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1.
Front Pharmacol ; 15: 1351882, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38650629

RESUMO

This work aimed to explore the mechanisms underlying the interaction of the active furanocoumarins in P. corylifolia on tofacitinib both in vivo and in vitro. The concentration of tofacitinib and its metabolite M8 was determined using UPLC-MS/MS. The peak area ratio of M8 to tofacitinib was calculated to compare the inhibitory ability of furanocoumarin contained in the traditional Chinese medicine P. corylifolia in rat liver microsomes (RLMs), human liver microsomes (HLMs) and recombinant human CYP3A4 (rCYP3A4). We found that bergapten and isopsoralen exhibited more significant inhibitory activity in RLMs than other furanocoumarins. Bergapten and isopsoralen were selected to investigate tofacitinib drug interactions in vitro and in vivo. Thirty rats were randomly allocated into 5 groups (n = 6): control (0.5% CMC-Na), low-dose bergapten (20 mg/kg), high-dose bergapten (50 mg/kg), low-dose isopsoralen (20 mg/kg) and ketoconazole. 10 mg/kg of tofacitinib was orally intervented to each rat and the concentration level of tofacitinib in the rats were determined by UPLC-MS/MS. More imporrantly, the results showed that bergapten and isopsoralen significantly inhibited the metabolism of tofacitinib metabolism. The AUC(0-t), AUC(0-∞), MRT(0-t), MRT(0-∞) and Cmax of tofacitinib increased in varying degrees compared with the control group (all p < 0.05), but CLz/F decreased in varying degrees (p < 0.05) in the different dose bergapten group and isopsoralen group. Bergapten, isopsoralen and tofacitinib exhibit similar binding capacities with CYP3A4 by AutoDock 4.2 software, confirming that they compete for tofacitinib metabolism. P. corylifolia may considerably impact the metabolism of tofacitinib, which can provide essential information for the accurate therapeutic application of tofacitinib.

2.
BMJ Open ; 14(4): e074928, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38642999

RESUMO

OBJECTIVES: This study aimed to assess the desire for smoke-free housing, determine the choice of smoke-free policies for multiunit housing (MUH), and identify the factors associated with policy choice among MUH residents in Bangladesh. DESIGN: We conducted a cross-sectional study from April to November 2019 using a semi-structured survey questionnaire. SETTING: This study was conducted in seven divisional cities of Bangladesh: Dhaka, Chattogram, Rajshahi, Khulna, Sylhet, Barishal, and Rangpur. PARTICIPANTS: A total of 616 adult individuals living in MUH for at least 2 years participated in the study. PRIMARY OUTCOME MEASURE: Multinomial logistic regression was used to identify the determinants of the choice of smoke-free policies for MUH. RESULTS: Overall, 94.8% of the respondents wanted smoke-free housing. Among those who wanted smoke-free housing, 44.9% preferred a smoke-free building policy, 28.3% preferred a smoke-free common area policy, 20.2% favoured a smoke-free unit policy, and 6.7% did not know what policy they should choose. Three factors were found to be significantly associated with the choice of a smoke-free building policy: staying at home for more than 12 hours (adjusted OR (aOR): 2.6; 95% CI 1.035 to 6.493), being a non-smoker (aOR: 3.2; 95% CI 1.317 to 7.582), and having at least one family member who smoked (aOR: 3.0; 95% CI 1.058 to 8.422). Results also showed that residents having at least one child under 15 in the family (aOR: 0.3; 95% CI 0.152 to 0.778) were less likely to choose a smoke-free common area policy and that women (aOR: 3.7; 95% CI 1.024 to 13.188) were more likely to choose a smoke-free unit policy. CONCLUSIONS: MUH residents in urban Bangladesh highly demanded smoke-free housing. Most residents favoured a smoke-free building policy for MUH. Those who stayed at home for a longer time, were non-smokers, and had smoking family members were more likely to choose this policy.


Assuntos
Política Antifumo , Poluição por Fumaça de Tabaco , Adulto , Criança , Humanos , Feminino , Habitação , Estudos Transversais , Bangladesh , Poluição por Fumaça de Tabaco/prevenção & controle
3.
J Ethnopharmacol ; 328: 118132, 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38565411

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Infections caused by parasitic worms or helminth continue to pose a great burden on human and animal health, particularly in underdeveloped tropical and subtropical countries where they are endemic. Current anthelmintic drugs present serious limitations and the emergence of drug resistance has made it increasingly challenging to combat such infections (helminthiases). In Bangladesh, medicinal plants are often used by indigenous communities for the treatment of helminthiases. Knowledge on such plants along with screening for their anthelmintic activity has the potential to lead to the discovery of phytochemicals that could serve as novel molecular scaffolds for the development of new anthelminthic drugs. AIM OF THE STUDY: The purpose of this study was i) to conduct an ethnobotanical survey to gather data on Bangladeshi medicinal plants used in the treatment of helminthiases, ii) to test plants with the highest use values for their in vitro anthelmintic activity, and iii) to carry out in silico screening on phytochemicals present in the most active plant extract to investigate their ability to disrupt ß-tubulin function in helminths. METHODS: The ethnobotanical survey was conducted across three sub-districts of Bangladesh, namely Mathbaria, Phultala and Khan Jahan Ali. The in vitro screening for anthelmintic activity was performed in a motility test using adult Haemonchus contortus worms. Virtual screening using PyRx was performed on the phytochemicals reported from the most active plant, exploring their interactions with the colchicine binding site of the ß-tubulin protein target (PDB ID: 1SA0). RESULTS: The survey respondents reported a total of 32 plants for treating helminthiases. Based on their use values, the most popular choices were Ananas comosus (L.) Merr., Azadirachta indica A.Juss., Carica papaya L., Citrus maxima (Burm.) Merr., Curcuma longa L., Momordica charantia L., Nigella sativa L. and Syzygium cumini (L.) Skeels. In vitro anthelmintic testing revealed that A. indica leaves and bark had the highest activity with LC50 values of 16 mg/mL in both cases. Other plant extracts also exhibited good anthelmintic activity with LC50 values ranging from 16 to 52 mg/mL, while the value for albendazole (positive control) was 8.39 mg/mL. The limonoids nimbolide and 28-deoxonimbolide showed a binding affinity of -8.9 kcal/mol, and satisfied all drug-likeness parameters. The control ligand N-deacetyl-N-(2-mercaptoacetyl)colchicine had a binding affinity of -6.9 kcal/mol. CONCLUSION: Further in silico and in vitro studies are warranted on the identified limonoids to confirm the potential of these derivatives as novel drug templates for helminthiases. The current study supports the need for an ethnobotanical survey-based approach to discover novel drug templates for helminthiases.


Assuntos
Anti-Helmínticos , Haemonchus , Helmintíase , Limoninas , Plantas Medicinais , Adulto , Animais , Humanos , Plantas Medicinais/química , Tubulina (Proteína) , Anti-Helmínticos/farmacologia , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Compostos Fitoquímicos/farmacologia , Colchicina
4.
Front Pharmacol ; 15: 1359815, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487168

RESUMO

Introduction: Plants and their extracts have been integral to the development of medicinal treatments throughout history, offering a vast array of compounds for innovative therapies. Baccaurea motleyana Müll. Arg., commonly known as Rambai, is an evergreen tree with economic importance in the Old-World Tropics. Method: The study investigates its phytochemical composition through Gas Chromatography-Mass Spectrometry (GC-MS) and evaluates its pharmacological properties, including antidiabetic, antidiarrheal, antimicrobial, and antidepressant effects. Result and Discussion: The GC-MS analysis revealed 15 bioactive compounds in the methanol extract, with Phenol, 3,5-bis(1,1-dimethylethyl)-, Methyl stearate, and Hexadecanoic acid, methyl ester being the predominant ones. The cytotoxicity assay demonstrated significant activity in the ethyl acetate fraction. Antimicrobial assays indicated mild to moderate antibacterial activity. In vivo studies on mice revealed significant hypoglycemic, antidiarrheal, and antidepressant properties. Molecular docking studies against EGFR, DHFR, GLUT-3, KOR, and MOA identified promising compounds with potential therapeutic effects. The identified compounds exhibited favorable ADME/T properties, emphasizing their potential for drug development. The study underscores the promising therapeutic potential of Baccaurea motleyana, showcasing its diverse bioactive compounds with significant medicinal properties. Conclusion: These findings lay the groundwork for future research, emphasizing the exploration of B. motleyana as a source of natural remedies for addressing prevalent health conditions.

5.
Front Pharmacol ; 15: 1349745, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487172

RESUMO

Natural compounds hold promise in the search for cancer therapies due to their unique chemical structures and combinations that may effectively combat cancer while minimizing toxicity and side effects compared to conventional treatments. Silibinin, a natural lignan, has been found to possess strong anti-cancer activity against several types of human cancers based on emerging research. This study aims to provide an overview of the therapeutic potential of silibinin in the treatment and prevention of cancers. A comprehensive search was conducted using various internet databases such as PubMed, Google Scholar, and ScienceDirect to identify relevant research papers. Silibinin has been shown to exhibit anticancer activity against several types of cancers, including liver, lungs, breast, prostate, colorectal, skin, and bladder cancers. Its multifaceted mechanisms of action contribute to its therapeutic effects. Silibinin exerts antioxidant, anti-inflammatory, anti-proliferative, pro-apoptotic, anti-metastatic, and anti-angiogenic activities, making it a promising candidate for cancer therapy. One of the key mechanisms underlying the anticancer effects of silibinin is its ability to modulate multiple signaling pathways involved in cancer development and progression. It can inhibit the activation of various oncogenic pathways, including PI3K/Akt, NF-κB, Wnt/ß-catenin, and MAPK pathways, thereby suppressing cancer cell proliferation, inducing cell cycle arrest, and promoting apoptosis. Silibinin possesses great potential as an effective treatment agent for cancer. The multifaceted mechanisms of action, favorable safety profile, and potential synergistic effects of silibinin with conventional therapies make it an attractive candidate for further investigation and development as a cancer treatment. However, more extensive clinical studies are necessary to fully establish the efficacy, optimal dosage, and long-term effects of silibinin in cancer treatment.

6.
Front Pharmacol ; 15: 1347069, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38495091

RESUMO

Introduction: Natural plant-based medicines have gained popularity recently as a major source of inventive, risk-free, and more potent secondary bioactive compounds with medicinal potential. Catharanthus ovalis is a perennial shrub containing various indole alkaloids cultivated extensively for local medical purposes. Methods: This research is conducted to identify the phytocompounds present in the leaves of C. ovalis and its central and peripheral analgesic, thrombolytic, and membrane-stabilizing activities through tail immersion, acetic acid-induced writhing, human blood clot lysis, and erythrocyte lysis by heat and hypotonic solution methods, respectively. Results and discussion: A total of 39 compounds were identified using GC-MS/MS techniques, including hexadecanoic acid, methyl ester (56.749%), methyl stearate (29.782%), carvacrol and its TBDMS derivative (12.586%), and 9-octadecenoic acid, methyl ester, (E)-] (9.297%) presented in high quantity. The highest tail immersion latency was observed for the 600 mg/kg extract of C. ovalis crude extract. Both 400 and 600 mg/kg doses of C. ovalis crude extract exhibited prominent peripheral analgesic activity. The maximum thrombolytic effect was observed by DCM soluble fraction extract by inhibiting 54.87% of the clot. However, the aqueous-soluble fraction of this extract manifested an excellent membrane-stabilizing effect by showing 73.98% and 87.51% hemolysis against heat- and hypotonic-induced hemolysis, respectively. Some of the compounds were identified as active agents against different receptors related to these diseases, which supported the findings of in vitro and in vivo tests. Conclusion: Further investigation needs to be conducted to specify and identify the exact mechanism of action of these compounds.

7.
Int J Biol Sci ; 20(4): 1332-1355, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38385077

RESUMO

Polyphenolic compounds have shown promising neuroprotective properties, making them a valuable resource for identifying prospective drug candidates to treat several neurological disorders (NDs). Numerous studies have reported that polyphenols can disrupt the nuclear factor kappa B(NF-κB) pathway by inhibiting the phosphorylation or ubiquitination of signaling molecules, which further prevents the degradation of IκB. Additionally, they prevent NF-κB translocation to the nucleus and pro-inflammatory cytokine production. Polyphenols such as curcumin, resveratrol, and pterostilbene had significant inhibitory effects on NF-κB, making them promising candidates for treating NDs. Recent experimental findings suggest that polyphenols possess a wide range of pharmacological properties. Notably, much attention has been directed towards their potential therapeutic effects in NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemia, anxiety, depression, autism, and spinal cord injury (SCI). Much preclinical data supporting the neurotherapeutic benefits of polyphenols has been developed. Nevertheless, this study has described the significance of polyphenols as potential neurotherapeutic agents, specifically emphasizing their impact on the NF-κB pathway. This article offers a comprehensive analysis of the involvement of polyphenols in NDs, including both preclinical and clinical perspectives.


Assuntos
Doença de Alzheimer , NF-kappa B , Humanos , NF-kappa B/metabolismo , Polifenóis/farmacologia , Polifenóis/uso terapêutico , Transdução de Sinais , Proteínas I-kappa B/metabolismo
8.
Front Chem ; 12: 1341308, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38389724

RESUMO

Byttneria pilosa, a flowering plant from the Malvaceae family traditionally used to treat ailments such as boils and scabies, is here investigated for its potential health benefits. The study focused on evaluating its antioxidant and antidiabetic properties in vitro, as well as the in vivo anxiolytic and antidepressant activities of the methanol extract of B. pilosa leaf (MEBP). The study employed various assays to evaluate antioxidant activity, including 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, reducing power capacity, and quantification of the total phenolic and flavonoid contents of MEBP. Additionally, anxiolytic and antidepressant activities were evaluated through four tests: elevated plus-maze test (EPMT), light-dark box test (LDBT), forced swimming test (FST), and tail suspension test (TST). Antidiabetic effect was determined using α-amylase inhibition assay. Docking analysis was performed using BIOVIA and Schrödinger Maestro (v11.1), and the absorption, distribution, metabolism, and excretion/toxicity (ADME/T) properties of bioactive substances were investigated using a web-based technique. MEBP exhibited moderate antioxidant activity in DPPH radical scavenging and reducing power capacity assays, with a dose-dependent response. The total phenolic and flavonoid contents measured were 70 ± 1.53 mg and 22.33 ± 1.20 mg, respectively. MEBP demonstrated significant effects in α-amylase inhibition comparable to acarbose. In behavioral tests, MEBP dose-dependently altered time spent in open arms/light box and closed arms/dark box, indicating anxiolytic effects. Moreover, MEBP significantly reduced immobility duration in FST and TST, suggesting antidepressant properties. Molecular docking analysis revealed favorable interactions between beta-sitosterol and specific targets, suggesting the potential mediation of anxiolytic and antidiabetic effects. Overall, MEBP exhibits notable anxiolytic and antidepressant properties, along with moderate antioxidant and antidiabetic activities.

9.
Front Pharmacol ; 15: 1344123, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38420193

RESUMO

Zingiber roseum (Roxb.) Roscoe, a perennial herb from the Zingiberaceae family, has a long history of traditional use in the treatment of several ailments including pain, inflammation, fever, cough, arthritis, skin diseases, and liver infections. This study sought to confirm the efficacy of Zingiber roseum (Roxb.) Roscoe leaves methanol extract (ZrlME) as reported in traditional usage by evaluating its analgesic, anti-inflammatory, and antipyretic capabilities. In addition, in silico molecular docking of the metabolites identified in ZrlME was studied to verify the experimental outcomes. ZrlME demonstrated strong dose-dependent analgesic efficacy against all analgesic tests. ZrlME (400 mg/kg) showed higher anti-inflammatory activity than the standard in the carrageenan-induced paw edema test model. A significant reduction of rectal temperature (3.97°F↓) was also recorded at the same dose of ZrLME after 24 h of treatment. Seven polyphenolic metabolites were identified and quantified by HPLC-DAD analysis, including 3, 4- dihydroxy benzoic acid, (-) epicatechin, rutin hydrate, p-coumaric acid, trans-ferulic acid, rosmarinic acid, and myricetin. Strong binding affinities (ranges from -5.8 to -8.5 Kcal/mol) between the aforesaid polyphenols and cyclooxygenase-2 were discovered. Moreover, molecular dynamics simulations (MDS) demonstrated that these polyphenols exhibit significant COX-2 inhibitory activity due to their high stability in the COX-2 active site. In computational prediction, the polyphenols were also found to be nontoxic, and a variety of biological activities, such as antioxidant, analgesic, anti-inflammatory, antipyretic, and hepatoprotective, were observed. The results of this study revealed that ZrlME possesses notable analgesic, anti-inflammatory, and antipyretic properties.

10.
Cancer Med ; 13(3): e6924, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38230908

RESUMO

BACKGROUND: Calycosin may be a potential candidate regarding chemotherapeutic agent, because already some studies against multivarious cancer have been made with this natural compound. AIM: This review elucidated a brief overview of previous studies on calycosin potential effects on various cancers and its potential mechanism of action. METHODOLOGY: Data retrieved by systematic searches of Google Scholar, PubMed, Science Direct, Web of Science, and Scopus by using keywords including calycosin, cancer types, anti-cancer mechanism, synergistic, and pharmacokinetic and commonly used tools are BioRender, ChemDraw Professional 16.0, and ADMETlab 2.0. RESULTS: Based on our review, calycosin is available in nature and effective against around 15 different types of cancer. Generally, the anti-cancer mechanism of this compound is mediated through a variety of processes, including regulation of apoptotic pathways, cell cycle, angiogenesis and metastasis, oncogenes, enzymatic pathways, and signal transduction process. These study conducted in various study models, including in silico, in vitro, preclinical and clinical models. The molecular framework behind the anti-cancer effect is targeting some oncogenic and therapeutic proteins and multiple signaling cascades. Therapies based on nano-formulated calycosin may make excellent nanocarriers for the delivery of this compound to targeted tissue as well as particular organ. This natural compound becomes very effective when combined with other natural compounds and some standard drugs. Moreover, proper use of this compound can reverse resistance to existing anti-cancer drugs through a variety of strategies. Calycosin showed better pharmacokinetic properties with less toxicity in human bodies. CONCLUSION: Calycosin exhibits excellent potential as a therapeutic drug against several cancer types and should be consumed until standard chemotherapeutics are available in pharma markets.


Assuntos
Isoflavonas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Oncogenes , Pesquisa , Isoflavonas/farmacologia , Isoflavonas/uso terapêutico
11.
Brain Res Bull ; 207: 110864, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38157992

RESUMO

Ischemic stroke induced inflammatory responses contribute significantly to neuronal damage and stroke outcomes. CD200 ligand and its receptor, CD200R, constitute an endogenous inhibitory signaling that is being increasingly recognized in studies of neuroinflammation in various central nervous system disorders. CD200 is a type 1 membrane glycoprotein that is broadly expressed by endothelia and neurons in the brain. In the present study, we have examined the role of endothelial CD200 signaling in acute ischemic stroke. Endothelial CD200 conditional knock out (CKO) mice were generated by breeding CD200 gene floxed mice with Cdh5Cre mice. The mice were subjected to a 60-min transient middle cerebral artery occlusion (MCAO). Flow cytometry, Immunohistochemical staining, and Western blotting were performed to assess the post-stroke inflammation; stroke outcomes (infarct volume and neurobehavioral deficits) were evaluated at 72 h after MCAO. We found CD200R was near-null expressed on microglia at 24 h after stoke. Endothelial CKO of CD200 had no impact on peripheral immune cell development. Immunohistochemical staining confirmed CD200 was expressed on CD200 floxed but not on CD200 CKO endothelia. CD200 CKO mice exhibited larger infarct size, worse neurological deficit scores (NDS), and more deficits in the adhesive removal when compared with control mice, 72 h after MCAO. Western blot results showed that endothelial CKO of CD200 did not change BBB protein expression. Together it suggests that endothelial CD200 signaling protects brains against ischemic injury through a mechanism not directly related to microglial activation.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Camundongos , Encéfalo/metabolismo , Isquemia Encefálica/metabolismo , Infarto/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , AVC Isquêmico/metabolismo , Camundongos Knockout , Microglia/metabolismo , Acidente Vascular Cerebral/metabolismo
12.
Int J Biol Sci ; 19(13): 4340-4359, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37705747

RESUMO

An essential pathogenic element of acute limb ischemia/reperfusion (I/R) injury is microvascular dysfunction. The majority of studies indicates that fibroblast growth factor 2 (FGF2) exhibits protective properties in cases of acute I/R injury. Albeit its specific role in the context of acute limb I/R injury is yet unknown. An impressive post-reperfusion increase in FGF2 expression was seen in a mouse model of hind limb I/R, followed by a decline to baseline levels, suggesting a key role for FGF2 in limb survivability. FGF2 appeared to reduce I/R-induced hypoperfusion, tissue edema, skeletal muscle fiber injury, as well as microvascular endothelial cells (ECs) damage within the limb, according to assessments of limb vitality, Western blotting, and immunofluorescence results. The bioinformatics analysis of RNA-sequencing revealed that ferroptosis played a key role in FGF2-facilitated limb preservation. Pharmacological inhibition of NFE2L2 prevented ECs from being affected by FGF2's anti-oxidative and anti-ferroptosis activities. Additionally, silencing of kruppel-like factor 2 (KLF2) by interfering RNA eliminated the antioxidant and anti-ferroptosis effects of FGF2 on ECs. Further research revealed that the AMPK-HDAC5 signal pathway is the mechanism via which FGF2 regulates KLF2 activity. Data from luciferase assays demonstrated that overexpression of HDAC5 prevented KLF2 from becoming activated by FGF2. Collectively, FGF2 protects microvascular ECs from I/R injury by KLF2-mediated ferroptosis inhibition and antioxidant responses.


Assuntos
Fator 2 de Crescimento de Fibroblastos , Traumatismo por Reperfusão , Animais , Camundongos , Antioxidantes , Western Blotting , Células Endoteliais , Fator 2 de Crescimento de Fibroblastos/genética , Traumatismo por Reperfusão/genética
13.
Sensors (Basel) ; 23(16)2023 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-37631707

RESUMO

Capsule endoscopy (CE) is a widely used medical imaging tool for the diagnosis of gastrointestinal tract abnormalities like bleeding. However, CE captures a huge number of image frames, constituting a time-consuming and tedious task for medical experts to manually inspect. To address this issue, researchers have focused on computer-aided bleeding detection systems to automatically identify bleeding in real time. This paper presents a systematic review of the available state-of-the-art computer-aided bleeding detection algorithms for capsule endoscopy. The review was carried out by searching five different repositories (Scopus, PubMed, IEEE Xplore, ACM Digital Library, and ScienceDirect) for all original publications on computer-aided bleeding detection published between 2001 and 2023. The Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) methodology was used to perform the review, and 147 full texts of scientific papers were reviewed. The contributions of this paper are: (I) a taxonomy for computer-aided bleeding detection algorithms for capsule endoscopy is identified; (II) the available state-of-the-art computer-aided bleeding detection algorithms, including various color spaces (RGB, HSV, etc.), feature extraction techniques, and classifiers, are discussed; and (III) the most effective algorithms for practical use are identified. Finally, the paper is concluded by providing future direction for computer-aided bleeding detection research.


Assuntos
Endoscopia por Cápsula , Humanos , Computadores , Sistemas Computacionais , Algoritmos , Hemorragia
14.
Cancer Res ; 83(18): 3145-3158, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37404061

RESUMO

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKI) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. It is unknown whether these secondary HER2 mutations, other than the HER2T798I gatekeeper mutation, are causal to neratinib resistance. Herein, we show that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling, which was blocked by combined inhibition of HER2 and MEK. Together, these findings reveal the driver function of secondary HER2 mutations in resistance to HER2 inhibition and provide a potential treatment strategy to overcome acquired resistance to HER2 TKIs in HER2-mutant breast cancer. SIGNIFICANCE: HER2-mutant breast cancers acquire secondary HER2 mutations that drive resistance to HER2 tyrosine kinase inhibitors, which can be overcome by combined inhibition of HER2 and MEK.


Assuntos
Neoplasias da Mama , Quinolinas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Mutação , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico
15.
Nutrients ; 15(11)2023 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-37299393

RESUMO

Food-based interventions to improve linear growth are most often applied in low- and middle-income countries. However, not all food interventions have been proven to be effective in promoting linear growth. This study aimed to assess the impact and effectiveness of food interventions for improving linear growth in children under five years old. This study was conducted by following the PRISMA guidelines and the data were extracted and presented following the PRISMA recommendations. Studies were identified through a literature search of the SCOPUS, Web of Science, PubMed, ScienceDirect, and ProQuest databases from 2000 to 2022. Only randomized control studies were included in this review based on the inclusion and exclusion criteria. Out of 1125 studies identified, a total of 15 studies were included in this systematic review and meta-analysis. The review result indicated that food-based intervention can help to improve linear growth (MD: 0.20, 95% CI: 0.04 to 0.35, p = 0.01) among children under five. However, there was no significant difference in changes in underweight status (MD: 0.25; CI: -0.15 to 0.64; p = 0.22) and wasting status (MD: 0.09; CI: -0.02 to 0.20; p = 0.12) between the intervention and control groups. Overall, food-based interventions were found to be helpful for improving children's linear growth.


Assuntos
Alimentos , Transtornos do Crescimento , Humanos , Criança , Pré-Escolar , Transtornos do Crescimento/prevenção & controle
16.
Digit Health ; 9: 20552076231180728, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37325073

RESUMO

Objective: The current study explores the formation of an intention to use wearable fitness devices (WFDs) with wearable fitness attributes and health consciousness (HCS). Moreover, the research examines the use of WFDs with the health motivation (HMT) and intention to use WFDs. The study also exposes the moderating effect of HMT between the intention to use WFDs and the use of WFDs. Methods: Five hundred and twenty-five adults participated in the current study, and data were collected from January 2021 to March 2021 through the online survey of Malaysian respondents. The cross-sectional data was analyzed using the second-generation statistical method of partial least square structural equation modeling. Results: HCS is insignificantly associated with the intention to use WFDs. Perceived compatibility, perceived product value, perceived usefulness, and perceived technology accuracy significantly influence the intention to use WFDs. HMT significantly impacts the adoption of WFDs; however, the intention to use WFDs negatively but significantly influences the use of WFDs. Lastly, the association between the intention to use WFDs and the adoption of WFDs is significantly moderated by HMT. Conclusions: Our study findings illuminate the significant impact of technology-level attributes of WFDs on the intention to use WFDs. However, an insignificant impact of HCS on the intention to use WFDs was reported. Our result confirms that HMT plays a significant role in the use of WFDs. Such as the moderating role of HMT is vital to transform the intention to use WFDs into the adoption of WFDs.

17.
PLoS One ; 18(5): e0286382, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37256860

RESUMO

For logistics service providers (LSPs), improving customer satisfaction and obtaining customer re-use intention are key to gaining sustainable competitive advantages and success. Logistics service quality (LSQ) is a concern for logistics service providers, retailers, and customers. The proposed model, which is based on the stimuli-organism-response theory and the logistics service quality framework, integrates operational quality, resource quality, information quality, personal contact quality, customization quality, and customer satisfaction to study logistics service re-use intentions. The data were obtained from an online survey using a structured questionnaire given to those with experience in logistics service. Using partial least squares structural equation modeling on 810 respondents who were adult Chinese customers, this study discovered that operational, resource, information, personal contact, and customization qualities positively affect the satisfaction of logistics service customers, while customer satisfaction positively affects re-use intention. Moreover, the results of the mediation analysis revealed that customer satisfaction mediated the connection between the five components of LSQ and the re-use intention of logistics services. The originality of the study lies in its comprehensive examination of the direct and indirect effects of service quality dimensions on customer satisfaction and logistics service re-use intention in the context of logistics services. This study provides valuable insights into the importance of customer satisfaction in the logistics industry and highlights the need for logistics companies to prioritize customer satisfaction and improve their overall performance and competitiveness.


Assuntos
Comportamento do Consumidor , Intenção , Satisfação Pessoal , Inquéritos e Questionários , Satisfação do Paciente
18.
Cancer Med ; 12(13): 14556-14583, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37132286

RESUMO

BACKGROUND: The most common and deadly cancer in female is breast cancer (BC) and new incidence and deaths related to this cancer are rising. AIMS: Several issues, that is, high cost, toxicity, allergic reactions, less efficacy, multidrug resistance, and the economic cost of conventional anti-cancer therapies, has prompted scientists to discover innovative approaches and new chemo-preventive agents. MATERIALS: Numerous studies are being conducted on plant-based and dietary phytochemicals to discover new-fangled and more advanced therapeutic approaches for BC management. RESULT: We have identified that natural compounds modulated many molecular mechanisms and cellular phenomena, including apoptosis, cell cycle progression, cell proliferation, angiogenesis and metastasis, up-regulation of tumor-suppressive genes, and down-regulation of oncogenes, modulation of hypoxia, mammosphere formation, onco-inflammation, enzymatic regulation, and epigenetic modifications in BC. We found that a number of signaling networks and their components such as PI3K/Akt/mTOR, MMP-2 and 9, Wnt/-catenin, PARP, MAPK, NF-κB, Caspase-3/8/9, Bax, Bcl2, Smad4, Notch1, STAT3, Nrf2, and ROS signaling can be regulated in cancer cells by phytochemicals. They induce up-regulation of tumor inhibitor microRNAs, which have been highlighted as a key player for ani-BC treatments followed by phytochemical supplementation. CONCLUSION: Therefore, this collection offers a sound foundation for further investigation into phytochemicals as a potential route for the development of anti-cancer drugs in treating patients with BC.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Antineoplásicos/farmacologia , Transdução de Sinais , Apoptose , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/uso terapêutico
19.
Int J Mol Sci ; 24(8)2023 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-37108476

RESUMO

Autophagy is a highly conserved intracellular degradation pathway by which misfolded proteins or damaged organelles are delivered in a double-membrane vacuolar vesicle and finally degraded by lysosomes. The risk of colorectal cancer (CRC) is high, and there is growing evidence that autophagy plays a critical role in regulating the initiation and metastasis of CRC; however, whether autophagy promotes or suppresses tumor progression is still controversial. Many natural compounds have been reported to exert anticancer effects or enhance current clinical therapies by modulating autophagy. Here, we discuss recent advancements in the molecular mechanisms of autophagy in regulating CRC. We also highlight the research on natural compounds that are particularly promising autophagy modulators for CRC treatment with clinical evidence. Overall, this review illustrates the importance of autophagy in CRC and provides perspectives for these natural autophagy regulators as new therapeutic candidates for CRC drug development.


Assuntos
Neoplasias Colorretais , Humanos , Neoplasias Colorretais/patologia , Autofagia
20.
Nutrients ; 15(8)2023 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-37111180

RESUMO

The high malnutrition rate in children under five makes this problem one of the public health problems. Various efforts have been made to reduce malnutrition in children under five, one of which is the implementation of community programs with a positive deviance approach which is considered an effective way because the solution to the problem comes from the local community. Thus, we conducted a systematic review and meta-analysis to determine the effect of interventions with a positive deviance approach to reducing under-five children's malnutrition. Systematic searches were conducted using the following journal databases: Science Direct, Pubmed, Proquest, SAGE journal, Web of Science, and Scopus. The article was included if using an intervention design. Data analysis used Review Manager 5.4 software, random effect model, outcome mean of difference, and 95% confidence interval. There were no significant differences between the intervention and control groups on the length for age z-scores (LAZ), weight for age z-scores (WAZ), and weight for height z-scores (WHZ) indicators. There was an increase in LAZ, WAZ, and WHZ scores in the intervention group, with a greater z-score than in the control group. In conclusion, interventions with the positive deviance approach can be used as an alternative to improving the nutritional status of under-five children. However, further research is needed to determine the effective duration of interventions in improving the nutritional status of children.


Assuntos
Desnutrição , Humanos , Criança , Lactente , Desnutrição/prevenção & controle , Estado Nutricional , Transtornos do Crescimento
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