Nascent shifts in renal cellular metabolism, structure, and function due to chronic empagliflozin in prediabetic mice.

Sodium-glucose cotransporter, type 2 inhibitors (SGLT2i) are emerging as the gold standard for treatment of type 2 diabetes (T2D) with renal protective benefits independent of glucose lowering. We took a high-level approach to evaluate the effects of the SGLT2i, empagliflozin (EMPA) on renal metabolism and function in a prediabetic model of metabolic syndrome. Male and female 12-wk-old TallyHo (TH) mice, and their closest genetic lean strain (Swiss-Webster, SW) were treated with a high-milk-fat diet (HMFD) plus/minus EMPA (@0.01%) for 12-wk. Kidney weights and glomerular filtration rate were slightly increased by EMPA in the TH mice. Glomerular feature analysis by unsupervised clustering revealed sexually dimorphic clustering, and one unique cluster relating to EMPA. Periodic acid Schiff (PAS) positive areas, reflecting basement membranes and mesangium were slightly reduced by EMPA. Phasor-fluorescent life-time imaging (FLIM) of free-to-protein bound NADH in cortex showed a marginally greater reliance on oxidative phosphorylation with EMPA. Overall, net urine sodium, glucose, and albumin were slightly increased by EMPA. In TH, EMPA reduced the sodium phosphate cotransporter, type 2 (NaPi-2), but increased sodium hydrogen exchanger, type 3 (NHE3). These changes were absent or blunted in SW. EMPA led to changes in urine exosomal microRNA profile including, in females, enhanced levels of miRs 27a-3p, 190a-5p, and 196b-5p. Network analysis revealed "cancer pathways" and "FOXO signaling" as the major regulated pathways. Overall, EMPA treatment to prediabetic mice with limited renal disease resulted in modifications in renal metabolism, structure, and transport, which may preclude and underlie protection against kidney disease with developing T2D.NEW & NOTEWORTHY Renal protection afforded by sodium glucose transporter, type 2 inhibitors (SGLT2i), e.g., empagliflozin (EMPA) involves complex intertwined mechanisms. Using a novel mouse model of obesity with insulin resistance, the TallyHo/Jng (TH) mouse on a high-milk-fat diet (HMFD), we found subtle changes in metabolism including altered regulation of sodium transporters that line the renal tubule. New potential epigenetic determinants of metabolic changes relating to FOXO and cancer signaling pathways were elucidated from an altered urine exosomal microRNA signature.

Could poor glycaemic control be a predictor of walking speed decline in older adults? Evidence from the English Longitudinal Study of Ageing.

AIM: Although diabetes is a risk factor for walking speed decline in older adults, it remains unclear how glycaemic control [assessed by glycated haemoglobin (HbA1c)] might affect the long-term trajectories of walking speed. We investigated whether the glycaemic control status accelerates the walking speed decline and whether this decline differs depending on previous mobility conditions. MATERIALS AND METHODS: In total, 3202 individuals aged ≥60 years from the English Longitudinal Study of Ageing (ELSA) were classified at baseline and after 4 and 8 years of follow-up according to glycaemic control status as 'without diabetes' (no self-reported diabetes and HbA1c <6.5%), 'good glycaemic control' (self-reported diabetes and HbA1c ≥6.5% and <7.0%) and 'poor glycaemic control' (PGC) (self-reported diabetes and HbA1c ≥7.0%). The generalized linear mixed models verified the walking speed trajectories in m/s. A second analysis was performed, including only participants without slowness at baseline (>0.8 m/s). RESULTS: Compared with the status 'without diabetes', the annual walking speed decline was -0.015 m/s for PGC and -0.011 m/s for good glycaemic control, totalling -0.160 and -0.130 m/s, respectively, over 8 years. Among those without slowness at baseline, only PGC had a significant walking speed decline, corresponding to -0.014 m/s per year and -0.222 m/s over 8 years. CONCLUSIONS: Poor glycaemic control is a discriminator of walking speed decline in older adults, regardless of previous mobility conditions. It may serve as an early screening tool for those at risk of decreased functional performance later in life.

Delivery of hereditary cancer genetics services to patients newly diagnosed with ovarian and endometrial cancers at three gynecologic oncology clinics in the USA, Brazil, and Mexico.

OBJECTIVE: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic. METHODS: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer (microsatellite instability/immunohistochemistry, MSI/IHC), referral to genetics services for patients with ovarian cancer, completed genetics consultations, and germline genetic testing for patients with ovarian and endometrial cancers. Timeliness was calculated as the average number of days between diagnosis and the relevant delivery metric. Descriptive statistics were used to analyze data. RESULTS: In total, 1195 patients (596 with ovarian cancer, 599 with endometrial cancer) were included in the analysis, and rates of genetics service delivery varied by clinic. For patients with ovarian cancer, referral rates ranged by clinic from 32.6% to 89.5%; 30.4-65.1% of patients completed genetics consultation and 32.6-68.7% completed genetic testing. The timeliness to genetic testing for patients with ovarian cancer ranged by clinic from 107 to 595 days. A smaller proportion of patients with endometrial cancer completed MSI/IHC testing (10.0-69.2%), with the average time to MSI/IHC ranging from 15 to 282 days. Rates of genetics consultation among patients with endometrial cancer ranged by clinic from 10.8% to 26.0% and 12.5-16.6% completed genetic testing. CONCLUSIONS: All clinics successfully established baseline rates and timeliness of delivering hereditary cancer genetics services to patients with ovarian and endometrial cancers. Lower rates of delivering genetics services to patients with endometrial cancer warrant additional research and quality improvement efforts.

Is dynapenic abdominal obesity a risk factor for cardiovascular mortality? A competing risk analysis.

BACKGROUND: Dynapenic abdominal obesity has been shown as a risk factor for all-cause mortality in older adults. However, there is no evidence on the association between this condition and cardiovascular mortality. OBJECTIVE: We aimed to investigate whether dynapenic abdominal obesity is associated with cardiovascular mortality in individuals aged 50 and older. METHODS: A longitudinal study with an 8-year follow-up was conducted involving 7,030 participants of the English Longitudinal Study of Ageing study. Abdominal obesity and dynapenia were respectively defined based on waist circumference (> 102 cm for men and > 88 cm for women) and grip strength (< 26 kg for men and < 16 kg for women). The sample was divided into four groups: non-dynapenic/non-abdominal obesity (ND/NAO), non-dynapenic/abdominal obesity (ND/AO), dynapenic/non-abdominal obesity (D/NAO) and dynapenic/abdominal obesity (D/AO). The outcome was cardiovascular mortality. The Fine-Grey regression model was used to estimate the risk of cardiovascular mortality as a function of abdominal obesity and dynapenia status in the presence of competing events controlled by socio-demographic, behavioural and clinical variables. RESULTS: The risk of cardiovascular mortality was significantly higher in individuals with D/AO compared with ND/NAO (SHR 1.85; 95% CI: 1.15-2.97). D/NAO was also associated with cardiovascular mortality (SHR: 1.62; 95% CI: 1.08-2.44). CONCLUSION: Dynapenic abdominal obesity is associated with cardiovascular mortality, with a larger effect size compared to dynapenia alone in individuals older than 50 years. Thus, prevention strategies and clinical interventions that enable mitigating the harmful effects of these conditions should be adopted to diminish such risk.

Erythema elevatum diutinum in a patient with rheumatoid arthritis.

Erythema elevatum diutinum (EED) is a rare cutaneous neutrophilic vasculitis with many associated diseases reported in the literature. We report a 65-year-old woman with painful and itchy lesions on her elbows, hands, knees, and foot for a year. Histopathologic examination confirmed the diagnosis of erythema elevatum diutinum and treatment with dapsone produced significant clinical improvement within few weeks. Erythema elevatum diutinum is a rare disease that should be considered in patients with violaceous nodular plaques located over the extensor regions of the limbs. Knowledge of this unusual pathology and its association helps to avoid misdiagnosis and late treatment.

Caloric Restriction and Cardiovascular Health: the Good, the Bad, and the Renin-Angiotensin System.

Much excitement exists over the cardioprotective and life-extending effects of caloric restriction (CR). This review integrates population studies with experimental animal research to address the positive and negative impact of mild and severe CR on cardiovascular physiology and pathophysiology, with a particular focus on the renin-angiotensin system (RAS). We also highlight the gaps in knowledge and areas ripe for future physiological research.

Are Serum 25-Hydroxyvitamin D Deficiency and Insufficiency Risk Factors for the Incidence of Dynapenia?

Epidemiological evidence showing the association between low 25(OH)D and age-related reduction in neuromuscular strength (dynapenia) is a paucity and controversial and, to date, the effect of osteoporosis and vitamin D supplementation on these associations has not been measured. Thus, we analyze whether serum 25(OH)D deficiency and insufficiency are risk factors for the incidence of dynapenia in individuals aged 50 or older and whether osteoporosis or vitamin D supplementation modify these associations. For that, 3205 participants of the ELSA study who were non-dynapenic at baseline were followed for 4 years. Vitamin D was measured at baseline by the serum concentration of 25(OH)D and classified as sufficient (> 50 nmol/L), insufficient (≥ 30 and ≤ 50 nmol/L) or deficient (< 30 nmol/L). The incidence of dynapenia was determined by a grip strength < 26 kg for men and < 16 kg for women at the end of the 4-year follow-up. Poisson regression models were adjusted by sociodemographic, behavioral, clinical and biochemical characteristics. Serum 25(OH)D deficient was a risk factor for the incidence of dynapenia (IRR = 1.70; 95% CI 1.04-2.79). When only individuals without osteoporosis and those who did not use vitamin D supplementation were analyzed, both serum 25(OH)D deficiency (IRR = 1.78; 95% CI 1.01-3.13) and insufficiency (IRR = 1.77; 95% CI 1.06-2.94) were risk factors for the incidence of dynapenia. In conclusion, a serum level of 25(OH)D < 30 nmol/L is a risk factor for the incidence of dynapenia. Among individuals without osteoporosis and those who do not take vitamin D supplementation, the threshold of risk is higher (≤ 50 nmol/L).

The effect of seed-dispersal timing on seedling recruitment is modulated by environmental conditions that vary across altitude in a threatened palm.

BACKGROUND AND AIMS: The timing of seed dispersal determines the environmental conditions that plants face during early life stages. In seasonal environments, selection is expected to favour dispersal timing that is matched to environmental conditions suitable for successful recruitment. Our aim here was to test whether the timing of seed dispersal influences seedling establishment success in two populations of Euterpe edulis that are located at contrasting altitudes, have different seed-dispersal phenologies and are subjected to distinct climatic conditions. METHODS: We sowed E. edulis seeds in contrasting altitudes on different dates, and monitored seed germination, emergence and seedling establishment at each altitude over 4 years. At the high-altitude site, five seed-dispersal cohorts were established during the natural dispersal period. At the low-altitude site, three seed-dispersal cohorts were established during natural dispersal, and two were established either before or after natural dispersal. KEY RESULTS: At the high-altitude site, seed-dispersal timing did not affect seed germination, seedling emergence or seedling establishment success. In contrast, at the low-altitude site, late seed dispersal near the end of the wet season resulted in a lower probability of seedling establishment, possibly due to the exposure of seeds, germinants and seedlings to unfavourable drought conditions. In addition, at the low-altitude site, the natural seed-dispersal period was poorly matched to favourable environmental conditions for seedling establishment. CONCLUSIONS: The greater effect of seed-dispersal timing on seedling establishment at the low-altitude site is probably related to a more seasonal and drought-prone environment that favours a restricted period of seed dispersal. The magnitude of the effect of dispersal timing on seedling establishment success was modulated by environmental conditions that vary across altitude. Furthermore, reproductive phenology appears to be subject to more intense selection at the lower limit of the altitudinal range, due to a more restrictive window of opportunity for successful seedling establishment.

Direct Synthesis of α-Sulfenylated Ketones under Electrochemical Conditions.

We investigated the electrochemical sulfenylation reaction in both batch and continuous flow regimes, involving thiophenols/thiols and enol-acetates to yield α-sulfenylated ketones, without using additional oxidants or catalysts. Studies with different electrolytes were also performed, revealing that quaternary ammonium salts are the best mediators for this reaction. Notably, during the study of the reaction scope, a Boc-cysteine proved to be extremely tolerant to our protocol, thus increasing its relevance. The methodology also proved to be scalable in both batch and continuous flow conditions, opening up possibilities for further studies since these relevant functional groups are important moieties in organic synthesis.

Lipid profile, apolipoproteins A-1 and B in owl monkeys (Aotus infulatus) in captivity.

BACKGROUND: Owl monkeys (Aotus infulatus) are frequently affected by heart diseases and, as in humans, dyslipidemia is one of the predisposing factors for adverse cardiovascular events. In view of this, the study of the lipid profile and plasma apolipoproteins can contribute to the clinical management of this neotropical primate species. METHODS: Lipid profile as well as A-1 and B apolipoprotein values were analyzed in 60 owl monkeys, studying their relationship with body biometry and the presence of cardiac alterations. RESULTS: Animals suspected of having heart disease did not show significant differences (p < .05) in terms of biometry or in relation to lipid profile and apolipoproteins A-1 and B values; however, higher values of LDL and ApoB and ApoB/ApoA-1 were observed in this group. CONCLUSIONS: This study is the first to describe the lipid profile and apolipoprotein values in owl monkeys, and further work will be needed to better elucidate the worthiness of LDL, ApoB, and the ApoB/ApoA-1 ratio in this primate species.

In Vitro Study of Cytotoxic Mechanisms of Alkylphospholipids and Alkyltriazoles in Acute Lymphoblastic Leukemia Models.

This study investigates the efficacy of miltefosine, alkylphospholipid, and alkyltriazolederivative compounds against leukemia lineages. The cytotoxic effects and cellular and molecular mechanisms of the compounds were investigated. The inhibitory potential and mechanism of inhibition of cathepsins B and L, molecular docking simulation, molecular dynamics and binding free energy evaluation were performed to determine the interaction of cathepsins and compounds. Among the 21 compounds tested, C9 and C21 mainly showed cytotoxic effects in Jurkat and CCRF-CEM cells, two human acute lymphoblastic leukemia (ALL) lineages. Activation of induced cell death by C9 and C21 with apoptotic and necrosis-like characteristics was observed, including an increase in annexin-V+propidium iodide-, annexin-V+propidium iodide+, cleaved caspase 3 and PARP, cytochrome c release, and nuclear alterations. Bax inhibitor, Z-VAD-FMK, pepstatin, and necrostatin partially reduced cell death, suggesting that involvement of the caspase-dependent and -independent mechanisms is related to cell type. Compounds C9 and C21 inhibited cathepsin L by a noncompetitive mechanism, and cathepsin B by a competitive and noncompetitive mechanism, respectively. Complexes cathepsin-C9 and cathepsin-C21 exhibited significant hydrophobic interactions, water bridges, and hydrogen bonds. In conclusion, alkyltriazoles present cytotoxic activity against acute lymphoblastic lineages and represent a promising scaffold for the development of molecules for this application.

Male bias in ACE2 basic science research: missed opportunity for discovery in the time of COVID-19.

Throughout the world, including the United States, men have worse outcomes from COVID-19 than women. SARS-CoV-2, the causative virus of the COVID-19 pandemic, uses angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. ACE2 is a member of the renin-angiotensin system (RAS) and plays an important role in counteracting the harmful effects mediated by the angiotensin type 1 receptor. Therefore, we conducted Ovid MEDLINE and Embase database searches of basic science studies investigating the impact of the biological variable of sex on ACE2 expression and regulation from 2000, the year ACE2 was discovered, through December 31, 2020. Out of 2,131 publications, we identified 853 original research articles on ACE2 conducted in primary cells, tissues, and/or whole mammals excluding humans. The majority (68.7%) of these studies that cited the sex of the animal were conducted in males, while 11.2% were conducted solely in females; 9.26% compared ACE2 between the sexes, while 10.8% did not report the sex of the animals used. General findings are that sex differences are tissue-specific and when present, are dependent upon gonadal state. Renal, cardiac, and adipose ACE2 is increased in both sexes under experimental conditions that model co-morbidities associated with worse COVID-19 outcomes including hypertension, obesity, and renal and cardiovascular diseases; however, ACE2 protein was generally higher in the males. Studies in Ace2 knockout mice indicate ACE2 plays a greater role in protecting the female from developing hypertension than the male. Studying the biological variable of sex in ACE2 research provides an opportunity for discovery in conditions involving RAS dysfunction and will shed light on sex differences in COVID-19 severity.

Proteinase-activated receptor-2 (PAR2) on blood pressure and electrolyte handling in the late pregnant rat.

NEW FINDINGS: What is the central question of this study? Pregnancy requires marked renal sodium and potassium retention and cumulative plasma volume expansion, in the setting of reduced blood pressure. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in virgin and normal pregnant rats. What is the main finding and its importance? PAR2 expression and sensitivity to activation are increased in pregnancy. This implicates a possible role for PAR2 in supporting the renal/vascular adaptations of pregnancy required for normal maternal plasma volume expansion. ABSTRACT: A healthy pregnancy involves renal and systemic haemodynamic adaptations, which allow renal sodium and potassium retention and cumulative plasma volume expansion, accompanied by a decline in blood pressure attributable to a reduction in the total peripheral vascular resistance. When these adaptations do not occur, pregnancy is compromised. The mechanisms permitting these opposing adaptations are largely unknown. Research in male rodents has shown that activation of PAR2 can produce peripheral vasodilatation, stimulate renal sodium chloride reabsorption and inhibit renal potassium secretion. Here, we investigate PAR2 activation in female virgin and normal late pregnant (LP) rats. We measured the mRNA expression of PAR2 in the renal cortex, outer medulla and inner medulla of virgin and LP rats using quantitative real-time PCR. We also measured in vivo blood pressure, natriuretic and kaliuretic responses to PAR2-activating peptide (SLIGRL-NH2 ) in anaesthetized virgin and LP rats. We found that PAR2 mRNA was increased in the inner medulla of LP rats. We also found that LP rats had larger decreases in blood pressure and increases in net sodium retention compared with virgin rats. These findings suggest that pregnancy enhances sensitivity to the blood pressure-lowering and sodium-retaining effects of PAR2.

Dynapenia, abdominal obesity or both: which accelerates the gait speed decline most?

OBJECTIVE: to investigate whether the combination of dynapenia and abdominal obesity is worse than these two conditions separately regarding gait speed decline over time. METHODS: a longitudinal study was conducted involving 2,294 individuals aged 60 years or older free of mobility limitation at baseline (gait speed >0.8 m/s) who participated in the English Longitudinal Study of Ageing. Dynapenia was determined as a grip strength <26 kg for men and <16 kg for women. Abdominal obesity was determined as a waist circumference >102 cm for men and >88 cm for women. The participants were divided into four groups: non-dynapenic/non-abdominal obese (ND/NAO); only abdominal obese (AO); only dynapenic (D) and dynapenic/abdominal obese (D/AO). Generalised linear mixed models were used to analyse gait speed decline (m/s) as a function of dynapenia and abdominal obesity status over an 8-year follow-up period. RESULTS: over time, only the D/AO individuals had a greater gait speed decline (-0.013 m/s per year, 95% CI: -0.024 to -0.002; P < 0.05) compared to ND/NAO individuals. Neither dynapenia nor abdominal obesity only was associated with gait speed decline. CONCLUSION: dynapenic abdominal obesity is associated with accelerated gait speed decline and is, therefore, an important modifiable condition that should be addressed in clinical practice through aerobic and strength training for the prevention of physical disability in older adults.

Young haploidentical donor versus fully matched elderly donor: An observational study on patients aged 50 years or older underwent hematopoietic progenitor cells transplantation.

INTRODUCTION: Stem cell transplantation has been a therapeutic option for increasingly older patients but the search for the donor is an additional question in this context. Currently the ideal donor is a sibiling with fully compatible human leukocyte antigens, but when it is an elderly patient there is a high probability that this donor is also elderly, and the donor age has been related to worse outcomes and the possible comorbidities may render the donor ineligible. OBJECTIVE: To compare, in patients aged 50 years or older, the overall survival of patients whose donor had haploidentical HLA compatibility and under 50 years of age ("young" donor) versus patients whose donor had a total HLA compatibility and 50 years of age or older ("elderly" donor). METHODS: This is a consecutive retrospective descriptive observational epidemiological study. All patients were treated during the period from January, 2010 to April, 2019. Overall survival of patients 50 years of age and older was the primary outcome of the study. RESULT: We included 53 patients. In the multivariate analysis we found no statistically significant difference in overall survival between patients whose donor had fully HLA compatible aged 50 years and older and patients whose donor had haploidentical HLA compatible and aged up to 50 years (p = 0.135). CONCLUSION: The results obtained in the study show that for patients aged 50 years or older, a donor with haploidentical human leukocyte antigen compatibility and age below 50 years can be chosen without impairing overall survival.

Actions and Roles of FSH in Germinative Cells.

Follicle stimulating hormone (FSH) is produced by the pituitary gland in a coordinated hypothalamic-pituitary-gonadal (HPG) axis event, plays important roles in reproduction and germ cell development during different phases of reproductive development (fetal, neonatal, puberty, and adult life), and is consequently essential for fertility. FSH is a heterodimeric glycoprotein hormone of two dissociable subunits, α and ß. The FSH ß-subunit (FSHß) function starts upon coupling to its specific receptor: follicle-stimulating hormone receptor (FSHR). FSHRs are localized mainly on the surface of target cells on the testis and ovary (granulosa and Sertoli cells) and have recently been found in testicular stem cells and extra-gonadal tissue. Several reproduction disorders are associated with absent or low FSH secretion, with mutation of the FSH ß-subunit or the FSH receptor, and/or its signaling pathways. However, the influence of FSH on germ cells is still poorly understood; some studies have suggested that this hormone also plays a determinant role in the self-renewal of germinative cells and acts to increase undifferentiated spermatogonia proliferation. In addition, in vitro, together with other factors, it assists the process of differentiation of primordial germ cells (PGCLCs) into gametes (oocyte-like and SSCLCs). In this review, we describe relevant research on the influence of FSH on spermatogenesis and folliculogenesis, mainly in the germ cell of humans and other species. The possible roles of FSH in germ cell generation in vitro are also presented.

Association of Serum 25-Hydroxyvitamin D Deficiency with Risk of Incidence of Disability in Basic Activities of Daily Living in Adults >50 Years of Age.

BACKGROUND: Vitamin D deficiency compromises muscle function and is related to the etiology of several clinical conditions that can contribute to the development of disability. However, there are few epidemiological studies investigating the association between vitamin D deficiency and the incidence of disability. OBJECTIVES: We aimed to assess whether vitamin D deficiency is associated with the incidence of disability in basic activities of daily living (BADL) and to verify whether there are sex differences in this association. METHODS: A 4-y follow-up study was conducted involving individuals aged 50 y or older who participated in ELSA (English Longitudinal Study of Ageing). The sample consisted of 4814 participants free of disability at baseline according to the modified Katz Index. Vitamin D was assessed by serum 25-hydroxyvitamin D [25(OH)D] concentrations and the participants were classified as sufficient (>50 nmol/L), insufficient (>30 to ≤50 nmol/L), or deficient (≤30 nmol/L). Sociodemographic, behavioral, and clinical characteristics were also investigated. BADL were re-evaluated after 2 and 4 y of follow-up. The report of any difficulty to perform ≥1 BADL was considered as an incident case of disability. Poisson models stratified by sex and controlled for sociodemographic, behavioral, and clinical characteristics were carried out. RESULTS: After 4-y follow-up, deficient serum 25(OH)D was a risk factor for the incidence of BADL disability in both women (IRR: 1.53; 95% CI: 1.16, 2.03) and men (IRR: 1.44; 95% CI: 1.02, 2.02). However, insufficient serum 25(OH)D was not a risk factor for the incidence of BADL disability in either men or women. CONCLUSIONS: Independently of sex, deficient serum 25(OH)D concentrations were associated with increased risk of incidence of BADL disability in adults >50 y old and should be an additional target of clinical strategies to prevent disability in these populations.

The Angiotensin Type 1 Receptor Antagonist Losartan Prevents Ovariectomy-Induced Cognitive Dysfunction and Anxiety-Like Behavior in Long Evans Rats.

Women who have bilateral oophorectomies prior to the age of natural menopause are at increased risk of developing mild cognitive decline, dementia, anxiety, and depressive type disorders. Clinical and animal studies indicate angiotensin type 1 receptor (AT1R) blockers (ARBs) have blood pressure (BP)-independent neuroprotective effects. To investigate the potential use of ARBs in normotensive women at increased risk of developing neurocognitive problems, we studied a rat model of bilateral oophorectomy. Long Evans rats were sham-operated (Sham) or ovariectomized (Ovx) at 3 months of age and immediately treated continuously with vehicle (Veh) or the ARB losartan (Los) for the duration of the experiment. In contrast to many hypertensive rat models, ovariectomy did not increase mean arterial pressure (MAP) in these normotensive rats. Ovariectomized rats spent less time in the open arms of the elevated plus maze (EPM) [(% total time): Veh, 34.1 ± 5.1 vs. Ovx, 18.7 ± 4.4; p < 0.05] and in the center of the open field (OF) [(s): Veh, 11.1 ± 1.7 vs. Ovx, 6.64 ± 1.1; p < 0.05]. They also had worse performance in the novel object recognition (NOR) test as evidenced by a reduction in the recognition index [Veh, 0.62 ± 0.04 vs. Ovx, 0.45 ± 0.03; p < 0.05]. These adverse effects of ovariectomy were prevented by Los. Losartan also reduced plasma corticosterone in Ovx rats compared to Veh treatment [(ng/mL): Ovx-Veh, 238 ± 20 vs. Ovx-Los, 119 ± 42; p < 0.05]. Ovariectomy increased AT1R mRNA expression in the CA3 region of the hippocampus (Hc) [(copies x 106/µg RNA): Sham-Veh, 7.15 ± 0.87 vs. Ovx-Veh, 9.86 ± 1.7; p < 0.05]. These findings suggest the neuroprotective effects of this ARB in normotensive Ovx rats involve reduction of plasma corticosterone and blockade of increased AT1R activity in the hippocampus. These data suggest ARBs have therapeutic potential for normotensive women at increased risk of developing cognitive and behavioral dysfunction due to bilateral oophorectomy prior to the natural age of menopause.

Short-term very low caloric intake causes endothelial dysfunction and increased susceptibility to cardiac arrhythmias and pathology in male rats.

NEW FINDINGS: What is the central question of this study? What are the effects of a 2 week period of severe food restriction on vascular reactivity of resistance arteries and on cardiac structure and function? What is the main finding and its importance? This study showed, for the first time, that a 2 week period of severe food restriction in adult male Fischer rats caused endothelial dysfunction in mesenteric arteries and increased the susceptibility to ischaemia-reperfusion-induced arrhythmias and cardiac pathology. Our findings might have ramifications for cardiovascular risk in people who experience periods of inadequate caloric intake. ABSTRACT: Severe food restriction (sFR) is a common dieting strategy for rapid weight loss. Male Fischer rats were maintained on a control (CT) or sFR (40% of CT food intake) diet for 14 days to mimic low-calorie crash diets. The sFR diet reduced body weight by 16%. Haematocrits were elevated by 10% in the sFR rats, which was consistent with the reduced plasma volume. Mesenteric arteries from sFR rats had increased sensitivity to vasoconstrictors, including angiotensin II [maximum (%): CT, 1.30 ± 0.46 versus sFR, 11.5 ± 1.6; P < 0.0001; n = 7] and phenylephrine [maximum (%): CT, 78.5 ± 2.8 versus sFR, 94.5 ± 1.7; P < 0.001; n = 7] and reduced sensitivity to the vasodilator acetylcholine [EC50 (nm): CT, 49.2 ± 5.2 versus sFR, 71.6 ± 6.8; P < 0.05; n = 7]. Isolated hearts from sFR rats had a 1.7-fold increase in the rate of cardiac arrhythmias in response to ischaemia-reperfusion and more cardiac pathology, including myofibrillar disarray with contractions and cardiomyocyte lysis, than hearts from CT rats. The sFR dietary regimen is similar to very low-calorie commercial and self-help weight-loss programmes, which provide ∼800-1000 kcal day-1 . Therefore, these findings in rats warrant the study of cardiovascular function in individuals who engage in extreme dieting or are subjected to bouts of very low caloric intake for other reasons, such as socioeconomic factors and natural disasters.

Xylella fastidiosa subsp. pauca Strains Fb7 and 9a5c from Citrus Display Differential Behavior, Secretome, and Plant Virulence.

Xylella fastidiosa colonizes the xylem of various cultivated and native plants worldwide. Citrus production in Brazil has been seriously affected, and major commercial varieties remain susceptible to Citrus Variegated Chlorosis (CVC). Collective cellular behaviors such as biofilm formation influence virulence and insect transmission of X. fastidiosa. The reference strain 9a5c produces a robust biofilm compared to Fb7 that remains mostly planktonic, and both were isolated from symptomatic citrus trees. This work deepens our understanding of these distinct behaviors at the molecular level, by comparing the cellular and secreted proteomes of these two CVC strains. Out of 1017 identified proteins, 128 showed differential abundance between the two strains. Different protein families were represented such as proteases, hemolysin-like proteins, and lipase/esterases, among others. Here we show that the lipase/esterase LesA is among the most abundant secreted proteins of CVC strains as well, and demonstrate its functionality by complementary activity assays. More severe symptoms were observed in Nicotiana tabacum inoculated with strain Fb7 compared to 9a5c. Our results support that systemic symptom development can be accelerated by strains that invest less in biofilm formation and more in plant colonization. This has potential application in modulating the bacterial-plant interaction and reducing disease severity.