Nanoemulsions containing amphotericin b and paromomycin for the treatment of cutaneous leishmaniasis.

Cutaneous leishmaniasis (CL) is a vector-borne disease characterized by skin lesions that can evolve into high-magnitude ulcerated lesions. Thus, this study aimed to develop an innovative nanoemulsion (NE) with clove oil, Poloxamer® 407, and multiple drugs, such as amphotericin B (AmB) and paromomycin (PM), for use in the topical treatment of CL. METHODS: Droplet size, morphology, drug content, stability, in vitro release profile, in vitro cytotoxicity on RAW 264.7 macrophages, and antileishmanial activity using axenic amastigotes of Leishmania amazonensis were assessed for NEs. RESULTS: After optimizing the formulation parameters, such as the concentration of clove oil and drugs, using an experimental design, it was possible to obtain a NE with an average droplet size of 40 nm and a polydispersion index of 0.3, and these parameters were maintained throughout the 365 days. Furthermore, the NE showed stability of AmB and PM content for 180 days under refrigeration (4 °C), presented a pH compatible with the skin, and released modified AmB and PM. NE showed the same toxicity as free AmB and higher toxicity than free PM against RAW 264.7 macrophages. The same activity as free AmB, and higher activity than free PM against amastigotes L. amazonensis. CONCLUSION: It is possible to develop a NE for the treatment of CL; however, complementary studies regarding the antileishmanial activity of NE should be carried out.

2-Azabicyclo[3.2.1]octane scaffold: synthesis and applications.

2-Azabicyclo[3.2.1]octanes are nitrogen containing heterocycles with significant potential in the field of drug discovery. This core has been applied as key synthetic intermediate in several total synthesis, while their unique structure can make them a challenging scaffold to acquire. This Minireview summarizes the synthetic approaches to access this bicyclic architecture and highlights its presence in the total synthesis of several target molecules.

Antibody-Drug Conjugates in Breast Cancer: A Comprehensive Review of How to Selectively Deliver Payloads.

Antibody-drug conjugates (ADCs) have surfaced as a promising group of anticancer agents employing the precise targeting capacity of monoclonal antibodies to transport highly effective cytotoxic payloads. Compared to conventional chemotherapy, they aim to selectively eradicate cancer cells while minimizing off-target toxicity on healthy tissues. An increasing body of evidence has provided support for the efficacy of ADCs in treating breast cancer across various contexts and tumor subtypes, resulting in significant changes in clinical practice. Nevertheless, unlocking the full potential of these therapeutic agents demands innovative molecular designs to address complex clinical challenges, including drug resistance, tumor heterogeneity, and treatment-related adverse events. This thorough review provides an in-depth analysis of the clinical data on ADCs, offering crucial insights from pivotal clinical trials that assess the efficacy of ADCs in diverse breast cancer settings. This aids in providing a comprehensive understanding of the current state of ADCs in breast cancer therapy, while also providing valuable perspectives for the future.

Signatures of metabolic diseases on spermatogenesis and testicular metabolism.

Diets leading to caloric overload are linked to metabolic disorders and reproductive function impairment. Metabolic and hormonal abnormalities stand out as defining features of metabolic disorders, and substantially affect the functionality of the testis. Metabolic disorders induce testicular metabolic dysfunction, chronic inflammation and oxidative stress. The disruption of gastrointestinal, pancreatic, adipose tissue and testicular hormonal regulation induced by metabolic disorders can also contribute to a state of compromised fertility. In this Review, we will delve into the effects of high-fat diets and metabolic disorders on testicular metabolism and spermatogenesis, which are crucial elements for male reproductive function. Moreover, metabolic disorders have been shown to influence the epigenome of male gametes and might have a potential role in transmitting phenotype traits across generations. However, the existing evidence strongly underscores the unmet need to understand the mechanisms responsible for transgenerational paternal inheritance of male reproductive function impairment related to metabolic disorders. This knowledge could be useful for developing targeted interventions to prevent, counteract, and most of all break the perpetuation chain of male reproductive dysfunction associated with metabolic disorders across generations.

Influence of preconception body mass index on perinatal outcomes after metabolic and bariatric surgery.

INTRODUCTION: Metabolic and bariatric surgery (MBS) is a very effective weight loss intervention, although does not invariably reverses the obesity status. Our aim was to evaluate whether despite successful weight loss after MBS, persistence of obesity at time of conception still carries additional risks of adverse perinatal pregnancy outcomes. METHODS: Retrospective study comparing pregnancy outcomes of women previously submitted to MBS with a preconception (PC) body mass index BMI < 30 kg/m2 or PC BMI ≥ 30 kg/m2. RESULTS: Eighty pregnancies (n = 80) were included, 49 from women with a PC BMI < 30 kg/m2 and 31 with a PC BMI ≥ 30 kg/m2. Gestational weight gain was significantly lower (9.72 ± 7.10 vs. 13.81 ± 7.16 respectively; p = 0.01) and neonatal intensive care unit admissions were significantly higher (5% vs. 0% respectively; p = 0.02) in women with PC BMI ≥ 30 kg/m2 as compared to those with PC BMI < 30 kg/m2. There were no statistically significant differences in gestational diabetes, anemia, fetal growth restriction, prematurity rate, mode of delivery or birth weight between groups. CONCLUSION: Perinatal outcomes of pregnancies after MBS may be significantly influenced by PC BMI. The benefits of MBS induced weight loss on obesity-associated adverse pregnancy outcomes can be maximized if the obesity status can be reverted before pregnancy.

Incomplete recovery of the CD4+/CD8+ ratio is associated with the late introduction of antiretroviral therapy among people living with HIV infection.

Despite being subject to lower AIDS-related mortality rates and having a higher life expectancy, patients with HIV are more prone to develop non-AIDS events. A low CD4+/CD8+ ratio during antiretroviral therapy identifies people with heightened immune senescence and increased risk of mortality. In clinical practice, finding determinants of a low CD4+/CD8+ ratio may be useful for identifying patients who require close monitoring due to an increased risk of comorbidities and death. We performed a prospective study on the evolution of the CD4+/CD8+ ratio in 60 patients infected with HIV (80% males), who were subjected to two different antiretroviral regimens: early and deferred therapy. The initial CD4+/CD8+ ratio was ≤1 for 70% of the patients in both groups. Older age, CD4+ cell count at inclusion, Nadir CD8+T-cell count, and Initial CD4+/CD8+ ratio ≤ 1 were risk factors for lack of ratio recovery. In the multivariate analysis, a CD4+/CD8+ ratio > 1 at the start of the treatment was found to be a determinant factor in maintaining a CD4+/CD8+ ratio > 1. The nadir CD4+T-cell count was lower in the deferred therapy group (p=0.004), and the last CD4+/CD8+ ratio ≤1 was not associated with comorbidities. Ratio recovery was not associated with the duration of HIV infection, time without therapy, or absence of AIDS incidence. A greater improvement was observed in patients treated early (p=0.003). In contrast, the slope of increase was slower in patients who deferred treatment. In conclusion, the increase in the CD4+/CD8+ ratio occurred mostly for patients undergoing early strategy treatment and its extension did not seem to be related to previous HIV-related factors.

Age-dependent energy metabolism and transcriptome changes in urine-derived stem cells.

The global population over 60 years old is projected to reach 1.5 billion by 2050. Understanding age-related disorders and gender-specificities is crucial for a healthy aging. Reliable age-related biomarkers are needed, preferentially obtained through non-invasive methods. Urine-derived stem cells (UDSCs) can be easily obtained, although a detailed bioenergetic characterization, according to the donor aging, remain unexplored. UDSCs were isolated from young and elderly adult women (22-35 and 70-94 years old, respectively). Surprisingly, UDSCs from elderly subjects exhibited significantly higher maximal oxygen consumption and bioenergetic health index than those from younger individuals, evaluated through oxygen consumption rate. Exploratory data analysis methods were applied to engineer a minimal subset of features for the classification and stratification of UDSCs. Additionally, RNAseq of UDSCs was performed to identify age-related transcriptional changes. Transcriptional analysis revealed downregulation of genes related to glucuronidation and estrogen metabolism, and upregulation of inflammation-related genes in UDSCs from elderly individuals. This study demonstrates unexpected differences in the UDSCs' OCR between young and elderly individuals, revealing improved bioenergetics in concurrent with an aged-like transcriptome signature. UDSCs offer a non-invasive model for studying age-related changes, holding promise for aging research and therapeutic studies.

Bacaba, Pracaxi and Uxi Oils for Therapeutic Purposes: A Scoping Review.

Fruits such as bacaba (Oenocarpus bacaba Mart), pracaxi (Pentaclethra macroloba Kuntze) and uxi (Endopleura uchi (Huber) Cuatrec), from the Amazon rainforest, are potentially interesting for studies of natural products. The current article aims at mapping and characterizing studies on the bacaba, pracaxi and uxi species. This review reports the main bioactive compounds identified in these species and discusses their therapeutic potential. Searches were performed in MEDLINE (Via Pubmed) and Web of Science. Thirty-one studies that described or evaluated the development of formulations aimed at the therapeutic use of the species were included. The findings suggest that species have the potential for the development of pharmaceutical formulations due to their therapeutic properties. However, further studies are required to assess safety and efficacy of these products. Therefore, it is suggested that new research studies propose strategies so that technological development is based on awareness and preservation of the biome.

Effects of Simulated Gastrointestinal Conditions on Combined Potentially Probiotic Limosilactobacillus fermentum 296, Quercetin, and/or Resveratrol as Bioactive Components of Novel Nutraceuticals.

This study evaluated the effects of simulated gastrointestinal conditions (SGIC) on combined potentially probiotic Limosilactobacillus fermentum 296 (~ 10 log CFU/mL), quercetin (QUE, 160 mg), and/or resveratrol (RES, 150 mg) as the bioactive components of novel nutraceuticals. Four different nutraceuticals were evaluated during exposure to SGIC and analyzed the plate counts and physiological status of L. fermentum 296, contents and bioaccessibility of QUE and RES, and antioxidant capacity. Nutraceuticals with QUE and RES had the highest plate counts (4.94 ± 0.32 log CFU/mL) and sizes of live cell subpopulations (28.40 ± 0.28%) of L. fermentum 296 after SGIC exposure. An index of injured cells (Gmean index, arbitrary unit defined as above 0.5) indicated that part of L. fermentum 296 cells could be entered the viable but nonculturable state when the nutraceuticals were exposed to gastric and intestinal conditions while maintaining vitality. The nutraceuticals maintained high contents (QUE ~ 29.17 ± 0.62 and RES ~ 23.05 mg/100 g) and bioaccessibility (QUE ~ 41.0 ± 0.09% and RES ~ 67.4 ± 0.17%) of QUE and RES, as well as high antioxidant capacity (ABTS assay ~ 88.18 ± 1.16% and DPPH assay 75.54 ± 0.65%) during SGIC exposure, which could be linked to the protective effects on L. fermentum 296 cells. The developed nutraceuticals could cross along the gastrointestinal tract with high concentrations of functioning potentially probiotic cells and bioavailable phenolic compounds to exert their beneficial impacts on consumer health, being an innovative strategy for the co-ingestion of these bioactive components.

A rare case of oral squamous cell carcinoma in a patient with Cowden syndrome: Association or coincidence?

Cowden Syndrome (CS) is a rare genetic disease caused by mutations in the PTEN tumor suppressor gene, often presenting a challenging diagnosis due to its diverse clinical manifestations. Although extensively linked to several types of cancer, the precise association between CS and oral malignancies, particularly squamous cell carcinoma (SCC), remains poorly understood. This report describes a unique case of late diagnosis of CS in a 53-year-old female patient who later developed SCC in the inferior alveolar ridge, even without exposure to classic risk factors. The need to increase awareness in the medical and dental communities about CS and its manifestations in the oral cavity is highlighted. Early recognition and management of conditions associated with CS have a significant impact on patients' quality of life. Encouraging the publication of similar cases is recommended to encourage detailed analyzes and investigations in order to better understand the possible association between the syndrome and the development of malignancies in the oral cavity.

Mitochondrial uncoupling proteins regulate the metabolic function of human Sertoli cells.

In brief: Mitochondrial uncoupling proteins (UCPs) regulate mitochondrial activity and reactive oxygen species production through the transport of protons and metabolites. This study identified the expression of UCPs in human Sertoli cells, which proved to be modulators of their mitochondrial activity. Abstract: Mitochondrial uncoupling proteins (UCPs) are mitochondrial channels responsible for the transport of protons and small molecular substrates across the inner mitochondrial membrane. Altered UCP expression or function is commonly associated with mitochondrial dysfunction and increased oxidative stress, which are both known causes of male infertility. However, UCP expression and function in the human testis remain to be characterized. This study aimed to assess the UCP homologs (UCP1-6) expression and function in primary cultures of human Sertoli cells (hSCs). We identified the mRNA expression of all UCP homologs (UCP1-6) and protein expression of UCP1, UCP2, and UCP3 in hSCs. UCP inhibition by genipin for 24 h decreased hSCs proliferation without causing cytotoxicity (n = 6). Surprisingly, the prolonged UCP inhibition for 24 h decreased mitochondrial membrane potential, oxygen consumption rate (OCR), and endogenous reactive oxygen species (ROS) production. The metabolism of hSCs was also affected as UCP inhibition shifted their metabolism toward an increased pyruvate consumption. Taken together, these findings demonstrate that UCPs play a role as regulators of the mitochondrial function in hSCs, emphasizing their potential as targets in the study of male (in)fertility.

Incomplete recovery of the CD4+/CD8+ ratio is associated with the late introduction of antiretroviral therapy among people living with HIV infection

ABSTRACT Despite being subject to lower AIDS-related mortality rates and having a higher life expectancy, patients with HIV are more prone to develop non-AIDS events. A low CD4+/CD8+ ratio during antiretroviral therapy identifies people with heightened immune senescence and increased risk of mortality. In clinical practice, finding determinants of a low CD4+/CD8+ ratio may be useful for identifying patients who require close monitoring due to an increased risk of comorbidities and death. We performed a prospective study on the evolution of the CD4+/CD8+ ratio in 60 patients infected with HIV (80% males), who were subjected to two different antiretroviral regimens: early and deferred therapy. The initial CD4+/CD8+ ratio was ≤1 for 70% of the patients in both groups. Older age, CD4+ cell count at inclusion, Nadir CD8+T-cell count, and Initial CD4+/CD8+ ratio ≤ 1 were risk factors for lack of ratio recovery. In the multivariate analysis, a CD4+/CD8+ ratio > 1 at the start of the treatment was found to be a determinant factor in maintaining a CD4+/CD8+ ratio > 1. The nadir CD4+T-cell count was lower in the deferred therapy group (p=0.004), and the last CD4+/CD8+ ratio ≤1 was not associated with comorbidities. Ratio recovery was not associated with the duration of HIV infection, time without therapy, or absence of AIDS incidence. A greater improvement was observed in patients treated early (p=0.003). In contrast, the slope of increase was slower in patients who deferred treatment. In conclusion, the increase in the CD4+/CD8+ ratio occurred mostly for patients undergoing early strategy treatment and its extension did not seem to be related to previous HIV-related factors.

High glucose impairs human periodontal ligament cells migration through lowered microRNAs 221 and 222.

OBJECTIVE: To investigate the effects of miR-221 and miR-222 and high glucose on human periodontal ligament (PL) cells morphology, cytoskeleton, adhesion, and migration. BACKGROUND: Chronic hyperglycemia is common in uncontrolled diabetes mellitus (DM) and plays a central role in long-term DM complications, such as impaired periodontal healing. We have previously shown that high glucose increases apoptosis of human PL cells by inhibiting miR-221 and miR-222 and consequently augmenting their target caspase-3. However, other effects of miR-221/222 downregulation on PL cells are still unknown. METHODS: Cells from young humans' premolar teeth were cultured for 7 days under 5 or 30 mM glucose. Directional and spontaneous migration on fibronectin were studied using transwell and time-lapse assays, respectively. F-actin staining was employed to study cell morphology and the actin cytoskeleton. MiR-221 and miR-222 were inhibited using antagomiRs, and their expressions were evaluated by real-time RT-PCR. RESULTS: High glucose inhibited PL cells early adhesion, spreading, and migration on fibronectin. Cells exposed to high glucose showed reduced polarization, velocity, and directionality. They formed several simultaneous unstable and short-lived protrusions, suggesting impairment of adhesion maturation. MiR-221 and miR-222 inhibition also reduced migration, decreasing cell directionality but not significantly cell velocity. After miR-221 and miR-222 downregulation cells showed morphological resemblance with cells exposed to high glucose. CONCLUSION: High glucose impairs human PL cells migration potentially through a mechanism involving reduction of microRNA-221 and microRNA-222 expression. These effects may contribute to the impairment of periodontal healing, especially after surgery and during guided regeneration therapies.

Elevated Anti-Müllerian Hormone as a Prognostic Factor for Poor Outcomes of In Vitro Fertilization in Women with Polycystic Ovary Syndrome.

Women with polycystic ovary syndrome (PCOS) tend to have elevated anti-Müllerian hormone (AMH) levels, which appear to correlate with disease severity and pregnancy outcomes. This was a retrospective observational study designed to assess the relationship between circulating AMH levels and in vitro fertilization (IVF) outcomes. The study involved 150 women with PCOS who underwent IVF treatments. The women's IVF cycles were allocated into three subgroups according to AMH levels: 'low' (AMH < 3.7 ng/mL; n = 49), 'middle' (AMH 3.7-7.4 ng/mL; n = 94), and 'high' (AMH > 7.4 ng/mL; n = 56). All pregnancy-related outcomes (positive beta human chorionic gonadotropin (ßHCG), clinical pregnancy rate, live birth rate, and cumulative live birth rate) were greater in women's IVF cycles with 'low' AMH when compared to those with 'middle' or 'high' AMH (p < 0.05). AMH levels below 3.7 ng/mL were found to be associated with lower oocyte immaturity rate and better pregnancy outcomes, although baseline AMH was not shown to have any significant predictive power for live birth and cumulative live birth in the multivariable logistic regression analysis after adjusting for possible confounders nor in the ROC analyses. In summary, the current study lays the groundwork to validate high AMH levels as a poor prognostic factor for pregnancy outcomes after IVF in women with PCOS.

The relationship between acute pain and other types of suffering in pre-hospital trauma victims: An observational study.

BACKGROUND: Acute pain is an important complaint reported by trauma victims, however, the relationship between it and other types of discomfort, such as discomfort caused by cold, discomfort caused by immobilization, and psychological distress such as fear, anxiety, and sadness is limitedly studied and documented. AIM: To assess the relationship between acute trauma pain and other types of suffering in pre-hospital trauma victims. METHODS: This is a prospective multicentre cohort study conducted in Immediate Life Support Ambulances in Portugal. All adult trauma victims with a mechanism of blunt and penetrating injuries, falls, road accidents and explosions, were included. RESULTS: 605 trauma victims were included, mainly male, with a mean age of 53.4 years. Before the intervention of the rescue teams, 90.5 % of the victims reported some level of pain, 39.0 % reported discomfort caused by cold, while 15.7 % felt fear, 8.4 % sadness, 49.8 % anxiety and 4.5 % apathy. Victims with high discomfort caused by cold tend to have higher pain levels. Significantly higher pain intensity were observed in victims with fear and anxiety. Univariate and multivariate analysis indicates that immobilization is associated with increased pain levels. CONCLUSIONS: There is a statistically significant relationship between acute trauma pain, anxiety, fear, cold and immobilization.

Thyroid Volume in Pregnancy is Associated with Parity, Gestational Age, and Body Mass Index in an Iodine-sufficient Area.

OBJECTIVE: We compared thyroid volume (TV) and presence of nodular goiter (NG) in pregnant vs. non-pregnant women in an iodine-sufficient area. We also evaluated the relationship between gestational age, parity, and TV in the pregnant women group, and determined the 2.5th and 97.5th percentiles of normal TV in pregnancy. METHODS: This cross-sectional study included 299 healthy women (216 pregnant) without previous thyroid diseases. Thyroid ultrasounds were performed and compared between pregnant and non-pregnant women. The range of normal distribution of TV (2.5th and 97.5th percentiles) in pregnancy was determined after excluding individuals with positive thyroid antibodies, NG, and/or abnormal serum thyrotropin (TSH) or free thyroxine (FT4). RESULTS: Thyroid volume was larger among pregnant compared to non-pregnant women (8.6 vs 6.1 cm3; p < 0.001) and was positively correlated with gestational age (rs = 0.221; p = 0.001), body mass index (BMI, rs 0.165; p = 0.002), and FT4 levels (rs 0.118 p = 0.021). Nodular goiter frequency did not differ between the two groups. There was a negative correlation between TV and TSH (rs -0.13; p = 0.014). Thyroid volume was lower among primiparous compared to multiparous patients (7.8 vs 8.9; p < 0.001) and was positively correlated with parity (rs 0.161; p = 0.016). The 2.5th and 97.5th percentiles of TV were 4.23 and 16.47 cm3, respectively. CONCLUSION: Thyroid volume was higher in pregnant compared to non-pregnant women and was positively related to parity, BMI, and gestational age in a normal iodine status population. Pregnancy did not interfere with the development of NG.

OBJETIVO: Comparamos o volume tireoidiano (VT) e a presença de bócio nodular (BN) em mulheres grávidas e não grávidas em uma área suficiente em iodo. Também avaliamos a relação entre idade gestacional, paridade e VT no grupo de gestantes e determinamos os percentis 2,5 e 97,5 de VT normal na gestação. MéTODOS: Este estudo transversal incluiu 299 mulheres saudáveis (216 grávidas) sem doenças tireoidianas prévias. Ultrassonografias de tireoide foram realizadas e comparadas entre mulheres grávidas e não grávidas. A faixa de distribuição normal de VT (percentis 2,5 e 97,5) na gestação foi determinada após a exclusão de indivíduos com anticorpos tireoidianos positivos, BN e/ou tireotropina sérica (TSH) ou tiroxina livre (T4L) anormais. RESULTADOS: O VT foi maior entre as gestantes em comparação com as mulheres não grávidas (8,6 vs 6,1 cm3; p < 0,001) e foi positivamente correlacionado com a idade gestacional (rs = 0,221; p = 0,001), índice de massa corporal (IMC, rs 0,165; p = 0,002) e níveis de T4L (rs 0,118 p = 0,021). A frequência de BN não diferiu entre os dois grupos. Houve correlação negativa entre VT e TSH (rs -0,13; p = 0,014). O VT foi menor entre as primíparas em comparação com as multíparas (7,8 vs 8,9; p < 0,001) e foi positivamente correlacionado com a paridade (rs 0,161; p = 0,016). Os percentis 2,5 e 97,5 de VT foram 4,23 e 16,47 cm3, respectivamente. CONCLUSãO: O VT foi maior em gestantes em comparação com mulheres não grávidas e foi positivamente relacionado à paridade, IMC e idade gestacional em uma população com status iódico normal. A gravidez não interferiu no desenvolvimento de BN.

The Impact of Early-Stage Chronic Kidney Disease on Weight Loss Outcomes After Gastric Bypass.

PURPOSE: Weight loss achieved through bariatric metabolic surgery was demonstrated to be effective at reversing chronic kidney dysfunction associated with obesity-related glomerulopathy. However, robust data on how pre-operative kidney status impacts on bariatric metabolic surgery weight loss outcomes is still lacking. The aim of this study was to evaluate the impact of kidney dysfunction on weight loss outcomes after bariatric metabolic surgery. METHODS: Patients with obesity to be submitted to gastric bypass surgery underwent a pre-operative evaluation of creatinine clearance, estimated glomerular filtration rate (eGFR), proteinuria, and albuminuria in 24-hour urine. Body mass index (BMI), % total weight loss (%TWL), and % excess BMI loss (%EBMIL) were assessed at 6 and 12 months after surgery. RESULTS: Before surgery, patients (N=127) had a mean BMI of 39.6 ± 3.0 kg/m2, and 56.7% (n=72) had a creatinine clearance > 130 mL/min, 23.6% (n= 30) presented proteinuria > 150 mg/24h, and 15.0% (n= 19) presented albuminuria > 30 mg/24h. After surgery, the mean BMI was 27.7 kg/m2 and 25.0 kg/m2 at 6 and 12 months, respectively (p<0.0001). The %TWL was lower in patients with pre-operative eGFR < percentile 25 (34.4 ± 5.8% vs 39.4 ± 4.9%, p=0.0007, at 12 months). There were no significant correlations between weight loss metrics and pre-operative creatinine clearance rate, proteinuria, or albuminuria. CONCLUSION: Early-stage chronic kidney disease (G2) has a negative impact on short-term weight loss outcomes after bariatric metabolic surgery, albeit in a magnitude inferior to the clinically relevant threshold.