment groups were given the same diet with different proportions of FR and β-glucan. Broilers supplemented with 4% β-glucan and 4% FR presented the highest and second-highest growth performance, respectively. The 4% β-glucan and 4% FR treatments resulted in the highest carcass characteristic values without significantly affecting the breast or thigh meat pH or cooking loss. The 4% β-glucan and 4% FR treatments maximally increased the Newcastle disease (ND) antibody titers at 28, 42 and 56 days, respectively as well as thymus organ index. The foregoing treatments did not significantly affect the blood profiles relative to the control. However, the 4% FR treatment lowered the blood cholesterol levels (p > 0.05). The total FA profiles did not significantly differ among treatments. Nevertheless, both the β-glucan and FR treatments increased the MUFA levels compared to that of the control (p > 0.05). Hence, the dietary administration of 4% β-glucan and FR to turkey broilers could effectively improve their growth performance and immunity. 相似文献
3.
The chemical transformation of phosphinic acid is a well-considered mature area of research on account of the historical significant reactions such as Kabachnik–Fields, Mannich, Arbuzov, Michaelis–Becker, etc. Considerable advances have been made over last years especially in metal-catalyzed, free-radical processes and asymmetric synthesis using catalytic enantioselective. As a result, the aim of this synopsis is to make the reader familiar with advances in the approaches of phosphinic acids toward the synthesis of highly functionalized and valuable buildings blocks. Another purpose of this survey is to provide the current status of the applications of phosphinic acids in the synthesis of drugs. 相似文献
4.
Khadija Ridaoui Ismail Guenaou Ikram Taouam Mounia Cherki Noureddine Bourhim Abdelaziz Elamrani Mostafa Kabine 《Saudi Journal of Biological Sciences》2022,29(3):1842-1852
The purpose of this work was to investigate the protective effect of five essential oils (EOs); Rosmarinus officinalis, Thymus vulgaris, Origanum compactum Benth., Eucalyptus globulus Labill. and Ocimum basilicum L.; against oxidative stress induced by hydrogen peroxide in Saccharomyces cerevisiae. The chemical composition of the EOs was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The in vitro antioxidant activity was evaluated and the protective effect of EOs was investigated. Yeast cells were pretreated with different concentrations of EOs (6.25–25 µg/ml) for an hour then incubated with H2O2 (2 mM) for an additional hour. Cell viability, antioxidants (Catalase, Superoxide dismutase and Glutathione reductase) and metabolic (Succinate dehydrogenase) enzymes, as well as the level of lipid peroxidation (LPO) and protein carbonyl content (PCO) were evaluated. The chemical composition of EOs has shown the difference qualitatively and quantitatively. Indeed, O. compactum mainly contained Carvacrol, O. basilicum was mainly composed of Linalool, T. vulgaris was rich in thymol, R. officinalis had high α-Pinene amount and for E. globulus, eucalyptol was the major compound. The EOs of basil, oregano and thyme were found to possess the highest amount of total phenolic compounds. Moreover, they have shown the best protective effect on yeast cells against oxidative stress induced by H2O2. In addition, in a dose dependent manner of EOs in yeast medium, treated cells had lower levels of LPO, lower antioxidant and metabolic enzymes activity than cells exposed to H2O2 only. The cell viability was also improved. It seems that the studied EOs are efficient natural antioxidants, which can be exploited to protect against damages and serious diseases related to oxidative stress. 相似文献
5.
《Bioorganic & medicinal chemistry》2019,27(19):115032
Combretastatin A-4 (CA-4) is a highly cytotoxic natural product and several derivatives have been prepared which underwent clinical trial. These investigations revealed that the cis-stilbene moiety of the natural product is prone to undergo cis/trans isomerization under physiological conditions, reducing the overall activity of the drug candidates. Herein, we report the preparation of cis-restrained carbocyclic analogs of CA-4. The compounds, which differ by the size and hybridization of the carbocyclic ring have been evaluated for their cytotoxic properties and their ability to inhibit tubulin polymerization. Biological data, supported by molecular docking studies, identified cyclobutenyl and cyclobutyl derivatives of the natural product as highly promising drug candidates. 相似文献
6.
The genera Raabena and Pararaabena (Ciliophora, Entodiniomorphida, Blepharocorythidae) were monospecific, and their type species are Raabena bella Wolska, 1967 and Pararaabena dentata Wolska, 1968. They have been found in Asian elephants and closely resemble each other: ovoid and laterally compressed body; non-retractable adoral ciliary zone; funnel-shaped vestibulum; three non-retractable somatic ciliary arches. Furthermore, the positional relationship between the vestibular ciliary zone and the anterior dorsal ciliary zone identifies Raabena and Pararaabena: these two ciliary zones are connected in Raabena while they are separated in Pararaabena. While investigating entodiniomorphid ciliates of Asian elephants, the author often encountered ciliates similar to Raabena bella but with a sinuous body or with a small body and ciliates similar to Pararaabena dentata but with a slender body or with no or two caudal lobes. In this study, their general morphology and infraciliature were compared to R. bella and P. dentata to know whether they are new species or morphological variations in a species. As a result, the present study redescribed R. bella and P. dentata, and described R. sinuosa n. sp., R. bellafilia n. sp., P. gracilis n. sp., and morphotypes of P. dentata. 相似文献
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8.
《Saudi Journal of Biological Sciences》2023,30(3):103579
BackgroundCardiovascular diseases (CVD) are leading cause of mortality in patients with type 2 diabetes mellitus (T2DM). Increased soluble sP-selectin and 715Thr > Pro polymorphism were studied in CVD and T2DM, but association between them hasn’t been explored in Saudi Arabia. We aimed to assess sP-selectin levels in T2DM and T2DM-associated CVD patients in comparison to healthy control cohort. Also, we sought to investigate relationship between Thr715Pro polymorphism and sP-selectin levels and disease state.MethodsThis is a cross-sectional case-control study. sP-selectin level (measured by Enzyme-linked immunosorbent assay) and prevalence of Thr715Pro polymorphism (assessed by Sanger sequencing) were investigated in 136 Saudi participants. The study comprised 3 groups: group1 included 41 T2DM patients; group 2 (48 T2DM patients with CVD), and group 3 (47 healthy controls).ResultssP-selectin levels were significantly higher in diabetics and diabetics + CVD groups as compared to the corresponding control. In addition, results showed that the prevalence of 715Thr > Pro polymorphism is 11.75 % in the study population amongst the three study groups (9.55 % Thr/Pro, and 2.2 % Pro/Pro). No statistical difference was found between sP-selectin levels in subject carrying the wildtype genotype of this polymorphism and these who carry the mutant gene. There could be an association between this polymorphism and T2DM, whilst the polymorphism may protect diabetic patients from having CVD. However, odds ratio is not statistically significant in both cases.ConclusionOur study supports the previous researches’ results that Thr715Pro is neither influencing the sP-selectin level nor the risk of CVD in T2DM patients. 相似文献
9.
《Journal of molecular biology》2023,435(18):168211
Heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) is a multifunctional RNA-binding protein that is associated with neurodegenerative diseases, such as amyotrophic lateral sclerosis and multisystem proteinopathy. In this study, we have used cryo-electron microscopy to investigate the three-dimensional structure of amyloid fibrils from full-length hnRNPA1 protein. We find that the fibril core is formed by a 45-residue segment of the prion-like low-complexity domain of the protein, whereas the remaining parts of the protein (275 residues) form a fuzzy coat around the fibril core. The fibril consists of two fibril protein stacks that are arranged into a pseudo-21 screw symmetry. The ordered core harbors several of the positions that are known to be affected by disease-associated mutations, but does not encompass the most aggregation-prone segments of the protein. These data indicate that the structures of amyloid fibrils from full-length proteins may be more complex than anticipated by current theories on protein misfolding. 相似文献
10.
《Journal of molecular biology》2022,434(17):167610
Drug research and development is a multidisciplinary field with its own successes. Yet, given the complexity of the process, it also faces challenges over the long development stages and even includes those that develop once a drug is marketed, i.e. drug toxicity and drug resistance. Better success can be achieved via well designed criteria in the early drug development stages. Here, we introduce the concepts of allostery and missense mutations, and argue that incorporation of these two intermittently linked biological phenomena into the early computational drug discovery stages would help to reduce the attrition risk in later stages of the process. We discuss the individual or in concert mechanisms of actions of mutations in allostery. Design of allosteric drugs is challenging compared to orthosteric drugs, yet they have been gaining popularity in recent years as alternative systems for the therapeutic regulation of proteins with an action-at-a-distance mode and non-invasive mechanisms. We propose an easy-to-apply computational allosteric drug discovery protocol which considers the mutation effect, and detail it with three case studies focusing on (1) analysis of effect of an allosteric mutation related to isoniazid drug resistance in tuberculosis; (2) identification of a cryptic pocket in the presence of an allosteric mutation of falcipain-2 as a malarial drug target; and (3) deciphering the effects of SARS-CoV-2 evolutionary mutations on a potential allosteric modulator with changes to allosteric communication paths. 相似文献
11.
《Saudi Journal of Biological Sciences》2022,29(5):3167-3176
The acquisition of multi-drug resistance (MDR) genes by pathogenic bacterial bugs and their dispersal to different food webs has become a silent pandemic. The multiplied use of different antibacterial therapeutics during COVID-19 pandemic has accelerated the process among emerging pathogens. Wild migratory birds play an important role in the spread of MDR pathogens and MDR gene flow due to the consumption of contaminated food and water. Escherichia fergusonii is an emerging pathogen of family Enterobacteriaceae and commonly causes disease in human and animals. The present study focused on the isolation of E. fergusonii from blood, saliva, and intestine of selected migratory birds of the Hazara Division. The sensitivity of isolated strains was assessed against ten different antibiotics. The isolation frequency of E. fergusonii was 69%. In blood samples, a high rate of resistance was observed against ceftriaxone (80%) followed by ampicillin (76%) whereas, in oral and intestinal samples, ceftriaxone resistant strains were 56% and 57% while ampicillin resistance was 49% and 52% respectively. The overall ceftriaxone and ampicillin-resistant cases in all three sample sources were 71% and 65% respectively. In comparison to oral and intestinal samples, high numbers of ceftriaxone-resistant strains were isolated from the blood of mallard while ampicillin-resistant strains were observed in blood samples of cattle egrets. 16S rRNA-based confirmed strains of E. fergusonii were processed for detection of CTX-M and TEM-1 gene through Polymerase chain reaction (PCR) after DNA extraction. Hundred percent ceftriaxone resistant isolates possessed CTX-M and all ampicillin-resistant strains harbored TEM-1 genes. Amplified products were sequenced by using the Sanger sequencing method and the resulted sequences were checked for similarity in the nucleotide Database through the BLAST program. TEM-1 gene showed 99% and the CTX-M gene showed 98% similar sequences in the Database. The 16S rRNA sequence and nucleotide sequences for TEM-1 and CTX-M genes were submitted to Gene Bank with accession numbers LC521304, LC521306, LC521307 respectively. We posit to combat MDR gene flow among the bacterial pathogens across different geographical locations, regular surveillance of new zoonotic pathogens must be conducted. 相似文献
12.
《Saudi Journal of Biological Sciences》2023,30(5):103649
The aim of this research is to analyze the potential impact of the COVID-19 infection on the serum biochemical concentration of children 6 months after recovery from the infection.The study included 72 children with a median age of 11 years. The case group consisted of 37 children who had contracted COVID-19 6 months prior to the analysis. They reported no other pre- or post-covid chronic or systemic diseases. The control group consisted of 35 children who had no prior record of COVID-19 infection.The analysis showed a substantial variation (P = 0.026) in the mean urea values (mmol/L) between the case group (4.513 ± 0.839) and the control group (5.425 ± 1.173). However, both groups' urea levels were within the normal range of their age group. No statistical differences were found analyzing the variations between the two groups in the levels of LDH, AST, ALT, BiliT, GGT, AlbBCG2, CRP, CK, AlKP, UA, Phos, Crea2, Gluc, Ca, Na, K, Cl, TP, TC, TG, and HDL (P > 0.05). The DMFT score was substantially greater (P < 0.002) in the infected team (5.38 ± 2.841) in comparison to the non-infected group (2.6 ± 2.257).The study indicates that COVID-19 infection does not leave biochemical alterations among children who did not have pre-existing conditions. The biochemical analysis suggests that children recover better than adults from COVID-19. Furthermore, it calls for investigating non-lethal COVID-19 infection as a tool to discover underlying conditions. The DMFT score shows a correlation between COVID-19 infection and caries. However, the nature of the correlation is yet to be investigated. 相似文献
13.
B.M.M. Baharoon A.M. Shaik Salim M. El-Hamidy Rady Eid El-Araby Ashwaq H. Batawi Mohamed Abdel Salam 《Saudi Journal of Biological Sciences》2022,29(5):3626-3634
Herein, the impact of the halloysite nanotubes to suppress the side effects of Asparaginase (ANase) cellular proliferation was investigated. Methods: A total of 100 adult male mice was employed. These mice were divided into four equal groups; Group 1 (control), Group 2 (ESC group) of a single dose of 0.15 ml Ehrlich cells (2 × 106) intraperitoneal infusion(IP), Group 3 (ESC + ANase group) received six doses equal treatments of Intratumoral (IT) 0.07 ml Aspragnase (7 mg/kg) over two weeks. For two weeks, Group 4 (ESC + ASNase + HNTs) received an IT administration of 0.07 ml Asparaginase stocked on Halloysite nanotubes (HNTs) (30 mg/kg) three times per week. A blood specimen was collected, and the liver was removed to be investigated histologically. Results: TEM measurements for the Halloysite nanoclay showed their tubular cylindrical shape with a mean diameter of 50 nm and an average length of 1 μm, whereas The X-ray diffraction pattern of the Halloysite nanoclay showed their characteristic peaks. ESC increases the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin than control and other groups, even as albumin and total protein were decreasing. After using Halloysite Nanotube, the rates of these variables were enhanced up to 75%. The hepatocytes histological studies showed protection against Ehrlich Solid carcinoma-induced degenerative, necrotic, and inflammatory changes up to 70%. In conclusion, halloysite nanotubes have demonstrated effective removal of Ehrlich solid carcinoma in mice using an ASNase delivery system. It promoted the ASNase to inhibit the adverse effect of ANase's on the liver and remove the tumour cells. 相似文献
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15.
Safaa I. Khedr El Hassan M. Mokhamer Amal A.A. Hassan Asmaa S. El-Feki Gihan M. Elkhodary Mohamed S.A. El-Gerbed 《Saudi Journal of Biological Sciences》2021,28(1):427-439
Introduction and aimConsidering the magnitude of giardiasis problem, the side-effects of the used anti-giardia drugs and the resistance posed against them, the current study aimed to evaluate the in-vivo giardicidal effect of Psidium guajava leaf extract (PGLE).MethodsFor fulfilling this aim, five Swiss-albino mice groups were included; GI: non-infected, GII: Giardia-infected and non-treated, GIII: Giardia-infected and metronidazole-treated, GIV: Giardia-infected and PGLE-treated, and GV: Giardia-infected and treated with both metronidazole and PGLE. Treatment efficacy was assessed via; Giardia cyst viability and trophozoite count, trophozoite electron microscopic ultrastructure, duodenal histopathological scoring, immunohistochemistry for TNF-α and duodenal scanning electron microscopy. Moreover, mice serum liver enzymes, total bilirubin, albumin, lipid profile including; total cholesterol, HDL, LDL and triglycerides were assessed. Additionally, hepatic oxidative stress markers including; malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH) and superoxide dismutase (SOD) were measured.ResultsResults showed that PGLE whether alone or combined with metronidazole has induced significant trophozoite count reduction and major architectural changes. Duodenal histological improvement, and local protective anti-inflammatory effect were confirmed. PGLE has also helped in healing of Giardia-induced gut atrophy. Thus, offered a comprehensive therapy for both the pathogen and the resultant pathological sequalae. Serum markers showed favorable hepatoprotective effect. Total cholesterol, LDL and triglycerides levels were less in PGLE-treated group than in metronidazole-treated group. Hepatic oxidative stress markers revealed the promising extract antioxidant effect. This study highlights, the promising in-vivo giardicidal PGLE activity, that was comparable to metronidazole, thus, the extract would be an ideal strongly recommended treatment for giardiasis. When combined with metronidazole, the extract potentiated its therapeutic effect. Besides, having hepatoprotective, anti-inflammatory, and antioxidant properties, the extract can combat the major side effects of metronidazole therapy. 相似文献
16.
《Journal of molecular biology》2021,433(21):167224
Retinoblastoma-binding protein 1 (RBBP1) is involved in gene regulation, epigenetic regulation, and disease processes. RBBP1 contains five domains with DNA-binding or histone-binding activities, but how RBBP1 specifically recognizes chromatin is still unknown. An AT-rich interaction domain (ARID) in RBBP1 was proposed to be the key region for DNA-binding and gene suppression. Here, we first determined the solution structure of a tandem PWWP-ARID domain mutant of RBBP1 after deletion of a long flexible acidic loop L12 in the ARID domain. NMR titration results indicated that the ARID domain interacts with DNA with no GC- or AT-rich preference. Surprisingly, we found that the loop L12 binds to the DNA-binding region of the ARID domain as a DNA mimic and inhibits DNA binding. The loop L12 can also bind weakly to the Tudor and chromobarrel domains of RBBP1, but binds more strongly to the DNA-binding region of the histone H2A-H2B heterodimer. Furthermore, both the loop L12 and DNA can enhance the binding of the chromobarrel domain to H3K4me3 and H4K20me3. Based on these results, we propose a model of chromatin recognition by RBBP1, which highlights the unexpected multiple key roles of the disordered acidic loop L12 in the specific binding of RBBP1 to chromatin. 相似文献
17.
《Cytokine》2016
Type II diabetes regroups different physiological anomalies that ultimately lead to low-grade chronic inflammation, insulin resistance and loss of pancreatic β-cells. Obesity is one of the best examples of such a condition that can develop into Metabolic Syndrome, causing serious health problems of great socio-economic consequences. The pathological outcome of obesity has a genetic basis and depends on the delicate balance between pro- and anti-inflammatory effectors of the immune system. The causal link between obesity and inflammation is well established. While innate immunity plays a key role in the development of a pro-inflammatory state in obese adipose tissues, it has now become clear that adaptive immune cells are also involved and participate in the cascade of events that lead to metabolic perturbations. The efficacy of some immunotherapeutic protocols in reducing the symptoms of obesity-driven metabolic syndrome in mice implicated all arms of the immune response. Recently, the production of pathogenic immunoglobulins and pro-inflammatory cytokines by B and T lymphocytes suggested an auto-immune basis for the establishment of a non-healthy obese state. Understanding the cellular landscape of obese adipose tissues and how immune cells sustain chronic inflammation holds the key to the development of targeted therapies. In this review, we emphasize the role of antigen-presenting cells and MHC molecules in obese adipose tissue and the general contribution of the adaptive arm of the immune system in inflammation-induced insulin resistance. 相似文献
18.
《Journal of molecular biology》2023,435(10):168085
Monoclonal antibody (mAb)-based biologics are well established treatments of cancer. Antibody discovery campaigns are typically directed at a single target of interest, which inherently limits the possibility of uncovering novel antibody specificities or functionalities. Here, we present a target-unbiased approach for antibody discovery that relies on generating mAbs against native target cell surfaces via phage display. This method combines a previously reported method for improved whole-cell phage display selections with next-generation sequencing analysis to efficiently identify mAbs with the desired target cell reactivity. Applying this method to multiple myeloma cells yielded a panel of >50 mAbs with unique sequences and diverse reactivities. To uncover the identities of the cognate antigens recognized by this panel, representative mAbs from each unique reactivity cluster were used in a multi-omic target deconvolution approach. From this, we identified and validated three cell surface antigens: PTPRG, ICAM1, and CADM1. PTPRG and CADM1 remain largely unstudied in the context of multiple myeloma, which could warrant further investigation into their potential as therapeutic targets. These results highlight the utility of optimized whole-cell phage display selection methods and could motivate further interest in target-unbiased antibody discovery workflows. 相似文献
19.
《Journal of molecular biology》2022,434(17):167681
The FimH protein of Escherichia coli is a model two-domain adhesin that is able to mediate an allosteric catch bond mechanism of bacterial cell attachment, where the mannose-binding lectin domain switches from an ‘inactive’ conformation with fast binding to mannose to an ‘active’ conformation with slow detachment from mannose. Because mechanical tensile force favors separation of the domains and, thus, FimH activation, it has been thought that the catch bonds can only be manifested in a fluidic shear-dependent mode of adhesion. Here, we used recombinant FimH variants with a weakened inter-domain interaction and show that a fast and sustained allosteric activation of FimH can also occur under static, non-shear conditions. Moreover, it appears that lectin domain conformational activation happens intrinsically at a constant rate, independently from its ability to interact with the pilin domain or mannose. However, the latter two factors control the rate of FimH deactivation. Thus, the allosteric catch bond mechanism can be a much broader phenomenon involved in both fast and strong cell-pathogen attachments under a broad range of hydrodynamic conditions. This concept that allostery can enable more effective receptor-ligand interactions is fundamentally different from the conventional wisdom that allostery provides a mechanism to turn binding off under specific conditions. 相似文献
20.
Minmin Huang Entezar Mehrabi Nasab Seyyed Shamsadin Athari 《Saudi Journal of Biological Sciences》2021,28(12):6957-6962
Asthma is a complicated lung disease, which has increased morbidity and mortality rates in worldwide. There is an overlap between asthma pathophysiology and mitochondrial dysfunction and MSCs may have regulatory effect on mitochondrial dysfunction and treats asthma. Therefore, immune-modulatory effect of MSCs and mitochondrial signaling pathways in asthma was studied.After culturing of MSCs and producing asthma animal model, the mice were treated with MSCs via IV via IT. BALf's eosinophil Counting, The levels of IL-4, −5, −13, −25, –33, INF-γ, Cys-LT, LTB4, LTC4, mitochondria genes expression of COX-1, COX-2, ND1, Nrf2, Cytb were measured and lung histopathological study were done.BALf's eosinophils, the levels of IL-4, −5, −13, −25, –33, LTB4, LTC4, Cys-LT, the mitochondria genes expression (COX-1, COX-2, Cytb and ND-1), perivascular and peribronchial inflammation, mucus hyper-production and hyperplasia of the goblet cell in pathological study were significantly decreased in MSCs-treated asthma mice and reverse trend was found about Nrf-2 gene expression, IFN-γ level and ratio of the INF-γ/IL-4.MSC therapy can control inflammation, immune-inflammatory factors in asthma and mitochondrial related genes, and prevent asthma immune-pathology. 相似文献