CONSTANS, a HUB for all seasons: How photoperiod pervades plant physiology regulatory circuits.

How does a plant detect the changing seasons and make important developmental decisions accordingly? How do they incorporate daylength information into their routine physiological processes? Photoperiodism, or the capacity to measure the daylength, is a crucial aspect of plant development that helps plants determine the best time of the year to make vital decisions, such as flowering. The protein CONSTANS (CO) constitutes the central regulator of this sensing mechanism, not only activating florigen production in the leaves but also participating in many physiological aspects in which seasonality is important. Recent discoveries place CO in the center of a gene network that can determine the length of the day and confer seasonal input to aspects of plant development and physiology as important as senescence, seed size, or circadian rhythms. In this review, we discuss the importance of CO protein structure, function, and evolutionary mechanisms that embryophytes have developed to incorporate annual information into their physiology.

Blockade of the mineralocorticoid receptor improves markers of human endothelial cell dysfunction and hematological indices in a mouse model of sickle cell disease.

Increased endothelin-1 (ET-1) levels in patients with sickle cell disease (SCD) and transgenic mouse models of SCD contribute to disordered hematological, vascular, and inflammatory responses. Mineralocorticoid receptor (MR) activation by aldosterone, a critical component of the Renin-Angiotensin-Aldosterone-System, modulates inflammation and vascular reactivity, partly through increased ET-1 expression. However, the role of MR in SCD remains unclear. We hypothesized that MR blockade in transgenic SCD mice would reduce ET-1 levels, improve hematological parameters, and reduce inflammation. Berkeley SCD (BERK) mice, a model of severe SCD, were randomized to either sickle standard chow or chow containing the MR antagonist (MRA), eplerenone (156 mg/Kg), for 14 days. We found that MRA treatment reduced ET-1 plasma levels (p = .04), improved red cell density gradient profile (D50 ; p < .002), and increased mean corpuscular volume in both erythrocytes (p < .02) and reticulocytes (p < .024). MRA treatment also reduced the activity of the erythroid intermediate-conductance Ca2+ -activated K+ channel - KCa 3.1 (Gardos channel, KCNN4), reduced cardiac levels of mRNAs encoding ET-1, Tumor Necrosis Factor Receptor-1, and protein disulfide isomerase (PDI) (p < .01), and decreased plasma PDI and myeloperoxidase activity. Aldosterone (10-8 M for 24 h in vitro) also increased PDI mRNA levels (p < .01) and activity (p < .003) in EA.hy926 human endothelial cells, in a manner blocked by pre-incubation with the MRA canrenoic acid (1 µM; p < .001). Our results suggest a novel role for MR activation in SCD that may exacerbate SCD pathophysiology and clinical complications.

Impaired kidney function, cerebral small vessel disease and cognitive disorders: the Framingham Heart Study.

BACKGROUND AND HYPOTHESIS: It remains unclear whether the relation of chronic kidney disease (CKD) with cognitive dysfunction is independent of blood pressure (BP). We evaluated kidney function in relation to premorbid BP measurements, cerebral small vessel disease (CSVD), and incident mild cognitive impairment (MCI) and dementia in Framingham Offspring Cohort participants. METHODS: We included Framingham Offspring participants free of dementia, attending an examination during midlife (exam cycle 6, baseline) for ascertainment of kidney function status, with brain magnetic resonance imaging late in life (exam cycles 7-9), cognitive outcome data, and available interim hypertension and BP assessments. We related CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2) and albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) to CSVD markers and cognitive outcomes using multivariable regression analyses. RESULTS: Among 2604 participants (mean age 67.4 ± 9.2, 64% women, 7% had CKD, and 9% albuminuria), albuminuria was independently associated with covert infarcts [adjusted OR, 1.55 (1.00-2.38); P = 0.049] and incident MCI and dementia [adjusted hazard ratio (HR), 1.68 (1.18-2.41); P = 0.005 and 1.71, (1.11-2.64); P = 0.015, respectively]. CKD was not associated with CSVD markers but was associated with a higher risk of incident dementia [HR, 1.53 (1.02-2.29); P = 0.041]. While albuminuria was predictive of the Alzheimer's disease subtype [adjusted HR = 1.68, (1.03-2.74); P = 0.04), CKD was predictive of vascular dementia [adjusted HR, 2.78 (1.16-6.68); P = 0.023]. CONCLUSIONS: Kidney disease was associated with CSVD and cognitive disorders in asymptomatic community dwelling participants. The relation was independent of premorbid BP, suggesting that the link between kidney and brain disease may involve additional mechanisms beyond BP-related injury.

Antifungal capabilities of gut microbial communities of three dung beetle species (Scarabaeidae: Scarabaeinae).

Gut microbial communities are part of the regulatory array of various processes within their hosts, ranging from nutrition to pathogen control. Recent evidence shows that dung beetle's gut microbial communities release substances with antifungal activity. Because of the enormous diversity of gut microorganisms in dung beetles, there is a possibility of discovering novel compounds with antifungal properties. We tested the antifungal activity mediated by gut microbial communities of female dung beetles against nine phytopathogenic fungi strains (Colletotrichum asianum-339, C. asianum-340, C. asianum-1, C. kahawae-390, C. karstii-358, C. siamense-220, Fusarium oxysporum-ATCC338, Nectria pseudotrichia-232, Verticillium zaelandica-22). Our tests included the gut microbial communities of three species of dung beetles: Canthon cyanellus (roller beetle), Digitonthophagus gazella (burrower beetle), and Onthophagus batesi (burrower beetle), and we followed the dual confrontation protocol, i.e., we challenged each fungal strain with the microbial communities of each species of beetles in Petri dishes containing culture medium. Our results showed that gut microbial communities of the three dung beetle species exhibit antifungal activity against at least seven of the nine phytopathogenic fungal strains. The gut microbial communities of Onthophagus batesi significantly decreased the mycelial growth of the nine phytopathogenic fungi strains; the gut microbial communities of Canthon cyanellus and Digitonthophagus gazella significantly reduced the mycelial growth of seven strains. These results provide a basis for investigating novel antifungal substances within gut microbial communities of dung beetles.

A Simple Electron-Density Based Force Field Model for High-Energy Interactions between Atoms and Molecules.

In high-energy molecular dynamics or Monte Carlo simulations, standard force fields optimized for simulations at ambient temperatures are inadequate. This is largely because their repulsive parts have been regarded as not very significant, even well below zero interaction energies. It is, therefore, not obvious which force fields to resort to for simulating hot gases or plasmas. A force field model that uses the electronic densities of noninteracting atoms or molecules within the pair approximation is introduced. We start by deriving a naïve model that neglects any exchange and correlation effects between the electronic clouds and then correct this model by adding a term calibrated from ab initio calculations using the CCSD(T)/cc-pVTZ level of theory. The resulting expression for this term can be regarded as a simple exchange-correlation function. We compare the results for the repulsive part of the potential energy hypersurfaces with the force fields commonly used on some dimers of small molecules.

A polarizable valence electron density based force field for high-energy interactions between atoms and molecules.

High-accuracy molecular force field models suited for hot gases and plasmas are not as abundant as those geared toward ambient pressure and temperature conditions. Here, we present an improved version of our previous electron-density based force field model that can now account for polarization effects by adjusting the atomic valence electron contributions to match ab initio calculated Mulliken partial charges. Using a slightly modified version of the Hohenberg-Kohn theorem, we also include an improved theoretical formulation of our model when applied to systems with degenerate ground states. We present two variants of our polarizable model, fitted from ab initio reference data calculated at CCSD(T)/cc-pVTZ and CCSD(T)/CEP-31G levels of theory, that both accurately model water dimer interaction energies. Further improvements include the additional interaction components with fictitious non-spherically symmetric, yet atom-centered, electron densities and fitting the exchange and correlation coefficients against analytical expressions. The latter removes all unphysical oscillations that are observed in the previous non-polarizable variant of our force field.

Circulating blood biomarkers correlated with the prognosis of advanced triple negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) can improve survivals of metastatic triple negative breast cancer (mTNBC); however, we still seek circulating blood biomarkers to predict the efficacy of ICIs. MATERIALS AND METHODS: In this study, we analyzed the data of ICIs treated mTNBC collected in Anhui Medical University affiliated hospitals from 2018 to 2023. The counts of lymphocytes, monocytes, platelets, and ratio indexes (NLR, MLR, PLR) in peripheral blood were investigated via the Kaplan-Meier curves and the Cox proportional-hazards model. RESULTS: The total of 50 mTNBC patients were treated with ICIs. High level of peripheral lymphocytes and low level of NLR and MLR at baseline and post the first cycle of ICIs play the predictable role of immunotherapies. Lymphocytes counts (HR = 0.280; 95% CI: 0.095-0.823; p = 0.021) and NLR (HR = 1.150; 95% CI: 1.052-1.257; p = 0.002) are significantly correlated with overall survival. High NLR also increases the risk of disease progression (HR = 2.189; 95% CI:1.085-4.414; p = 0.029). When NLR at baseline ≥ 2.75, the hazard of death (HR = 2.575; 95% CI:1.217-5.447; p = 0.013) and disease progression (HR = 2.189; 95% CI: 1.085-4.414; p = 0.029) significantly rise. HER-2 expression and anti-tumor therapy lines are statistically correlated with survivals. CONCLUSIONS: Before the initiation of ICIs, enriched peripheral lymphocytes and poor neutrophils and NLR contribute to the prediction of survivals.

Metabolomic Approaches in Assessing the Insecticidal Activity of the Extracts from Argemone ochroleuca Sweet (Papaveraceae) Against Three Diverse Crop Pests of Economic Importance.

For years, crop protection from pest attack, has been dominated by the use of synthetic insecticides. However, many of them can cause severe environmental problems and human health. In this context, the use of plant extracts constitutes an alternative to avoid this kind of contaminants. In this work, we investigated the chemical constituents and insecticidal activity of different extracts of leaves and stems of Argemone ochroleuca Sweet (Papaveraceae) against three economically important pests Sitophilos zeamais (Coleoptera:Curculionidae), Galleria mellonella (Lepidoptera:Pyralidae) and Xyleborus ferrugineus (Coleoptera:Scolytidae). A GC-MS analysis mostly revealed the presence benzylisoquinoline alkaloids such as allocryptopine, protopine, among others. For the insecticidal activity, after nine hours of contact, the methanolic leaves extract showed a 100 % of mortality, followed by the dichloromethane stems extract with up to 93 % of mortality. The results suggest that the benzylisoquinoline alkaloids are involved in the insecticidal activity through the octopaminergic system of the tested insects.

Distributed Embedded System for Multiparametric Assessment of Infrastructure Durability Using Electrochemical Techniques.

We present an autonomous system that remotely monitors the state of reinforced concrete structures. This system performs real-time follow-up of the corrosion rate of rebars (iCORR), along with other relevant parameters such as temperature, corrosion potential (ECORR), and electrical resistance of concrete (RE), at many of a structure's control points by using embedded sensors. iCORR is obtained by applying a novel low-stress electrochemical polarization technique to corrosion sensors. The custom electronic system manages the sensor network, consisting of a measurement board per control point connected to a central single-board computer in charge of processing measurement data and uploading results to a server via 4G connection. In this work, we report the results obtained after implementing the sensor system into a reinforced concrete wall, where two well-differentiated representative areas were monitored. The obtained corrosion parameters showed consistent values. Similar conclusions are obtained with ECORR recorded in rebars. With the iCORR follow-up, the corrosion penetration damage diagram is built. This diagram is particularly useful for identifying critical events during the corrosion propagation period and to be able to estimate structures' service life. Hence, the system is presented as a useful tool for the structural maintenance and service life predictions of new structures.

Antioxidant and Antibacterial Activities of Selected Medicinal Plants from Addis Ababa against MDR-Uropathogenic Bacteria.

This study determined the antioxidant and antibacterial activities of Thymus schimperi (Ts), Rhamnus prinoides (Rp), and Justicia schimperiana (Js) from Addis Ababa against MDR-Uropathogenic bacteria. Accordingly, Thymus schimperi had the highest total phenolic (TPC), flavonoid (TFC) and proanthocyanidin content. In Ts, the GC-MS analyses predicted 14 bioactive compounds. And among these, hexanedioic acid, bis(2-ethylhexyl) ester, thymol, and o-cymen-5-ol were the most predominant compounds, respectively. Six compounds were also predicted in Rp, where hexanedioic acid, bis(2-ethylhexyl) ester, ß-D-glucopyranoside, methyl, and desulphosinigrin were the predominant, respectively. Whereas in the Js extract, five bioactive compounds were predicted, with hexanedioic acid, mono (2-ethylhexyl) ester, debrisoquine, and 8,11,14-heptadecatrienoate, methyl ester being predominant compounds, respectively. The extracts' TPC showed a strong negative correlation with the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay (r = -0.999; p = 0.023). In addition, the TFC correlated significantly with the ABTS (2,2'-azino-di-(3-ethylbenzthiazoline sulfonic acid)) assay (r = 0.999; p = 0.032). Thymus schimperi showed the highest antibacterial activity against clinical isolates of Escherichia coli and Klebsiella pneumoniae ESBL at 1000 mg/mL, and Ts had the lowest MIC (4 mg/mL) among evaluated extracts against E. coli (ATCC25922). In conclusion, Ts and Rp possess higher predicted bioactive molecules, including antioxidant and antibacterial activities, which are potentially useful in treating urinary tract infections.

Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.

BACKGROUND: The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer. METHODS: In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete. FINDINGS: Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction). INTERPRETATION: Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials. FUNDING: F Hoffmann-La Roche.

Hypoxia inhibits colonic uptake of the microbiota-generated forms of vitamin B1 via HIF-1α-mediated transcriptional regulation of their transporters.

Hypoxia exerts profound effects on cell physiology, but its effect on colonic uptake of the microbiota-generated forms of vitamin B1 (i.e., thiamin pyrophosphate [TPP] and free thiamine) has not been described. Here, we used human colonic epithelial NCM460 cells and human differentiated colonoid monolayers as in vitro and ex vivo models, respectively, and were subjected to either chamber (1% O2, 5% CO2, and 94% N2) or chemically (desferrioxamine; 250 µM)-induced hypoxia followed by determination of different physiological-molecular parameters. We showed that hypoxia causes significant inhibition in TPP and free thiamin uptake by colonic NCM460 cells and colonoid monolayers; it also caused a significant reduction in the expression of TPP (SLC44A4) and free thiamin (SLC19A2 and SLC19A3) transporters and in activity of their gene promoters. Furthermore, hypoxia caused a significant induction in levels of hypoxia-inducible transcription factor (HIF)-1α but not HIF-2α. Knocking down HIF-1α using gene-specific siRNAs in NCM460 cells maintained under hypoxic conditions, on the other hand, led to a significant reversal in the inhibitory effect of hypoxia on TPP and free thiamin uptake as well as on the expression of their transporters. Finally, a marked reduction in level of expression of the nuclear factors cAMP responsive element-binding protein 1 and gut-enriched Krüppel-like factor 4 (required for activity of SLC44A4 and SLC19A2 promoters, respectively) was observed under hypoxic conditions. In summary, hypoxia causes severe inhibition in colonic TPP and free thiamin uptake that is mediated at least in part via HIF-1α-mediated transcriptional mechanisms affecting their respective transporters.

Association of Apolipoprotein E ɛ4 Allele with Enlarged Perivascular Spaces.

OBJECTIVE: Enlarged perivascular spaces have emerged as markers of cerebral small vessel disease and are linked to perivascular drainage dysfunction. The apolipoprotein E-ɛ4 (APOE-ɛ4) allele is the strongest genetic risk factor for cerebral amyloid angiopathy and Alzheimer's neuropathology, but the underlying mechanisms remain unclear. We studied the relationship between APOE-ɛ4 and the topography and burden of enlarged perivascular spaces to elucidate underlying mechanisms between APOE-ɛ4 and adverse clinical outcomes. METHODS: We included 3,564 Framingham Heart Study participants with available genotypes and magnetic resonance imaging. Enlarged perivascular spaces in the basal ganglia and centrum semiovale were rated using a validated scale. We related APOE-ɛ4 allele presence to high burden of enlarged perivascular spaces in each region and a mixed score reflecting high burden in both regions using multivariable logistic regression. Exploratory analyses incorporated presence of cerebral microbleeds and assessed effect modification by hypertension. RESULTS: Mean age was 60.7 years (SD = 14.6), 1,644 (46.1%) were men, 1,486 (41.8%) were hypertensive, and 836 (23.5%) participants were APOE-ɛ4 carriers. APOE-ɛ4 was associated with high burden of enlarged perivascular spaces in the centrum semiovale (odds ratio [OR] = 1.45, 95% confidence interval [CI] = 1.16, 1.81) and mixed regions (OR = 1.37, 95% CI = 1.11, 1.68). Associations were slightly stronger in hypertensive subjects. INTERPRETATION: The APOE-ɛ4 allele plays a modest role in the burden of enlarged perivascular spaces in the centrum semiovale. Further studies are needed to clarify the underlying small vessel disease type in community-dwelling individuals with predominant centrum semiovale enlarged perivascular spaces, which may be hypertensive angiopathy in our sample. ANN NEUROL 2022;92:23-31.

Magnesium homeostasis in deoxygenated sickle erythrocytes is modulated by endothelin-1 via Na+ /Mg2+ exchange.

Painful crises in sickle cell disease (SCD) are associated with increased plasma cytokines levels, including endothelin-1 (ET-1). Reduced red cell magnesium content, mediated in part by increased Na+ /Mg2+ exchanger (NME) activity, contributes to erythrocyte K+ loss, dehydration and sickling in SCD. However, the relationship between ET-1 and the NME in SCD has remained unexamined. We observed increased NME activity in sickle red cells incubated in the presence of 500 nM ET-1. Deoxygenation of sickle red cells, in contrast, led to decreased red cell NME activity and cellular dehydration that was reversed by the NME inhibitor, imipramine. Increased NME activity in sickle red cells was significantly blocked by pre-incubation with 100 nM BQ788, a selective blocker of ET-1 type B receptors. These results suggest an important role for ET-1 and for cellular magnesium homeostasis in SCD. Consistent with these results, we observed increased NME activity in sickle red cells of three mouse models of sickle cell disease greater than that in red cells of C57BL/J6 mice. In vivo treatment of BERK sickle transgenic mice with ET-1 receptor antagonists reduced red cell NME activity. Our results suggest that ET-1 receptor blockade may be a promising therapeutic approach to control erythrocyte volume and magnesium homeostasis in SCD and may thus attenuate or retard the associated chronic inflammatory and vascular complications of SCD.

Behaviour of aerosols and their role in the transmission of SARS-CoV-2; a scoping review.

Covid-19 has triggered an unprecedented global health crisis. The highly contagious nature and airborne transmission route of SARS-CoV-2 virus requires extraordinary measures for its containment. It is necessary to know the behaviour of aerosols carrying the virus to avoid this contagion. This paper describes the behaviour of aerosols and their role in the transmission of SARS-CoV-2 according to published models using a scoping review based on the PubMed, Scopus, and WOS databases. From an initial 530 references, 9 papers were selected after applying defined inclusion criteria. The results reinforce the airborne transmission route as a means of contagion of the virus and recommend the use of face masks, extending social distance to more than 2 metres, and natural ventilation of enclosed spaces as preventive measures. These results contribute to a better understanding of SARS-CoV-2 and help design effective strategies to prevent its spread.

Corrosion Assessment in Reinforced Concrete Structures by Means of Embedded Sensors and Multivariate Analysis-Part 1: Laboratory Validation.

Reinforced Concrete Structures (RCS) are a fundamental part of a country's civil infrastructure. However, RCSs are often affected by rebar corrosion, which poses a major problem because it reduces their service life. The traditionally used inspection and management methods applied to RCSs are poorly operative. Structural Health Monitoring and Management (SHMM) by means of embedded sensors to analyse corrosion in RCSs is an emerging alternative, but one that still involves different challenges. Examples of SHMM include INESSCOM (Integrated Sensor Network for Smart Corrosion Monitoring), a tool that has already been implemented in different real-life cases. Nevertheless, work continues to upgrade it. To do so, the authors of this work consider implementing a new measurement procedure to identify the triggering agent of the corrosion process by analysing the double-layer capacitance of the sensors' responses. This study was carried out on reinforced concrete specimens exposed for 18 months to different atmospheres. The results demonstrate the proposed measurement protocol and the multivariate analysis can differentiate the factor that triggers corrosion (chlorides or carbonation), even when the corrosion kinetics are similar. Data were validated by principal component analysis (PCA) and by the visual inspection of samples and rebars at the end of the study.

Higher Dietary Inflammatory Index scores are associated with brain MRI markers of brain aging: Results from the Framingham Heart Study Offspring cohort.

INTRODUCTION: We investigated cross-sectional associations between the Dietary Inflammatory Index (DII) and measures of brain volume and cerebral small vessel disease among participants of the Framingham Heart Study Offspring cohort. METHODS: A total of 1897 participants (mean ± standard deviation, age 62±9) completed Food Frequency Questionnaires and brain magnetic resonance imaging (MRI). RESULTS: Higher (pro-inflammatory) DII scores, averaged across a maximum of three time points, were associated with smaller total brain volume (beta ± standard error: -0.16 ± 0.03; P < .0001) after adjustment for demographic, clinical, and lifestyle covariates. In addition, higher DII scores were associated with smaller total gray matter volume (-0.08 ± 0.03; P = .003) and larger lateral ventricular volume (0.04 ± 0.02; P = .03). No associations were observed with other brain MRI measures. DISCUSSION: Our findings showed associations between higher DII scores and global brain MRI measures. As we are one of the first groups to report on the associations between higher DII scores and brain volume, replication is needed to confirm our findings.

Effects of Mineralocorticoid Receptor Blockade and Statins on Kidney Injury Marker 1 (KIM-1) in Female Rats Receiving L-NAME and Angiotensin II.

Kidney injury molecule-1 (KIM-1) is a biomarker of renal injury and a predictor of cardiovascular disease. Aldosterone, via activation of the mineralocorticoid receptor, is linked to cardiac and renal injury. However, the impact of mineralocorticoid receptor activation and blockade on KIM-1 is uncertain. We investigated whether renal KIM-1 is increased in a cardiorenal injury model induced by L-NAME/ANG II, and whether mineralocorticoid receptor blockade prevents the increase in KIM-1. Since statin use is associated with lower aldosterone, we also investigated whether administering eiSther a lipophilic statin (simvastatin) or a hydrophilic statin (pravastatin) prevents the increase in renal KIM-1. Female Wistar rats (8-10 week old), consuming a high salt diet (1.6% Na+), were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/mL in drinking water)/ANG II (225 ug/kg/day on days 12-14); L-NAME/ANG II + eplerenone (100 mg/kg/day p.o.); L-NAME/ANG II + pravastatin (20 mg/kg/day p.o.); L-NAME/ANG II + simvastatin (20 mg/kg/day p.o.). Groups treated with L-NAME/ANG II had significantly higher blood pressure, plasma and urine aldosterone, cardiac injury/stroke composite score, and renal KIM-1 than the control group. Both eplerenone and simvastatin reduced 24-h urinary KIM-1 (p = 0.0046, p = 0.031, respectively) and renal KIM-1 immunostaining (p = 0.004, p = 0.037, respectively). Eplerenone also reduced renal KIM-1 mRNA expression (p = 0.012) and cardiac injury/stroke composite score (p = 0.04). Pravastatin did not affect these damage markers. The 24-h urinary KIM-1, renal KIM-1 immunostaining, and renal KIM-1 mRNA expression correlated with cardiac injury/stroke composite score (p < 0.0001, Spearman ranked correlation = 0.69, 0.66, 0.59, respectively). In conclusion, L-NAME/ANG II increases renal KIM-1 and both eplerenone and simvastatin blunt this increase in renal KIM-1.

Drug Reprofiling to Identify Potential HIV-1 Protease Inhibitors.

The use of protease inhibitors in human immunodeficiency virus type 1 (HIV-1) treatment is limited by adverse effects, including metabolic complications. To address these challenges, efforts are underway in the pursuit of more potent and less toxic HIV-1 protease inhibitors. Repurposing existing drugs offers a promising avenue to expedite the drug discovery process, saving both time and costs compared to conventional de novo drug development. This study screened FDA-approved and investigational drugs in the DrugBank database for their potential as HIV-1 protease inhibitors. Molecular docking studies and cell-based assays, including anti-HIV-1 in vitro assays and XTT cell viability tests, were conducted to evaluate their efficacy. The study findings revealed that CBR003PS, an antibiotic currently in clinical use, and CBR013PS, an investigational drug for treating endometriosis and uterine fibroids, exhibited significant binding affinity to the HIV-1 protease with high stability. Their EC50 values, measured at 100% cell viability, were 9.4 nM and 36.6 nM, respectively. Furthermore, cell-based assays demonstrated that these two compounds showed promising results, with therapeutic indexes higher than 32. In summary, based on their favorable therapeutic indexes, CBR003PS and CBR013PS show potential for repurposing as HIV-1 protease inhibitors.

Antioxidant and Anti-Inflammatory Compounds from Edible Plants with Anti-Cancer Activity and Their Potential Use as Drugs.

Food is our daily companion, performing numerous beneficial functions for our bodies. Many of them can help to alleviate or prevent ailments and diseases. In this review, an extensive bibliographic search is conducted in various databases to update information on unprocessed foods with anti-inflammatory and antioxidant properties that can aid in treating diseases such as cancer. The current state of knowledge on inflammatory processes involving some interleukins and tumor necrosis factor-alpha (TNF-α) is reviewed. As well as unprocessed foods, which may help reduce inflammation and oxidative stress, both of which are important factors in cancer development. Many studies are still needed to take full advantage of the food products we use daily.