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1.
Braz. j. biol ; 84: e259506, 2024. tab, ilus
Artigo em Inglês | VETINDEX | ID: biblio-1403847

RESUMO

Scorpion venom contains a variety of neurotoxins which interact with ion channels and affect their activities. The present study was designed to evaluate the potential of scorpion venom as acetylcholinesterase (AChE) inhibitor by using Aedes aegypti as model organism. Venoms of two species, Hottentota tamulus (Fabricus, 1798) and Androctonus finitimus (Pocock, 1897) were selected for this study. Two peptides (36 kDa from H. tamulus and 54 kDa from A. finitimus) were separated from scorpion venom by using HPLC. Selected peptides caused significantly higher mortality in larvae and adults of Aedes aegypti than control (no mortalities were observed in control groups). Significant acetylcholinesterase (AChE) inhibitory potential of both peptides was recorded by spectrophotometer. The peptide of A. finitimus caused significantly higher mortality (95±1.53% in larvae and 100% in adults) than the peptide of H. tamulus (84.33±2.33% in larvae and 95.37±1.45% in adults). While H. tamulus peptide was more efficient in reducing AChE activity (0.029±0.012 in larvae and 0.03±0.003 in adults) than the peptide of A. finitimus (0.049±0.005 in larvae and 0.047±0.001 in adults). It was concluded that H. tamulus venom peptide was more efficiently reducing AChE activity, thus it could be a potential bio-insecticide which can be synthesized at industrial scale for the control of harmful insects.


O veneno do escorpião contém uma variedade de neurotoxinas que interagem com os canais iônicos e afetam suas atividades. O presente estudo foi desenhado para avaliar o potencial do veneno de escorpião como inibidor da acetilcolinesterase (AChE) usando o Aedes aegypti como organismo modelo. Venenos de duas espécies, Hottentota tamulus (Fabricus, 1798) e Androctonus finitimus (Pocock, 1897) foram selecionados para este estudo. Dois peptídeos (36 kDa de H. tamulus e 54 kDa de A. finitimus) foram separados do veneno de escorpião usando HPLC. Peptídeos selecionados causaram mortalidade significativamente maior em larvas e adultos de Aedes aegypti do que o controle (não foram observadas mortalidades nos grupos controle). O potencial inibitório significativo da acetilcolinesterase (AChE) de ambos os peptídeos foi registrado por espectrofotômetro. O peptídeo de A. finitimus causou mortalidade significativamente maior (95 ± 1,53% em larvas e 100% em adultos) que o peptídeo de H. tamulus (84,33 ± 2,33% em larvas e 95,37 ± 1,45% em adultos). Enquanto o peptídeo de H. tamulus foi mais eficiente na redução da atividade da AChE (0,029 ± 0,012 em larvas e 0,03 ± 0,003 em adultos) do que o peptídeo de A. finitimus (0,049 ± 0,005 em larvas e 0,047 ± 0,001 em adultos). Concluiu-se que o peptídeo do veneno de H. tamulus foi mais eficiente na redução da atividade da AChE, podendo ser um potencial bioinseticida que pode ser sintetizado em escala industrial para o controle de insetos nocivos.


Assuntos
Peptídeos , Venenos de Escorpião , Aedes
2.
Braz. j. biol ; 84: e253696, 2024. graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1355862

RESUMO

Abstract Transplanting time and genotype contribute to improving crop yield and quality of eggplant (Solanum melongena L.). A field experiment was conducted to investigate the impact of foliar applied of triacontanol (TRIA) and eggplant genotypes 25919, Nirala, 28389 and Pak-10927,transplanted on 1 March,15 March, and 1 April on exposure to high air temperature conditions. The experiment was performed according to Randomized Complete Block Design and the data was analyzed by using Tuckey,s test . The TRIA was applied at 10µM at flowering stage; distilled water was used as the control. Rate of photosynthesis and transpiration, stomatal conductance, water use efficiency, and effects on antioxidative enzymes (superoxide dismutase, catalase and peroxidase) were evaluated. The 10µM TRIA increased photosynthesis rate and water use efficiency and yield was improved in all genotypes transplanted at the different dates. Foliar application of 10µM TRIA increased antioxidative enzyme activities (SOD, POD & CAT) and improved physiological as well as biochemical attributes of eggplant genotypes exposed to high heat conditions. Highest activity of dismutase enzyme 5.41mg/1g FW was recorded in Nirala genotype in second transplantation. Whereas, lowest was noted in PAK-10927 (2.30mg/g FW). Maximum fruit yield was found in accession 25919 (1.725kg per plant) at 1st transplantation with Triacontanol, whereas accession PAK-10927 gave the lowest yield (0.285 kg per plant) at control treatment on 3rd transplantation. Genotype, transplanting date and application of TRIA improved growth, yield and quality attributes under of heat stress in eggplant.


Resumo O tempo de transplante e o genótipo contribuem para melhorar a produtividade e a qualidade da cultura da berinjela (Solanum melongena L.). Um experimento de campo foi conduzido para investigar o impacto da aplicação foliar de triacontanol (TRIA) e genótipos de berinjela 25919, Nirala, 28389 e Pak-10927, transplantados em 1 de março, 15 de março e 1 de abril de exposição a condições de alta temperatura do ar. O experimento foi realizado de acordo com o Randomized Complete Block Design e os dados foram analisados pelo teste de Tuckey. O TRIA foi aplicado a 10 µM na fase de floração; água destilada foi utilizada como controle. Taxa de fotossíntese e transpiração, condutância estomática, eficiência do uso da água e efeitos sobre as enzimas antioxidantes (superóxido dismutase, catalase e peroxidase) foram avaliados. O TRIA 10 µM aumentou a taxa de fotossíntese e a eficiência do uso da água e o rendimento foi melhorado em todos os genótipos transplantados nas diferentes datas. A aplicação foliar de TRIA 10µM aumentou as atividades das enzimas antioxidantes (SOD, POD e CAT) e melhorou os atributos fisiológicos e bioquímicos de genótipos de berinjela expostos a condições de alto calor. A atividade mais elevada da enzima dismutase 5,41mg / 1g FW foi registrada no genótipo Nirala no segundo transplante. Considerando que o mais baixo foi observado em PAK-10927 (2,30 mg / g FW). A produtividade máxima de frutos foi encontrada no acesso 25919 (1,725 ​​kg por planta) no 1º transplante com Triacontanol, enquanto o acesso PAK-10927 deu a menor produção (0,285 kg por planta) no tratamento de controle no 3º transplante. Genótipo, data de transplante e aplicação de TRIA, melhoramento do crescimento, rendimento e atributos de qualidade sob estresse térmico em berinjela.


Assuntos
Solanum melongena/genética , Solanum melongena/metabolismo , Fotossíntese , Resposta ao Choque Térmico , Álcoois Graxos , Antioxidantes/metabolismo , Antioxidantes/farmacologia
4.
J Fungi (Basel) ; 9(1)2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36675924

RESUMO

Candida auris is a multi-drug-resistant fungal pathogen that can survive outside the host and can easily spread and colonize the healthcare environment, medical devices, and human skin. C. auris causes serious life-threatening infections (up to 60% mortality) in immunosuppressed patients staying in such contaminated healthcare facilities. Some isolates of C. auris are resistant to virtually all clinically available antifungal drugs. Therefore, alternative therapeutic approaches are urgently needed. Using in silico protein modeling and analysis, we identified a highly immunogenic and surface-exposed epitope that is conserved between C. albicans hyphal-regulated protein (Cal-Hyr1p) and Hyr1p/Iff-like proteins in C. auris (Cau-HILp). We generated monoclonal antibodies (MAb) against this Cal-Hyr1p epitope, which recognized several clinical isolates of C. auris representing all four clades. An anti-Hyr1p MAb prevented biofilm formation and enhanced opsonophagocytic killing of C. auris by macrophages. When tested for in vivo efficacy, anti-Hyr1p MAb protected 55% of mice against lethal systemic C. auris infection and showed significantly less fungal burden. Our study is highly clinically relevant and provides an effective alternative therapeutic option to treat infections due to MDR C. auris.

5.
BMC Microbiol ; 23(1): 9, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627557

RESUMO

Cytosine deaminase (CDA) is a prodrug mediating enzyme converting 5-flurocytosine into 5-flurouracil with profound broad-range anticancer activity towards various cell lines. Availability, molecular stability, and catalytic efficiency are the main limiting factors halting the clinical applications of this enzyme on prodrug and gene therapies, thus, screening for CDA with unique biochemical and catalytic properties was the objective. Thermotolerant/ thermophilic fungi could be a distinctive repertoire for enzymes with affordable stability and catalytic efficiency. Among the recovered thermotolerant isolates, Aspergillus niger with optimal growth at 45 °C had the highest CDA productivity. The enzyme was purified, with purification 15.4 folds, molecular mass 48 kDa and 98 kDa, under denaturing and native PAGE, respectively. The purified CDA was covalently conjugated with dextran with the highest immobilization yield of 75%. The free and CDA-dextran conjugates have the same optimum pH 7.4, reaction temperature 37 °C, and pI 4.5, and similar response to the inhibitors and amino acids suicide analogues, ensuring the lack of effect of dextran conjugation on the CDA conformational structure. CDA-Dextran conjugates had more resistance to proteolysis in response to proteinase K and trypsin by 2.9 and 1.5 folds, respectively. CDA-Dextran conjugates displayed a dramatic structural and thermal stability than the free enzyme, authenticating the acquired structural and catalytic stability upon dextran conjugation. The thermal stability of CDA was increased by about 1.5 folds, upon dextran conjugation, as revealed from the half-life time (T1/2). The affinity of CDA-conjugates (Km 0.15 mM) and free CDA (Km 0.22 mM) to deaminate 5-fluorocytosine was increased by 1.5 folds. Upon dextran conjugation, the antiproliferative activity of the CDA towards the different cell lines "MDA-MB, HepG-2, and PC-3" was significantly increased by mediating the prodrug 5-FC. The CDA-dextran conjugates strongly reduce the tumor size and weight of the Ehrlich cells (EAC), dramatically increase the titers of Caspase-independent apoptotic markers PARP-1 and AIF, with no cellular cytotoxic activity, as revealed from the hematological and biochemical parameters.


Assuntos
Citosina Desaminase , Pró-Fármacos , Humanos , Aspergillus niger , Citosina Desaminase/metabolismo , Dextranos/metabolismo , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Cinética , Peptídeo Hidrolases/metabolismo , Pró-Fármacos/farmacologia , Proteólise , Linhagem Celular Tumoral
6.
Can J Cardiol ; 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36626979

RESUMO

Multisystem inflammatory syndrome in children (MIS-C) has emerged as a rare, delayed hyperinflammatory response to SARS-CoV-2 infection, and causes severe morbidity in the pediatric age group. While MIS-C shares many clinical similarities to Kawasaki disease (KD), important differences in epidemiologic, clinical, immunologic and potentially genetic factors exist and suggest potential differences in pathophysiology and points to be explored and explained. Epidemiologic features include male predominance, peak age of 6-12 years, and specific racial and/or ethnicity predilections. MIS-C is characterized by fever, prominent gastrointestinal symptoms, mucocutaneous manifestations, respiratory symptoms, and neurological complaints, and patients often present with shock. Cardiac complications are frequent and include ventricular dysfunction, valvular regurgitation, pericardial effusion, coronary artery dilation and aneurysms, conduction abnormalities, and arrhythmias. Emerging evidence regarding potential immunologic mechanisms suggest that an exaggerated T-cell response to a superantigen on the SARS-CoV-2 spike glycoprotein, as well as the formation of autoantibodies against cardiovascular, gastrointestinal, and endothelial antigens, are major contributors to the inflammatory milieu of MIS-C. Further studies are needed to determine both shared and distinct immunologic pathway(s) that underlie the pathogenesis of MIS-C versus both acute SARS-CoV-2 infcction and KD. There is evidence to suggest that the rare risk of more benign mRNA vaccine -associated myopericarditis is outweighed by a reduced risk of more severe MIS-C. In the current review, we synthesize the published literature to describe associated factors and potential mechanisms regarding an increased risk of MIS-C and cardiac complications, provide insights into the underlying immunologic pathophysiology, and define similarities and differences with KD.

7.
mBio ; : e0338622, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625576

RESUMO

Mucormycosis is an invasive fungal infection caused by certain members of the fungal order of Mucorales. The species most frequently identified as the etiological agents of mucormycosis belong to the genera Rhizopus, Lichtheimia, and Mucor. The frequency of systemic mucormycosis has been increasing, mainly because of increasing numbers of susceptible patients. Furthermore, Mucorales display intrinsic resistance to the majority of routinely used antifungal agents (e.g., echinocandins and short-tailed azoles), which limits the number of possible therapeutic options. All the above-mentioned issues urge the improvement of molecular identification methods and the discovery of new antifungal targets and strategies. Spore coat proteins (CotH) constitute a kinase family present in many pathogenic bacteria and fungi and participate in the spore formation in these organisms. Moreover, some of them can act as virulence factors being receptors of the human GRP78 protein during Rhizopus delemar-induced mucormycosis. We identified 17 cotH-like genes in the Mucor lusitanicus genome database. Successful disruption of five cotH genes in Mucor was performed using the CRISPR-Cas9 system. The CotH3 and CotH4 proteins play a role in adaptation to different temperatures as well as in developing the cell wall structure. We also show CotH4 protein is involved in spore wall formation by affecting the total chitin content and, thus, the composition of the spore wall. The role of CotH3 and CotH4 proteins in virulence was confirmed in two invertebrate models and a diabetic ketoacidosis (DKA) mouse model. IMPORTANCE Current treatment options for mucormycosis are inadequate, resulting in high mortality rates, especially among immunosuppressed patients. The development of novel therapies for mucormycosis has been hampered by lack of understanding of the pathogenetic mechanisms. The importance of the cell surface CotH proteins in the pathogenesis of Rhizopus-mediated mucormycosis has been recently described. However, the contribution of this family of proteins to the virulence of other mucoralean fungi and their functionality in vital processes remain undefined. Through the use of the CRISPR-Case9 gene disruption system, we demonstrate the importance of several of the CotH proteins to the virulence of Mucor lusitanicus by using three infection models. We also report on the importance of one of these proteins, CotH4, to spore wall formation by affecting chitin content. Therefore, our studies extend the importance of CotH proteins to Mucor and identify the mechanism by which one of the CotH proteins contributes to the development of a normal fungal cell wall, thereby indicating that this family of proteins can be targeted for future development of novel therapeutic strategies of mucormycosis.

8.
Microb Cell Fact ; 22(1): 4, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609265

RESUMO

The metabolic potency of fungi as camptothecin producer elevates their prospective use as an industrial platform for commercial production, however, the loss of camptothecin productivity by fungi with the storage and subculturing are the major obstacle. Thus, screening for endophytic fungal isolates inhabiting ethnopharmacological plants with an obvious metabolic stability and sustainability for camptothecin biosynthesis could be one of the most feasible paradigms. Aspergillus terreus ON908494.1, an endophyte of Cestrum parqui was morphologically and molecularly verified, displaying the most potent camptothecin biosynthetic potency. The chemical identity of A. terreus camptothecin was confirmed from the HPLC, FTIR and LC-MS/MS analyses, gave the same molecular structure and mass fragmentation patterns of authentic one. The purified putative camptothecin displayed a strong anticancer activity towards HepG-2 and MCF-7 with IC50 values 0.96 and 1.4 µM, respectively, with no toxicity to OEC normal cells. As well as, the purified camptothecin displayed a significant antifungal activity towards fungal human pathogen Candida albicans, Aspergillus flavus, and A. parasiticus, ensuring the unique structural activity relationships of A. terreus camptothecin, as a powerful dually active anticancer and antimicrobial agent. The camptothecin productivity of A. terreus was maximized by bioprocessing with Plackett-Burman design, with an overall 1.5 folds increment (170.5 µg/L), comparing to control culture. So, the optimal medium components for maximum yield of camptothecin by A. terreus was acid why (2.0 mL/L), Diaion HP20 (2.0 g/L), Amberlite XAD (2.0 g/L), dextrin (5.0 g/L), glucose (10.0 g/L), salicylic acid (2.0 g/L), serine (4.0 g/L), cysteine (4.0 g/L) and glutamate (10.0 g/L), at pH 6 for 15 days incubation. By the 5th generation of A. terreus, the camptothecin yield was reduced by 60%, comparing to zero culture. Interestingly, the productivity of camptothecin by A. terreus has been completely restored and over increased (210 µg/L), comparing to the 3rd generation A. terreus (90 µg/L) upon addition of methanolic extracts of Citrus limonum peels, revealing the presence of some chemical signals that triggers the camptothecin biosynthetic machinery. The feasibility of complete restoring of camptothecin biosynthetic-machinery of A. terreus for stable and sustainable production of camptothecin, pave the way for using this fungal isolate as new platform for scaling-up the camptothecin production.


Assuntos
Camptotecina , Cestrum , Humanos , Camptotecina/farmacologia , Camptotecina/metabolismo , Endófitos/metabolismo , Cromatografia Líquida , Espectrometria de Massas em Tandem
9.
Braz. J. Biol. ; 83: 1-8, 2023. tab
Artigo em Inglês | VETINDEX | ID: vti-765456

RESUMO

During this one year study, blood and fecal samples of doves (Zenaida asiatica), ducks (Anas platyrhynchos), pigeons (Columba livia), partridges (Alectoris chukar), turkeys (Meleagris gallopavo) and goose (Chen caerulescens) were collected to assess the parasitic prevalence in these birds. The birds were kept at Avian Conservation and Research Center, Department of Wildlife and Ecology, University of Veterinary and Animal Sciences, Lahore. All these avian species were kept in separate cages and their entire body was inspected on regularly basis to record external parasites. For internal parasites, 100 blood and 100 fecal samples for each species were analyzed. During present study, two species of ectoparasites i.e. fowl ticks (Args persicus) and mite (Dermanyssus gallinae) while 17 species of endoparasites; three from blood and 14 from fecal samples were identified. Prevalence of blood parasites was Plasmodium juxtanucleare 29.3%, Aegyptinella pullorum 15% and Leucoctoyzoon simond 13%. Parasitic species recorded from fecal samples included 6 species of nematodes viz. Syngamus trachea with parasitic prevalence of 50%, Capillaria anatis 40%, Capillaria annulata 37.5%, Heterakis gallinarum 28.3%, Ascardia galli 24% and Allodpa suctoria 2%. Similarly, two species of trematodes viz. Prosthogonimus ovatus having parasitic prevalence of 12.1% and Prosthogonimus macrorchis 9.1% were also recorded from fecal samples of the birds. Single cestode species Raillietina echinobothrida having parasitic prevalence of 27% and 3 protozoan species i.e. Eimeria maxima having prevalence 20.1%, Histomonas meleagridis 8% and Giardia lamblia 5.3% were recorded. In our recommendation, proper medication and sanitation of the bird's houses and cages is recommended to avoid parasites.(AU)


Durante este estudo de um ano, amostras de sangue e fezes de pombos (Zenaida asiatica), patos (Anas platyrhynchos), pombos (Columba livia), perdizes (Alectoris chukar), perus (Meleagris gallopavo) e ganso (Chen caerulescens) foram coletados para avaliar a prevalência de parasitas nessas aves. As aves foram mantidas no Centro de Conservação e Pesquisa de Aves, Departamento de Vida Selvagem e Ecologia, Universidade de Veterinária e Ciências Animais, Lahore. Todas essas espécies de aves foram mantidas em gaiolas separadas e todo o seu corpo foi inspecionado regularmente para registrar parasitas externos. Para parasitas internos, foram analisadas 100 amostras de sangue e 100 amostras fecais de cada espécie. Durante o presente estudo, duas espécies de ectoparasitas, ou seja, carrapatos de aves (Args persicus) e ácaros (Dermanyssus gallinae), enquanto 17 espécies de endoparasitas, três de sangue e 14 de amostras fecais, foram identificadas. Os parasitas sanguíneos prevalentes foram Plasmodium juxtanucleare, 29,3%, Aegyptinella pullorum, 15%, e Leucoctoyzoon simond, 13%. As espécies parasitas registradas em amostras fecais incluíram 6 espécies de nematoides viz. Syngamus traqueia com prevalência parasitária de 50%, Capillaria anatis, 40%, Capillaria annulata, 37,5%, Heterakis gallinarum, 28,3%, Ascardia galli, 24% e Allodpa suctoria, 2%. Da mesma forma, duas espécies de trematódeos viz. Prosthogonimus ovatus com prevalência parasitária de 12,1% e Prosthogonimus macrorchis, 9,1%, também foram registrados nas amostras fecais das aves. Espécies de cestoide único Raillietina echinobothrida com prevalência parasitária de 27% e 3 espécies de protozoários, ou seja, Eimeria maxima tendo prevalência de 20,1%, Histomonas meleagridis, 8%, e Giardia lamblia, 5,3%, foram registradas. Em nossa recomendação, são indicados medicação adequada e saneamento das casas e gaiolas dos pássaros para evitar parasitas.(AU)


Assuntos
Animais , Doenças das Aves Domésticas/sangue , Doenças das Aves Domésticas/parasitologia , Carga Parasitária/veterinária , Columbidae , Perus , Gansos
10.
Can J Cardiol ; 2022 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-36455760

RESUMO

Multisystem inflammatory syndrome in children (MIS-C) is a new illness that evolved during the COVID-19 pandemic with initial reports of severe disease including use of extracorporeal membrane oxygenation and death. Institutions rapidly assembled task forces to develop treatment algorithms. At the national/international levels, collaboratives and associations assembled consensus writing groups to draft guidelines. These guidelines and algorithms were initially based on expert opinion and small case series. Some groups utilized the Delphi approach, and the resultant guidelines often mimicked those for other conditions that resembled MIS-C, like Kawasaki disease (KD). For instance, intravenous immunoglobulin (IVIG), a known effective treatment in KD, was recommended for MIS-C. Early in the pandemic many favored IVIG over steroids as first line therapy. As evidence evolved so did some guidelines which now endorse the dual use of IVIG plus steroids as first line therapy. In contrast, withholding immunotherapy became an option for some MIS-C patients with mild symptoms. Here, we review guidelines and discuss the evidence informing early recommendations, how this has evolved, the role and limitations of expert opinion and observational data, and the importance of leveraging existing research infrastructures, such as the intensive care unit collaborative (Overcoming COVID-19 surveillance registry), and the International KD Registry. Finally, we discuss strategies to rapidly develop, deploy and adapt clinical trials evaluating the treatment of such rare conditions in children, which may include alternatives to conventional clinical trial design. The emergence of MIS-C during the COVID-19 pandemic has highlighted unmet needs regarding research of a new condition.

12.
Adv Anesth ; 40(1): 185-200, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36333047

RESUMO

Obesity is a worldwide epidemic and is associated with an increased risk of hypertension, diabetes, and obstructive sleep apnea. Pregnant patients with obesity experience a higher risk of maternal and fetal complications. Anesthesia also poses higher risks for obese parturients and may be more technically challenging due to body habitus. Safe anesthesia practice for these patients must take into consideration the unique challenges associated with the combination of pregnancy and obesity.


Assuntos
Analgesia , Anestesia Obstétrica , Complicações na Gravidez , Gravidez , Feminino , Humanos , Anestesia Obstétrica/efeitos adversos , Cesárea , Complicações na Gravidez/etiologia , Obesidade/complicações
13.
Drug Dev Res ; 2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36380556

RESUMO

The strategy of utilizing nitrogen compounds in various biological applications has recently emerged as a powerful approach to exploring novel classes of therapeutics to face the challenge of diseases. A series of pyrazolo[1,5-a]pyrimidine-based compounds 3a-l and 5a-f were prepared by the direct cyclo-condensation reaction of 5-amino-1H-pyrazoles 1a, b with 2-(arylidene)malononitriles and 3-(dimethylamino)-1-aryl-prop-2-en-1-ones, respectively. The structures of the new pyrazolo[1,5-a]pyrimidine compounds were confirmed via spectroscopic techniques. The in vitro biological activities of all pyrazolo[1,5-a]pyrimidines 3a-l and 5a-f were evaluated by assaying total antioxidant capacity, iron-reducing power, the scavenging activity against 1-diphenyl-2-picryl-hydrazyl (DPPH) and 2, 2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals, anti-diabetic, anti-Alzheimer, and anti-arthritic biological activities. All compounds displayed good to potent bioactivity, and three compounds 3g, 3h, and 3l displayed the most active derivatives. Among these derivatives, compound 3l exhibited the highest antioxidant (total antioxidant capacity [TAC] = 83.09 mg gallic acid/g; iron-reducing power [IRP] = 47.93 µg/ml) and free radicals scavenging activities with (DPPH = 18.77 µg/ml; ABTS = 40.44%) compared with ascorbic acid (DPPH = 4.28 µg/ml; ABTS = 38.84%). Furthermore, compound 3l demonstrated the strongest inhibition of α-amylase with a percent inhibition of 72.91 ± 0.14 compared to acarbose = 67.92 ± 0.09%. Similarly, it displayed acetylcholinesterase inhibition of 62.80 ± 0.06%. However, compound 3i showed a significantly higher inhibition percentage for protein denaturation and proteinase at 20.66 ± 0.00 and 26.42 ± 0.06%, respectively. Additionally, some in silico ADMET properties were predicted and studied. Finally, molecular docking simulation was performed inside the active site of α-amylase and acetylcholinesterase to study their interactions.

14.
Cell Rep ; 41(6): 111628, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36351401

RESUMO

Pathogens evade host humoral responses by accumulating mutations in surface antigens. While variable, there are conserved regions that cannot mutate without compromising fitness. Antibodies targeting these conserved epitopes are often broadly protective but remain minor components of the repertoire. Rational immunogen design leverages a structural understanding of viral antigens to modulate humoral responses to favor these responses. Here, we report an epitope-enriched immunogen presenting a higher copy number of the influenza hemagglutinin (HA) receptor-binding site (RBS) epitope relative to other B cell epitopes. Immunization in a partially humanized murine model imprinted with an H1 influenza shows H1-specific serum and >99% H1-specific B cells being RBS-directed. Single B cell analyses show a genetically restricted response that structural analysis defines as RBS-directed antibodies engaging the RBS with germline-encoded contacts. These data show how epitope enrichment expands B cell responses toward conserved epitopes and advances immunogen design approaches for next-generation viral vaccines.


Assuntos
Vacinas contra Influenza , Influenza Humana , Humanos , Camundongos , Animais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Anticorpos Antivirais , Epitopos de Linfócito B
15.
J Fungi (Basel) ; 8(11)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36354888

RESUMO

Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician's armamentarium against these difficult-to-treat infections.

16.
Anesth Analg ; 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-36355613

RESUMO

BACKGROUND: Previous studies of obstructive sleep apnea (OSA) risk in gravidas with chronic hypertension (cHTN) did not control for obesity as a risk factor for OSA. We therefore performed this study to evaluate whether OSA is more prevalent among gravidas with cHTN compared to normotensive gravidas matched for body mass index (BMI) and gestational age (primary outcome). We also assessed whether OSA is more severe when comorbid with cHTN in pregnancy (secondary outcome). METHODS: This was a single-center, prospective cohort study. Adult gravidas at 10-20 weeks of gestation, with and without cHTN, were enrolled and BMI matched. All subjects answered OSA screening questionnaires and underwent a home sleep test when they were between 10 and 20 weeks of gestation. Pregnancy outcomes were followed for all subjects. We performed univariable and multivariable logistic regression to model the relationship between cHTN status and OSA. RESULTS: A total of 100 pregnant subjects (50 with cHTN and 50 normotensive) completed a home sleep test of 2 hours or more. There were no differences in demographic variables between the 2 groups, except that gravidas with cHTN were significantly older than normotensive subjects (mean ± standard deviation [SD] 34 ± 4 vs 30 ± 6 years; P < .001). OSA was more prevalent (64% vs 38%; P = .009; odds ratio [95% confidence interval (CI)] 2.90 [1.30-6.65]; P = .01) and more severe in gravidas with cHTN (moderate or severe OSA 59% vs 21%; P = .009). After controlling for age, we found no overall association between cHTN on OSA risk (adjusted odds ratio [95% CI] 2.22 [0.92-5.40]; P = .076). However, among gravidas older than 25 years of age, cHTN was associated with higher odds of OSA (adjusted odds ratio [95% CI], 2.64 [1.06-6.71], P = .038). CONCLUSIONS: cHTN and age are important risk factors for OSA in gravidas. Gravidas with cHTN should be screened for OSA in early pregnancy. Future studies may validate screening tools that include cHTN and age, and investigate the role of OSA therapy in blood pressure control.

17.
J Clin Med ; 11(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36431158

RESUMO

(1) Background: Resource intensive imaging tools have been employed to examine muscle and bone qualities after spinal cord injury (SCI). We tested the hypothesis that surface neuromuscular electrical stimulation (NMES) amplitude can be used to examine knee extensor muscle quality, distal femur and proximal tibia bone mineral density (BMD) in persons with SCI. (2) Methods: Seventeen persons (2 women) with chronic SCI participated in three weeks of NMES-resistance training twice weekly of 4 sets of 10 repetitions. Participants were classified according to the current amplitude (>100 mA) and the number of repetitions (>70 reps) of leg extension into greater (n = 8; 1 woman; group A) and lower (n = 9; 1 woman; group B) musculoskeletal qualities. Magnetic resonance imaging, dual energy x-ray absorptiometry, isometric peak torque, Modified Ashworth and Penn spasm frequency scales were conducted. (3) Results: In between group comparisons, current amplitude was lower (38-46%) in group A. Whole (27-32%; p = 0.02), absolute (26-33%, p = 0.02) thigh muscle and absolute knee extensor muscle cross-sectional areas (22-33%, p = 0.04) were greater in group A. Right distal femur (24%; p = 0.08) and proximal tibia (29%; p = 0.03) BMDs were lower in group B, and peak isometric torque (p < 0.01), extensor spasticity scorers (p = 0.04) and muscle spasm scores (p = 0.002) were significantly higher in group A. Regression models revealed that amplitude of current, repetitions and body weight can accurately predict musculoskeletal qualities in persons with SCI. (4) Conclusions: Surface NMES amplitude and repetitions of leg extension differentiated between SCI survivors with greater versus lower musculoskeletal qualities. The study may shed the light on the interplay between muscle and bone in persons with SCI.

18.
Braz J Biol ; 84: e259506, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36197409

RESUMO

Scorpion venom contains a variety of neurotoxins which interact with ion channels and affect their activities. The present study was designed to evaluate the potential of scorpion venom as acetylcholinesterase (AChE) inhibitor by using Aedes aegypti as model organism. Venoms of two species, Hottentota tamulus (Fabricus, 1798) and Androctonus finitimus (Pocock, 1897) were selected for this study. Two peptides (36 kDa from H. tamulus and 54 kDa from A. finitimus) were separated from scorpion venom by using HPLC. Selected peptides caused significantly higher mortality in larvae and adults of Aedes aegypti than control (no mortalities were observed in control groups). Significant acetylcholinesterase (AChE) inhibitory potential of both peptides was recorded by spectrophotometer. The peptide of A. finitimus caused significantly higher mortality (95±1.53% in larvae and 100% in adults) than the peptide of H. tamulus (84.33±2.33% in larvae and 95.37±1.45% in adults). While H. tamulus peptide was more efficient in reducing AChE activity (0.029±0.012 in larvae and 0.03±0.003 in adults) than the peptide of A. finitimus (0.049±0.005 in larvae and 0.047±0.001 in adults). It was concluded that H. tamulus venom peptide was more efficiently reducing AChE activity, thus it could be a potential bio-insecticide which can be synthesized at industrial scale for the control of harmful insects.


Assuntos
Aedes , Inseticidas , Venenos de Escorpião , Acetilcolinesterase , Animais , Inseticidas/farmacologia , Larva , Peptídeos , Venenos de Escorpião/química , Venenos de Escorpião/farmacologia
19.
BMJ Open ; 12(10): e064748, 2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36198461

RESUMO

INTRODUCTION: Long pulse width stimulation (LPWS; 120-150 ms) has the potential to stimulate denervated muscles and to restore muscle size in denervated people with spinal cord injury (SCI). We will determine if testosterone treatment (TT)+LPWS would increase skeletal muscle size, leg lean mass and improve overall metabolic health in persons with SCI with denervation. We hypothesise that the 1-year TT+LPWS will upregulate protein synthesis pathways, downregulate protein degradation pathways and increase overall mitochondrial health. METHODS AND ANALYSIS: Twenty-four male participants (aged 18-70 years with chronic SCI) with denervation of both knee extensor muscles and tolerance to the LPWS paradigm will be randomised into either TT+neuromuscular electrical stimulation via telehealth or TT+LPWS. The training sessions will be twice weekly for 1 year. Measurements will be conducted 1 week prior training (baseline; week 0), 6 months following training (postintervention 1) and 1 week after the end of 1 year of training (postintervention 2). Measurements will include body composition assessment using anthropometry, dual X-ray absorptiometry and MRI to measure size of different muscle groups. Metabolic profile will include measuring of basal metabolic rate, followed by blood drawn to measure fasting biomarkers similar to hemoglobin A1c, lipid panels, C reactive protein, interleukin-6 and free fatty acids and then intravenous glucose tolerance test to test for insulin sensitivity and glucose effectiveness. Finally, muscle biopsy will be captured to measure protein expression and intracellular signalling; and mitochondrial electron transport chain function. The participants will fill out 3 days dietary record to monitor their energy intake on a weekly basis. ETHICS AND DISSEMINATION: The study was approved by Institutional Review Board of the McGuire Research Institute (ID # 02189). Dissemination plans will include the Veteran Health Administration and its practitioners, the national SCI/D services office, the general healthcare community and the veteran population, as well as the entire SCI community via submitting quarterly letters or peer-review articles. TRIAL REGISTRATION NUMBER: NCT03345576.


Assuntos
Traumatismos da Medula Espinal , Testosterona , Biomarcadores , Proteína C-Reativa/metabolismo , Ácidos Graxos não Esterificados , Glucose/metabolismo , Humanos , Interleucina-6/metabolismo , Masculino , Músculo Esquelético , Ensaios Clínicos Controlados Aleatórios como Assunto , Traumatismos da Medula Espinal/terapia
20.
J Physiol Pharmacol ; 73(3)2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36302537

RESUMO

Systemic inflammation is a hallmark of severe coronavirus disease-19 (COVID-19). Anti-inflammatory therapy is considered crucial to modulate the hyperinflammatory response (cytokine storm) in hospitalized COVID-19 patients. There is currently no specific, conclusively proven, cost-efficient, and worldwide available anti-inflammatory therapy available to treat COVID-19 patients with cytokine storm. The present study aimed to investigate the treatment benefit of oral colchicine for hospitalized COVID-19 patients with suspected cytokine storm. Colchicine is an approved drug and possesses multiple anti-inflammatory mechanisms. This was a pilot, open-label randomized controlled clinical trial comparing standard of care (SOC) plus oral colchicine (colchicine arm) vs. SOC alone (control arm) in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. Colchicine treatment was initiated within first 48 hours of admission delivered at 1.5 mg loading dose, followed by 0.5 mg b.i.d. for next 6 days and 0.5 mg q.d. for the second week. A total of 96 patients were randomly allocated to the colchicine (n=48) and control groups (n=48). Both colchicine and control group patients experienced similar clinical outcomes by day 14 of hospitalization. Treatment outcome by day 14 in colchicine vs control arm: recovered and discharged alive: 36 (75.0%) vs. 37 (77.1%), remain admitted after 14-days: 4 (8.3%) vs. 5 (10.4%), ICU transferred: 4 (8.3%) vs. 3 (6.3%), and mortality: 4 (8.3%) vs. 3 (6.3%). The speed of improvement of COVID-19 acute symptoms including shortness of breath, fever, cough, the need of supplementary oxygen, and oxygen saturation level, was almost identical in the two groups. Length of hospitalization was on average 1.5 day shorter in the colchicine group. There was no evidence for a difference between the two groups in the follow-up serum levels of inflammatory biomarkers including C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), ferritin, interleukin-6 (IL-6), high-sensitivity troponin T (hs-TnT) and N-terminal pro b-type natriuretic peptide (NT pro-BNP). According to the results of our study, oral colchicine does not appear to show clinical benefits in non-ICU hospitalized COVID-19 patients with suspected cytokine storm. It is possible that the anti-inflammatory pathways of colchicine are not crucially involved in the pathogenesis of COVID-19.


Assuntos
Humanos , SARS-CoV-2 , Síndrome da Liberação de Citocina/tratamento farmacológico , Colchicina/uso terapêutico , Hospitalização , Anti-Inflamatórios/uso terapêutico , Resultado do Tratamento
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