Abstract Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are the latest class of drugs approved to treat type 2 DM (T2DM). Although adverse effects are often caused by a metabolite rather than the ...drug itself, only the safety assessment of disproportionate drug metabolites is usually performed, which is of particular concern for drugs of chronic use, such as SGLT2i. Bearing this in mind, in silico tools are efficient strategies to reveal the risk assessment of metabolites, being endorsed by many regulatory agencies. Thereby, the goal of this study was to apply in silico methods to provide the metabolites toxicity assessment of the SGLT2i. Toxicological assessment from SGLT2i metabolites retrieved from the literature was estimated using the structure and/or statistical-based alert implemented in DataWarrior and ADMET predictorTM softwares. The drugs and their metabolites displayed no mutagenic, tumorigenic or cardiotoxic risks. Still, M1-2 and M3-1 were recognized as potential hepatotoxic compounds and M1-2, M1-3, M3-1, M3-2, M3-3 and M4-3, were estimated to have very toxic LD50 values in rats. All SGLT2i and the metabolites M3-4, M4-1 and M4-2, were predicted to have reproductive toxicity. These results support the awareness that metabolites may be potential mediators of drug-induced toxicities of the therapeutic agents.
The pathogenic complexity of Alzheimer's disease (AD) demands the development of multitarget-directed agents aiming at improving actual pharmacotherapy. Based on the cholinergic hypothesis and ...considering the well-established role of butyrylcholinesterase (BuChE) in advanced stages of AD, the chemical structure of the acetylcholinesterase (AChE) inhibitor drug donepezil (1) was rationally modified for the design of new N-benzyl-piperidine derivatives (4a-d) as potential multitarget-direct AChE and BuChE inhibitors. The designed analogues were further studied through the integration of in silico and in vitro methods. ADMET predictions showed that 4a-d are anticipated to be orally bioavailable, able to cross the blood-brain barrier and be retained in the brain, and to have low toxicity. Computational docking and molecular dynamics indicated the formation of favorable complexes between 4a-d and both cholinesterases. Derivative 4a presented the lowest binding free energy estimation due to interaction with key residues from both target enzymes (-36.69 ± 4.47 and -32.23 ± 3.99 kcal/mol with AChE and BuChE, respectively). The in vitro enzymatic assay demonstrated that 4a was the most potent inhibitor of AChE (IC
2.08 ± 0.16 µM) and BuChE (IC
7.41 ± 0.44 µM), corroborating the in silico results and highlighting 4a as a novel multitarget-directed AChE/BuChE inhibitor.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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•New twenty-three hybrids bisnaphthoquinone x 1,2,3-1H-triazole were developed.•All compounds were screened against breast cancer cell lines MCF-7 and MDA-MB-231.•Some compounds ...presented as potential new drugs for cancer treatment.•Two of them (12g and 12h) two of them were selective with low toxicity.•12g and 12h are novel AMPK activators presenting selective antitumor effects.
The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) promotes challenging immune and inflammatory phenomena. Though various therapeutic possibilities have been tested against coronavirus ...disease 2019 (COVID-19), the most adequate treatment has not yet been established. Propolis is a natural product with considerable evidence of immunoregulatory and anti-inflammatory activities, and experimental data point to potential against viral targets. We hypothesized that propolis can reduce the negative effects of COVID-19.
In a randomized, controlled, open-label, single-center trial, hospitalized adult COVID-19 patients were treated with a standardized green propolis extract (EPP-AF®️) as an adjunct therapy. Patients were allocated to receive standard care plus an oral dose of 400 mg or 800 mg/day of green propolis for seven days, or standard care alone. Standard care included all necessary interventions, as determined by the attending physician. The primary end point was the time to clinical improvement, defined as the length of hospital stay or oxygen therapy dependency duration. Secondary outcomes included acute kidney injury and need for intensive care or vasoactive drugs. Patients were followed for 28 days after admission.
We enrolled 124 patients; 40 were assigned to EPP-AF®️ 400 mg/day, 42 to EPP-AF®️ 800 mg/day, and 42 to the control group. The length of hospital stay post-intervention was shorter in both propolis groups than in the control group; lower dose, median 7 days versus 12 days (95% confidence interval CI −6.23 to −0.07; p = 0.049) and higher dose, median 6 days versus 12 days (95% CI −7.00 to −1.09; p = 0.009). Propolis did not significantly affect the need for oxygen supplementation. In the high dose propolis group, there was a lower rate of acute kidney injury than in the controls (4.8 vs 23.8%), (odds ratio OR 0.18; 95% CI 0.03–0.84; p = 0.048). No patient had propolis treatment discontinued due to adverse events.
Addition of propolis to the standard care procedures resulted in clinical benefits for the hospitalized COVID-19 patients, especially evidenced by a reduction in the length of hospital stay. Consequently, we conclude that propolis can reduce the impact of COVID-19.
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•124 hospitalized COVID-19 patients were randomized into three groups.•0, 400 or 800 mg/day of a standardized Brazilian green propolis was provided.•Adjunct treatment with propolis anticipated hospital release by five to six days.•The 800 mg propolis dose reduced kidney damage associated with COVID-19.•Propolis was safe and effective as an adjunct treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cancer incidence represents an important public health problem worldwide. Nuclear factor kappa B (NF- κB) transcription factor plays a pivotal role in the regulation of genes that control various ...responses in eukaryotic cells, including proliferation and survival, cytoskeletal remodeling, cellular adhesion and apoptosis. Extensive studies have demonstrated the contribution of NF-κB transcription in the promotion and progression of several hematological malignancies and solid tumors, in which NF-κB constitutive activation and/or overexpression are common clinical features. Moreover, triggering the NF-κB pathway is already considered one of the important mechanisms of resistance development to chemotherapy and radiotherapy, indicating that the inhibition of this signaling cascade is a promising approach to enhancing efficacy and preventing acquired resistance in cancer treatment. In this review, research efforts dedicated to the identification of novel NF-κB signaling pathway inhibitors as promising anticancer drug candidates are described.
Diabetes mellitus is a chronic, complex and multifactorial disease associated characteristically with hyperglycemia. One of the most recently approved antidiabetic drug classes for clinical use are ...sodium-glucose cotransporter type 2 (SGLT-2) inhibitors. SGLT-2 is a protein expressed in the kidneys, responsible for glucose reabsorption from the glomerular filtrate to the plasma. It is known, nowadays, that diabetic patients show an increased glucose renal reabsorption capacity, caused by the overexpression of the SGLT-2 transporter, thus contributing to hyperglycemia. From establishing this correlation, the SGLT-2 transporter started to be considered as a therapeutic target of interest, culminating in the approval of the first antidiabetic SGLT-2 inhibitor, dapagliflozin (Forxiga® or Farxiga®, Bristol-Myers Squibb & AstraZeneca), in 2012 in Europe. On the other hand, canagliflozin (Invokana®, Janssen Pharmaceutical) was the first drug in this class to be approved by the FDA, the U.S. Food and Drug Administration, in 2013. This review concerns the discovery and development of the first representatives of this class of antidiabetic drugs, and the description of new optimized analogues that are currently in the clinical and preclinical stages of development.
Novel SGLT-2 selective inhibitors, an innovative therapeutic approach for glycemia control in diabetic patients.
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IJS, KILJ, NUK, UL, UM, UPUK
To analyze the relationships between sociodemographic variables, intolerance to uncertainty (INT), social support, and psychological distress (i.e., indicators of Common Mental Disorders (CMDs) and ...perceived stress (PS)) in Brazilian men during the COVID-19 pandemic.
A cross-sectional study with national coverage, of the web survey type, and conducted with 1006 Brazilian men during the period of social circulation restriction imposed by the health authorities in Brazil for suppression of the coronavirus and control of the pandemic. Structural equation modeling analysis was performed.
Statistically significant direct effects of race/skin color (λ = 0.268;
-value < 0.001), socioeconomic status (SES) (λ = 0.306;
-value < 0.001), household composition (λ = 0.281;
-value < 0.001), PS (λ = 0.513;
-value < 0.001), and INT (λ = 0.421;
-value < 0.001) were evidenced in the occurrence of CMDs. Black-skinned men with higher SES, living alone, and with higher PS and INT levels presented higher prevalence values of CMDs.
High levels of PS and INT were the factors that presented the strongest associations with the occurrence of CMDs among the men. It is necessary to implement actions to reduce the stress-generating sources as well as to promote an increase in resilience and the development of intrinsic reinforcements to deal with uncertain threats.
ABSTRACT In the Amazon-Cerrado ecotone, increased costs from non-organic inputs and transportation render substrates more expensive, prompting the use of decomposed biomass from native palm stem for ...seedlig production. The study was carried out with the objective of evaluate the physicochemical characteristics of the decomposed biomass of babassu palms (BDB), carnauba (BDC), and buriti (BBU) compared to the commercial substrate (SC) via multivariate analysis. This study employed a database comprising 90 substrates, obtained from Maranhão, Brazil farms. These samples underwent physicochemical characterization following the Brazilian protocol for seedling substrates. The substrates based on BDB and BDC have pH and nutrient contents at acceptable values, in addition to lower potential acidity and high base saturation compared to BBU and SC substrates. Principal component analysis and hierarchical clustering revealed similarities between BDB, BDC and SC. Biomass decomposed from the stems of babassu and carnauba palms is recommended as an alternative substrate for seedling producers in the in the Amazon-Cerrado ecotone.
RESUMO No ecótono Amazônia-Cerrado, o aumento dos custos com insumos não orgânicos e transporte torna os substratos mais caros, estimulando o uso da biomassa decomposta do caule da palmeira nativa para a produção de mudas. O estudo foi realizado com o objetivo de avaliar as características físico-químicas da biomassa decomposta de babaçu (BDB), carnaúba (BDC) e buriti (BBU) comparado ao substrato comercial (SC) via estatística multivariada. O estudo utilizou um banco de dados composto por 90 substratos, obtidos em fazendas do Maranhão, Brasil. Essas amostras passaram por caracterização físico-química seguindo o protocolo brasileiro para substratos de mudas. Os substratos à base de BDB e BDC apresentam pH e teores de nutrientes em valores aceitáveis, além de menor acidez potencial e elevada saturação por bases em comparação aos substratos BBU e SC. A análise de componentes principais e agrupamento hierárquico revelou similaridades entre BDB, BDC e SC. A biomassa decomposta dos caules das palmeiras babaçu e carnaúba é recomendada como substrato alternativo para produtores de mudas no ecótono Amazônia-Cerrado.
•A 2009 Bio-Manguinhos/Fiocruz YF vaccine dose–response study supported WHO's position for fractional dose for outbreaks.•Part of the original cohort was reassessed for immunity duration and ...seroconversion.•Seroconversion lasted 10 years.•Reduced doses have shown effective seroconversion (>80 %).•Antibody titers in reduced-dose versus full-dose groups remain equivalent.
A single dose of standard yellow fever (YF) vaccine is considered to provide life-long protection. In this study, we evaluate the seropositivity conferred by lower doses 10 years post-vaccination. In 2009, Bio-Manguinhos/Fiocruz performed a dose–response study with the 17DD yellow fever vaccine, administering the vaccine in the usual mean dose of 27.476 IU and in decreasing doses (10.447 IU, 3.013 IU, 587 IU, 158 IU and 31 IU), with the usual volume and route (0,5 ml subcutaneous). The decreasing doses were obtained by dilution in the laboratory of the manufacturer and the lots in test had standard quality control and were produced by good manufacturing practices (GMP). Around 30 days after the vaccination, doses down to 587 IU had similar immunogenicity and the 158 IU and 31 IU were inferior to the full dose. The seropositivity was maintained for 10 months, except on the 31 IU group. Eight years after, 85 % of 318 participants evaluated in a follow-up, maintained seropositivity that was similar across groups. Consistently, antibody titers in the reduced-dose groups were also comparable to those of the full-dose group. The current study, 10 years later, showed similarity between the vaccine groups (six arms who received the YF vaccine in decreasing doses: 27.476 IU, 10.447 IU, 3.013 IU, 587 IU, 158 IU, 31 IU) both in relation of seropositivity and in the evaluation of the geometric mean titers. The seropositivity rates across subgroups were 83,1%, 90 %, 87 %, 93 %, 83,8% and 85 %, correspondingly. These findings provides further support to the long-term immunogenicity of lower doses.
Clinical trial registry: NCT04416477.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Population surveillance in COVID-19 Pandemic is crucial to follow up the pace of disease and its related immunological status. Here we present a cross-sectional study done in Maricá, a seaside town ...close to the city of Rio de Janeiro, Brazil. Three rounds of study sampling, enrolling a total of 1134 subjects, were performed during May to August 2021. Here we show that the number of individuals carrying detectable IgG antibodies and the neutralizing antibody (NAb) levels were greater in vaccinated groups compared to unvaccinated ones, highlighting the importance of vaccination to attain noticeable levels of populational immunity against SARS-CoV-2. Moreover, we found a decreased incidence of COVID-19 throughout the study, clearly correlated with the level of vaccinated individuals as well as the proportion of individuals with detectable levels of IgG anti-SARS-CoV-2 and NAb. The observed drop occurred even during the introduction of the Delta variant in Maricá, what suggests that the vaccination slowed down the widespread transmission of this variant. Overall, our data clearly support the use of vaccines to drop the incidence associated to SARS-CoV-2.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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