The purpose was to assess prevalence of suicidality, depression, post-traumatic stress disorder (PTSD), and anxiety among female sex workers (FSW). A systematic review and meta-analysis was ...performed. Search strategy was performed in MEDLINE, Scopus, Web of Science, EMBASE, Ovid and Cochrane Central Database from inception until March 2020. Considered for inclusion were cross-sectional studies performed on FSW that assessed prevalence of any of the following: suicide attempt or suicidal ideation, depression, PTSD, or anxiety. Five reviewers, independently and in duplicate, selected all eligible articles in an abstract and full-text screening phase and, moreover, extracted information from each study. A binomial-normal generalized linear mixed model was employed to estimate prevalence of the conditions. From 8035 studies yielded in the search strategy, 55 were included for analysis. The overall prevalence of suicidal ideation and attempt was 27% (95% C.I. 18–39%) and 20% (95% C.I. 13–28%), respectively. Furthermore, overall prevalence of depression and PTSD was 44% (95% C.I. 35–54%) and 29% (95% C.I. 18–44%), respectively. Eleven studies were classified as high quality. Findings indicate that there is an overall high prevalence of suicidality, depression, and PTSD among FSW. Development of accessible large-scale interventions that assess mental health among this population remains critical.
Proper physiological function of mammalian airways requires the differentiation of basal stem cells into secretory or multiciliated cells, among others. In addition, the self‐renewal ability of these ...basal stem cells is crucial for developing a quick response to toxic agents in order to re‐establish the epithelial barrier function of the airways. Although these epithelial missions are vital, little is known about those mechanism controlling airway epithelial regeneration in health and disease. p53 has been recently proposed as the guardian of homeostasis, promoting differentiation programs, and antagonizing a de‐differentiation program. Here, we exploit mouse and human tracheal epithelial cell culture models to study the role of MDM2‐p53 signaling in self‐renewal and differentiation in the airway epithelium. We show that p53 protein regulation by MDM2 is crucial for basal stem cell differentiation and to keep proper cell proliferation. Therefore, we suggest that MDM2/p53 interaction modulation is a potential target to control regeneration of the mammalian airway epithelia without massively affecting the epithelium integrity and differentiation potential.
Metabolic Dysfunction-Associated Fatty Liver Disease and Diabetes Mellitus are two prevalent metabolic disorders that often coexist and synergistically contribute to the progression of each other. ...Several pathophysiological pathways are involved in the association, including insulin resistance, inflammation, and lipotoxicity, providing a foundation for understanding the complex interrelationships between these conditions. The presence of MASLD has a significant impact on diabetes risk and the development of microvascular and macrovascular complications, and diabetes significantly contributes to an increased risk of liver fibrosis progression in MASLD and the development of hepatocellular carcinoma. Moreover, both pathologies have a synergistic effect on cardiovascular events and mortality.
Therapeutic interventions targeting MASLD and diabetes are discussed, considering lifestyle modifications, pharmacological agents, and emerging treatment modalities. The review also addresses the challenges in managing these comorbidities, such as the need for personalized approaches and the potential impact on cardiovascular health. The insights gleaned from this analysis can inform clinicians, researchers, and policymakers in developing integrated strategies for preventing, diagnosing, and managing these metabolic disorders.
Major Depressive Disorder (MDD) and obesity are bidirectionally related, but the amount of weight-gain secondary to MDD is unknown. We aimed to estimate the adjusted effect of MDD on weight-change in ...prospective studies compared to individuals without MDD.
Scopus/MEDLINE, PsycInfo, Web of Science and Cochrane were systematically searched for prospective observational studies of participants with a diagnosis of MDD. We included studies that conducted regression analyses on weight-variables. We searched for weight-variables reported at baseline, follow-up, and regression analyses. A meta-analysis of the odds ratios reported in logistic regression models was performed using the generic inverse weight variance method.
Eight studies were included with a total of 60,443 subjects; 56.8 % with MDD. Weight-variables included weight, BMI, waist circumference, fat mass, and obesity incidence. In three follow-up reports, weight-variables increased more in participants with MDD and its subphenotypes than in control subjects, except for one MDD subphenotype. Meta-analysis of three eligible studies (n = 21,935) showed a significantly greater likelihood of incident obesity in participants with MDD (OR:1.48, 95%CI 1.03–2.13). MDD subphenotype reports might suggest a greater risk for atypical MDD.
Heterogeneity in weight related variables, follow-ups, and regression models; scarcity of follow-up data; and limited studies eligible for meta-analysis.
Despite previous associations between MDD and obesity, current prospective evidence on MDD related weight-change is scarce and heterogeneous. Our findings suggest a need to standardize weight-change assessment in MDD trials. Moreover, careful weight tracking and management should be incorporated in clinical settings.
PROSPERO registration CRD42020214427.
•We studied weight-change in prospective studies with MDD and controls.•Weight variables increased more in patients with MDD than controls.•Meta-analysis showed risk of incident obesity in MDD (OR:1.48, 95%CI 1.03–2.13).•Most MDD subphenotypes gained weight; atypical MDD showed greater odds.
Several diseases, such as cancer, are characterized by acidification of the extracellular environment. Acidosis can be employed as a target to specifically direct therapies to the diseased tissue. We ...have used first principles to design an acidity-triggered rational membrane (ATRAM) peptide with high solubility in solution that is able to interact with lipid membranes in a pH-dependent fashion. Biophysical studies show that the ATRAM peptide binds to the surface of lipid membranes at pH 8.0. However, acidification leads to the peptide inserting into the lipid bilayer as a transmembrane α-helix. The insertion of ATRAM into membranes occurs at a moderately acidic pH (with a pK of 6.5), similar to the extracellular pH found in solid tumors. Studies with human cell lines showed a highly efficient pH-dependent membrane targeting, without causing toxicity. Here we show that it is possible to rationally design a soluble peptide that selectively targets cell membranes in acidic environments.
pH-responsive peptides are promising therapeutic molecules that can specifically target the plasma membrane in the acidified extracellular medium that bathes cells in tumors. We designed the ...acidity-triggered rational membrane (ATRAM) peptide to have a pH-responsive membrane interaction. At physiological pH, ATRAM binds to the membrane surface in a largely unstructured conformation, while in acidic conditions it inserts into lipid bilayers forming a transmembrane helix. However, the molecular mechanism ATRAM uses to target and insert into tumor cells remains poorly understood. Here, we determined that ATRAM inserts into cancer cells with a preferential membrane orientation, where the C-terminus of the peptide traverses the plasma membrane and explores the cytoplasm. Using biophysical techniques, we determined that the membrane interaction of ATRAM is contingent on the concentration of the peptide. Kinetic studies showed that membrane insertion occurs in at least three steps, where only the first step was affected by the membrane density of ATRAM. These observations, combined with membrane binding and leakage data, indicate that the interaction of ATRAM with lipid membranes is dependent on its oligomerization state. SPECT/CT imaging in mice revealed that ATRAM accumulates in the blood pool, where it has a prolonged circulation time (> 4 h). Since fast peptide clearance and degradation in circulation are major problems for clinical development, we studied the mechanism ATRAM uses to remain in the blood stream. Using binding and transfer assays, we determined that ATRAM binds reversibly to human serum albumin. We propose that ATRAM uses albumin as a carrier in the blood stream to evade clearance and proteolysis before interacting with the plasma membrane of cancer cells. We also show that ATRAM is able to be deliver liposomes to cells in a pH dependent way. Our data highlight the potential of ATRAM as a specific therapeutic agent for diseases that lead to acidic tissues, including cancer.
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The present study aimed to analyse the relationship between functional movement and strength variables upon linear speed (Ls) and change of direction (COD) based on gender. It also aimed to identify ...the determinants of performance of Ls and COD according to gender. Fifty basketball players (54% female) completed the assessment in which the weight-bearing dorsiflexion test, the Y-balance test, the unilateral countermovement jump, the unilateral drop jump, the unilateral triple hop test, Ls and CODs were performed. Speed variables were divided according to time execution into "low-performance" and "high-performance" to establish a comparison between performance groups. Strength variables significantly influenced speed tests' performance in both genders (p < 0.05). For males, the greater the Ls, the higher the change of direction deficit (p < 0.001). Multiple regression analysis revealed that a long and vertical stretch-shortening cycle (SSC) was the most influential physical ability for speed performance in females (45-65% variance explained; p < 0.001), while in males, a short and horizontal SSC played a significant role (30-61% variance explained; p < 0.022). These results suggest that gender should be considered in programming strength training to improve speed, as each gender will benefit most from the application of different force-orientations and different SSC. Also, the faster the male players were in Ls, the less efficient they were in the COD performance. This is why for men, it would be recommended to perform eccentric exercises along with deceleration and technique drills to improve COD speed.
The cytotoxic and antifungal capacity of a set of turbomycin-based alkaloids, assembled by multicomponent reactions through exposure to near-infrared light (
λ
= 1.1 μm) in the presence of organic ...acid, was tested against six cancer cell lines (SW620, SW480, HeLa, K562, MCF-7, and Calo) and three life-threatening fungi (
C. albicans
,
C. parapsilosis
, and
C. neoformans
). Notably, the structurally elaborated compounds (> 10
3
Da) showed an antifungal effect against
C. parapsilosis
and
C. neoformans
at a concentration of 2.4 mM comparable to ketoconazole (22 vs. 20 mm). In contrast, its lower molecular weight homologous (< 500 Da) exhibited substantially the best cytotoxic effect against the growth of the colon adenocarcinoma cell lines SW620 and WS408 (IC
50
= 12.56 ± 3.3 μmol and 13.9 ± 2.7 μmol), values slightly higher than the m-AMSA positive control (IC
50
= 8.3 ± 2.6 and 7.4 ± 2.04 μmol). Highlight that only regioisomers containing the 1,1′-dimethyl-, 2,2′-dimethyl-, and 2,2′-diphenyl-DIM subunits attached on phenyl ring in a 1,3-substitution pattern exhibit substantial cytotoxic and antifungal effect.
Graphic abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) commonly targeted for inhibition by anticancer therapeutics. Current therapeutics target EGFR’s kinase domain or ...extracellular region. However, these types of inhibitors are not specific for tumors over healthy tissue and therefore cause undesirable side effects. Our lab has recently developed a new strategy to regulate RTK activity by designing a peptide that specifically binds to the transmembrane (TM) region of the RTK to allosterically modify kinase activity. These peptides are acidity-responsive, allowing them to preferentially target acidic environments like tumors. We have applied this strategy to EGFR and created the PET1 peptide. We observed that PET1 behaves as a pH-responsive peptide that modulates the configuration of the EGFR TM through a direct interaction. Our data indicated that PET1 inhibits EGFR-mediated cell migration. Finally, we investigated the mechanism of inhibition through molecular dynamics simulations, which showed that PET1 sits between the two EGFR TM helices; this molecular mechanism was additionally supported by AlphaFold-Multimer predictions. We propose that the PET1-induced disruption of native TM interactions disturbs the conformation of the kinase domain in such a way that it inhibits EGFR’s ability to send migratory cell signals. This study is a proof-of-concept that acidity-responsive membrane peptide ligands can be generally applied to RTKs. In addition, PET1 constitutes a viable approach to therapeutically target the TM of EGFR.
Endocrine Conditions and COVID-19 Shekhar, Skand; Wurth, Rachel; Kamilaris, Crystal D. C. ...
Hormone and metabolic research,
07/2020, Volume:
52, Issue:
7
Journal Article
Peer reviewed
Open access
Abstract
COVID-19 was declared a global pandemic by the WHO and has affected millions
of patients around the world. COVID-19 disproportionately affects persons
with endocrine conditions, thus putting ...them at an increased risk for severe
disease. We discuss the mechanisms that place persons with endocrine
conditions at an additional risk for severe COVID-19 and review the
evidence. We also suggest precautions and management of endocrine conditions
in the setting of global curfews being imposed and offer practical tips for
uninterrupted endocrine care.
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