Post-COVID-19 respiratory sequelae two years after hospitalization: an ambidirectional study.

Background: COVID-19 lung sequelae can impact the course of patient lives. We investigated the evolution of pulmonary abnormalities in post-COVID-19 patients 18-24 months after hospital discharge. Methods: A cohort of COVID-19 patients admitted to the Hospital das Clínicas da Faculdade de Medicina da USP in São Paulo, Brazil, between March and August of 2020, were followed-up 6-12 months after hospital discharge. A subset of patients with pulmonary involvement and chest computed tomography (CT) scans were eligible to participate in this second follow-up (18-24 months). Data was analyzed in an ambidirectional manner, including retrospective data from the hospitalization, and from the first follow-up (6-12 months after discharge), and compared with the prospective data collected in this new follow-up. Findings: From 348 patients eligible, 237 (68%) participated in this follow-up. Among participants, 139 (58%) patients presented ground-glass opacities and reticulations, and 80 (33%) presented fibrotic-like lesions (traction bronchiectasis and architectural distortion). Five (2%) patients improved compared to the 6-12-month assessment, but 20 (25%) of 80 presented worsening of lung abnormalities. For those with relevant assessments on both occasions, comparing the CT findings between this follow-up with the previous assessment, there was an increase in patients with architectural distortion (43 [21%] of 204 vs 57 [28%] of 204, p = 0.0093), as well as in traction bronchiectasis (55 [27%] of 204 vs 69 [34%] of 204, p = 0.0043). Patients presented a persistent functional impairment with demonstrated restrictive pattern in both follow-ups (87 [42%] of 207 vs 91 [44%] of 207, p = 0.76), as well as for the reduced diffusion capacity (88 [42%] of 208 vs 87 [42%] of 208, p = 1.0). Length of hospitalization (OR 1.04 [1.01-1.07], p = 0.0040), invasive mechanical ventilation (OR 3.11 [1.3-7.5] p = 0.011), patient's age (OR 1.03 [1.01-1.06] p = 0.0074 were consistent predictors for development of fibrotic-like lung lesions in post-COVID-19 patients. Interpretation: Post-COVID-19 lung sequelae can persist and progress after hospital discharge, suggesting airways involvement and formation of new fibrotic-like lesions, mainly in patients who were in intensive care unit (ICU). Funding: São Paulo Research Foundation (22/01769-5) and Instituto Todos pela Saúde (C1721).

Post-COVID-19 condition: systemic inflammation and low functional exercise capacity.

Introduction: Post-COVID-19 condition (PCC) is characterised by a plethora of symptoms, with fatigue appearing as the most frequently reported. The alterations that drive both the persistent and post-acute disease newly acquired symptoms are not yet fully described. Given the lack of robust knowledge regarding the mechanisms of PCC we have examined the impact of inflammation in PCC, by evaluating serum cytokine profile and its potential involvement in inducing the different symptoms reported. Methods: In this cross-sectional study, we recruited 227 participants who were hospitalised with acute COVID-19 in 2020 and came back for a follow-up assessment 6-12 months after hospital discharge. The participants were enrolled in two symptomatic groups: Self-Reported Symptoms group (SR, n = 96), who did not present major organ lesions, yet reported several debilitating symptoms such as fatigue, muscle weakness, and persistent loss of sense of smell and taste; and the Self-Reported Symptoms and decreased Pulmonary Function group (SRPF, n = 54), composed by individuals with the same symptoms described by SR, plus diagnosed pulmonary lesions. A Control group (n = 77), with participants with minor complaints following acute COVID-19, was also included in the study. Serum cytokine levels, symptom questionnaires, physical performance tests and general clinical data were obtained in the follow-up assessment. Results: SRPF presented lower IL-4 concentration compared with Control (q = 0.0018) and with SR (q = 0.030), and lower IFN-α2 serum content compared with Control (q = 0.007). In addition, SRPF presented higher MIP-1ß serum concentration compared with SR (q = 0.029). SR presented lower CCL11 (q = 0.012 and q = 0.001, respectively) and MCP-1 levels (q = 0.052 for both) compared with Control and SRPF. SRPF presented lower G-CSF compared to Control (q = 0.014). Female participants in SR showed lower handgrip strength in relation to SRPF (q = 0.0082). Male participants in SR and SRPF needed more time to complete the timed up-and-go test, as compared with men in the Control group (q = 0.0302 and q = 0.0078, respectively). Our results indicate that different PCC symptom profiles are accompanied by distinct inflammatory markers in the circulation. Of particular concern are the lower muscle function findings, with likely long-lasting consequences for health and quality of life, found for both PCC phenotypes.

Differential tempol effects in prostatic cancer: angiogenesis and short- and long-term treatments.

Prostate cancer (PCa) is the second cause of cancer death among men worldwide. Several processes are involved in the development and progression of PCa such as angiogenesis, inflammation and oxidative stress. The present study investigated the effect of short- or long-term Tempol treatment at different stages of prostate adenocarcinoma progression, focusing on angiogenic, proliferative, and stromal remodeling processes in TRAMP mice. The dorsolateral lobe of the prostate of TRAMP mice were evaluated at two different stages of PCa progression; early and late stages. Early stage was again divided into, short- or long-term. 50 mg/kg Tempol dose was administered orally. The results demonstrated that Tempol mitigated the prostate histopathological lesion progressions in the TRAMP mice in all treated groups. However, Tempol increased molecules involved in the angiogenic process such as CD31 and VEGFR2 relative frequencies, particularly in long-term treatment. In addition, Tempol upregulated molecule levels involved in angiogenesis and stromal remodeling process VEGF, TGF-ß1, VE-cadherin and vimentin, particularly, in T8-16 group. Thus, it was concluded that Tempol treatment delayed prostatic lesion progression in the dorsolateral lobe of the TRAMP mice. However, Tempol also led to pro-angiogenic effects and glandular stromal microenvironment imbalance, especially, in the long-term treatment.

Telemedicine in Brazil: Teleconsultations at the Largest University Hospital in the Country.

The coronavirus disease (COVID-19) pandemic leveraged telemedicine worldwide mainly due to the need for social distancing, patient safety, and infection prevention. The Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP) was a key reference site in the treatment of COVID-19 severe cases in the country. To continue patient's health care, it became necessary to increase the number of teleconsultations and standardize it institutionally. Herein, we briefly described how the HCFMUSP improved the teleconsultation health care service during the COVID-19 pandemic, highlighting the implementation of important innovations and the throughout standardization process, including patients and professional workflow. We also detailed the methodology used to implement or improve teleconsultation in a medical/multidisciplinary specialty at HCFMUSP. All these efforts made the HCFMUSP reach the goal of converting 15% of all face-to-face consultations into teleconsultations only in 2021. In addition, there were more than 370,000 teleconsultations until the end of 2022. Our experience has shown that having a supporting team, a digital certification process, and the data integration were key factors toward the successful implementation of the teleconsultation services. We believe that progressing toward teleconsultation will improve the population covered by health care services in Brazil, as well as contribute to a reduction of waiting time, and solving costs to health care institutions and patients. We expect this report of our experience in teleconsultation implementation could inspire and guide other health care institutions in the development of telemedicine.

Lobe-specific responses of TRAMP mice dorsolateral prostate following celecoxib and nintedanib therapy.

Delayed cancer progression in the ventral prostate of the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model has been previously reported upon celecoxib and nintedanib co-administration. Herein, we sought to further investigate the effects of these drugs association in some of their direct molecular targets (COX-2, VEGF and VEGFR-2) and in reactive stroma markers (TGF-ß, αSMA, vimentin and pro-collagen 1) in the dorsolateral prostate, looking for lobe-specific responses. Male TRAMP mice were treated with celecoxib (10 mg/Kg, i.o.) and/or nintedanib (15 mg/Kg, i.o.) for 6 weeks and prostate was harvested for morphological and protein expression analyses. Results showed that combined therapy resulted in unique antitumor effects in dorsolateral prostate, especially due to the respective stromal or epithelial antiproliferative actions of these drugs, which altogether led to a complete inversion in high-grade (HGPIN) versus low-grade (LGPIN) premalignant lesion incidences in relation to controls. At the molecular level, this duality in drug action was paralleled by the differential down/upregulation of TGF-ß signaling by celecoxib/nintedanib, thus leading to associated changes in stroma composition towards regression or quiescence, respectively. Additionally, combined therapy was able to promote decreased expression of inflammatory (COX-2) and angiogenesis (VEGF/VEGFR-2) mediators. Overall, celecoxib and nintedanib association provided enhanced antitumor effects in TRAMP dorsolateral as compared to former registers in ventral prostate, thus demonstrating lobe-specific responses of this combined chemoprevention approach. Among these responses, we highlight the ability in promoting TGF-ß signaling and its associated stromal maturation/stabilization, thus yielding a more quiescent stromal milieu and resulting in greater epithelial proliferation impairment.

Tele-Intensive Care Unit Program in Brazil: Implementation and Expansion.

In this scientific report, we aimed to describe the implementation and expansion of a Tele-Intensive Care Unit (Tele-ICU) program in Brazil, highlighting the pillars of success, improvements, and perspectives. Tele-ICU program emerged during the COVID-19 pandemic at the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), focusing on clinical case discussions and training of health practitioners in public hospitals of the state of São Paulo in Brazil, to support health care professionals for treating COVID-19 patients. The success of implementing this initiative endorsed the project expansion to other five hospitals from different macroregions of the country, leading to the Tele-ICU-Brazil. These projects assisted 40 hospitals, allowing more than 11,500 teleinterconsultations (exchange of medical information between health care professionals using a licensed online platform) and training more than 14,800 health care professionals, reducing mortality and length of hospitalized patients. A segment in telehealth for the obstetrics health care was implemented after detecting these were a susceptible group of patients to COVID-19 severity. As a perspective, this segment will be expanded to 27 hospitals in the country. The Tele-ICU projects reported here were the largest digital health ICU programs ever established in Brazilian National Health System until know. Their results were unprecedented and proved to be crucial for supporting health care professionals nationwide during the COVID-19 pandemic and guide future initiatives in digital health in Brazil's National Health System.

Miconazole Nitrate Microparticles in Lidocaine Loaded Films as a Treatment for Oropharyngeal Candidiasis.

Oral candidiasis is an opportunistic infection that affects mainly individuals with weakened immune system. Devices used in the oral area to treat this condition include buccal films, which present advantages over both oral tablets and gels. Since candidiasis causes pain, burning, and itching, the purpose of this work was to develop buccal films loaded with both lidocaine (anesthetic) and miconazole nitrate (MN, antifungal) to treat this pathology topically. MN was loaded in microparticles based on different natural polymers, and then, these microparticles were loaded in hydroxypropyl methylcellulose-gelatin-based films containing lidocaine. All developed films showed adequate adhesiveness and thickness. DSC and XRD tests suggested that the drugs were in an amorphous state in the therapeutic systems. Microparticles based on chitosan-alginate showed the highest MN encapsulation. Among the films, those containing the mentioned microparticles presented the highest tensile strength and the lowest elongation at break, possibly due to the strong interactions between both polymers. These films allowed a fast release of lidocaine and a controlled release of MN. Due to the latter, these systems showed antifungal activity for 24 h. Therefore, the treatment of oropharyngeal candidiasis with these films could reduce the number of daily applications with respect to conventional treatments.

Long-term respiratory follow-up of ICU hospitalized COVID-19 patients: Prospective cohort study.

BACKGROUND: Coronavirus disease (COVID-19) survivors exhibit multisystemic alterations after hospitalization. Little is known about long-term imaging and pulmonary function of hospitalized patients intensive care unit (ICU) who survive COVID-19. We aimed to investigate long-term consequences of COVID-19 on the respiratory system of patients discharged from hospital ICU and identify risk factors associated with chest computed tomography (CT) lesion severity. METHODS: A prospective cohort study of COVID-19 patients admitted to a tertiary hospital ICU in Brazil (March-August/2020), and followed-up six-twelve months after hospital admission. Initial assessment included: modified Medical Research Council dyspnea scale, SpO2 evaluation, forced vital capacity, and chest X-Ray. Patients with alterations in at least one of these examinations were eligible for CT and pulmonary function tests (PFTs) approximately 16 months after hospital admission. Primary outcome: CT lesion severity (fibrotic-like or non-fibrotic-like). Baseline clinical variables were used to build a machine learning model (ML) to predict the severity of CT lesion. RESULTS: In total, 326 patients (72%) were eligible for CT and PFTs. COVID-19 CT lesions were identified in 81.8% of patients, and half of them showed mild restrictive lung impairment and impaired lung diffusion capacity. Patients with COVID-19 CT findings were stratified into two categories of lesion severity: non-fibrotic-like (50.8%-ground-glass opacities/reticulations) and fibrotic-like (49.2%-traction bronchiectasis/architectural distortion). No association between CT feature severity and altered lung diffusion or functional restrictive/obstructive patterns was found. The ML detected that male sex, ICU and invasive mechanic ventilation (IMV) period, tracheostomy and vasoactive drug need during hospitalization were predictors of CT lesion severity(sensitivity,0.78±0.02;specificity,0.79±0.01;F1-score,0.78±0.02;positive predictive rate,0.78±0.02; accuracy,0.78±0.02; and area under the curve,0.83±0.01). CONCLUSION: ICU hospitalization due to COVID-19 led to respiratory system alterations six-twelve months after hospital admission. Male sex and critical disease acute phase, characterized by a longer ICU and IMV period, and need for tracheostomy and vasoactive drugs, were risk factors for severe CT lesions six-twelve months after hospital admission.

Tempol differential effect on prostate cancer inflammation: In vitro and in vivo evaluation.

BACKGROUND: Tempol is a redox-cycling nitroxide that acts directly on inflammation. However, few studies have reported the use of tempol in prostate cancer (PCa). The present study investigated the effects of tempol on inflammation related to NF-κB signaling, using hormone-dependent or hormone-independent cell lines and the transgenic adenocarcinoma of the mouse prostate PCa animal model in the early and late stages of cancer progression. METHODS: PC-3 and LnCaP cells were exposed to different tempol doses in vitro, and cell viability assays were performed. The optimal treatment dose was chosen for subsequent analysis using western blotting. Five experimental groups were evaluated in vivo to test for tempol effects in the early (CT12 and TPL12 groups) and late stages (CT20, TPL20-I, and TLP20-II) of PCa development. The TPL groups were treated with 50 or 100 mg/kg tempol. All control groups received water as the vehicle. The ventral lobe of the prostate was collected and subjected to immunohistochemical and western blot analysis. RESULTS: Tempol treatment reduced cellular proliferation in vitro and improved prostatic morphology in vivo, thereby decreasing tumor progression. Tempol reduced inflammation in preclinical models, and downregulated the initial inflammatory signaling through toll-like receptors, not always mediated by the MyD88 pathway. In addition, it upregulated iκB-α and iκB -ß levels, leading to a decrease in NF-κB, TNF-α, and other inflammatory markers. Tempol also influenced cell survival markers. CONCLUSIONS: Tempol can be considered a beneficial therapy for PCa treatment owing to its anti-inflammatory and antiproliferative effects. Nevertheless, the action of tempol was different depending on the degree of the prostatic lesion in vivo and hormone reliance in vitro. This indicates that tempol plays a multifaceted role in the prostatic tissue environment.

Brazilian Berry Extract Differentially Induces Inflammatory and Immune Responses in Androgen Dependent and Independent Prostate Cancer Cells.

Jaboticaba is a Brazilian berry, which is rich in fibers and bioactive compounds and shows high antioxidant and antiproliferative activities. Prostate cancer (PCa) is the second most common type of cancer among men and its progression is influenced by androgens and inflammation. Previous studies reported the ability of the jaboticaba to modulate pathways involved in prostate diseases. The main objective of this study was to provide significant data about molecular targets of the jaboticaba peel extract (JPE) and its mechanisms of action in PCa cell lines with different androgenic status (LNCaP and PC-3). The results showed that JPE was able to decrease cell viability in both cell lines. LNCaP showed more sensitivity to JPE exposure, indicating the efficacy of the JPE treatment in terms of androgen responsiveness. JPE showed a distinct hormone dependent effect on the NF-κB signaling, with reduced NF-κB levels for LNCaP and increased NF-κB levels in PC-3 cells. Mechanisms related to cell death by apoptosis were stimulated after the JPE treatment, modulating B-cell lymphoma 2 and BAX for LNCaP and PC-3. Particularly for PC-3, the JPE treatment resulted in cytokine-cytokine receptor interaction activation mostly by up regulating pro-inflammatory, pro-angiogenic, immunostimulatory and immunosuppressive genes. Also, a set of genes related to angiogenesis and metastasis were down-regulated by JPE. In conclusion, JPE exerted an antitumor effect on PCa for both cell lines which can be enhanced if androgenic reliance is considered.

Differential effects of omega-3 PUFAS on tumor progression at early and advanced stages in TRAMP mice.

BACKGROUND: In vitro studies evidenced antitumor effects of omega-3 polyunsaturated fatty acids ([n-3] PUFAs), but their effects on prostate cancer (PCa) remain controversial in epidemiological studies. Here we investigated whether an (n-3) PUFA-enriched diet affects tumor progression in transgenic adenocarcinoma of the mouse prostate (TRAMP), at early (12 weeks age) and advanced stages (20 weeks age). METHODS: TRAMP mice were fed with standard rodent diet (C12, C20) or (n-3) PUFA-enriched diet containing 10% fish oil (T12, T20). A group of 8 weeks age animals fed standard diet was also used for comparison (C8). The ventral prostate was processed for histopathological and immunohistochemical analyses and serum samples submitted to biochemical assays. RESULTS: At early stages, (n-3) PUFA increased the frequency of normal epithelium (3.8-fold) and decreased the frequency of high-grade intraepithelial neoplasia (3.3-fold) and in situ carcinoma (1.9-fold) in the gland, maintaining prostate pathological status similar to C8 group. At advanced stages, 50% of the animals developed a large primary tumor in both C20 and T20, and tumor weight did not differ (C20: 2.2 ± 2.4; T20: 2.8 ± 2.9 g). The ventral prostate of T12 and of T20 animals that did not develop primary tumors showed lower cell proliferation, tissue expressions of androgen (AR) and glucocorticoid (GR) receptors, than their respective controls. For these animals, (n-3) PUFA also avoided an increase in the number of T-lymphocytes, collagen fibers, and αSMA immunoreactivity, and preserved stromal gland microenvironment. (n-3) PUFA also lowered serum triglycerides and cholesterol, regulating the lipid metabolism of TRAMP mice. CONCLUSIONS: (n-3) PUFAs had a protective effect at early stages of PCa, delaying tumor progression in TRAMP mice, in parallel with reductions in cell proliferation, AR, and GR and maintenance of the stromal compartment of the gland. However, (n-3) PUFAs did not prevent the development of primary tumors for the T20 group, reinforcing the need for further investigation at advanced stages of disease.

Chronic lung lesions in COVID-19 survivors: predictive clinical model.

OBJECTIVE: This study aimed to propose a simple, accessible and low-cost predictive clinical model to detect lung lesions due to COVID-19 infection. DESIGN: This prospective cohort study included COVID-19 survivors hospitalised between 30 March 2020 and 31 August 2020 followed-up 6 months after hospital discharge. The pulmonary function was assessed using the modified Medical Research Council (mMRC) dyspnoea scale, oximetry (SpO2), spirometry (forced vital capacity (FVC)) and chest X-ray (CXR) during an in-person consultation. Patients with abnormalities in at least one of these parameters underwent chest CT. mMRC scale, SpO2, FVC and CXR findings were used to build a machine learning model for lung lesion detection on CT. SETTING: A tertiary hospital in Sao Paulo, Brazil. PARTICIPANTS: 749 eligible RT-PCR-confirmed SARS-CoV-2-infected patients aged ≥18 years. PRIMARY OUTCOME MEASURE: A predictive clinical model for lung lesion detection on chest CT. RESULTS: There were 470 patients (63%) that had at least one sign of pulmonary involvement and were eligible for CT. Almost half of them (48%) had significant pulmonary abnormalities, including ground-glass opacities, parenchymal bands, reticulation, traction bronchiectasis and architectural distortion. The machine learning model, including the results of 257 patients with complete data on mMRC, SpO2, FVC, CXR and CT, accurately detected pulmonary lesions by the joint data of CXR, mMRC scale, SpO2 and FVC (sensitivity, 0.85±0.08; specificity, 0.70±0.06; F1-score, 0.79±0.06 and area under the curve, 0.80±0.07). CONCLUSION: A predictive clinical model based on CXR, mMRC, oximetry and spirometry data can accurately screen patients with lung lesions after SARS-CoV-2 infection. Given that these examinations are highly accessible and low cost, this protocol can be automated and implemented in different countries for early detection of COVID-19 sequelae.

Systemic antioxidant and anti-inflammatory effects of yellow passion fruit bagasse extract during prostate cancer progression.

We evaluated the impact of yellow passion fruit (Passiflora edulis sp.) bagasse extract (PFBE) administration in systemic oxidative and inflammatory parameters in vivo, considering prostate cancer progression in transgenic mice (TRAMP). Piceatannol, scirpusin-B, dicaffeoylquinic acid, citric acid, and (+)-catechin were identified in PFBE, and the extract showed high in vitro antioxidant capacity. Some alterations in systemic parameters were verified during prostate cancer progression, as the increase in ALT and MDA levels, and SOD and GPx activities in the plasma. In the liver, higher MDA, TNF-α, and NF-κB levels, and GR and GPx activities were verified. Compared to their respective controls, the short- and long-term PFBE administration reduced MDA levels in the liver and plasma. The long-term treatment increased the catalase activity in the plasma, while the short-term treatment increased the hepatic SOD and catalase activities. Still, a reduction in hepatic TNF-α and NF-κB levels was verified after long-term treatment. PRACTICAL APPLICATIONS: Prostate cancer progression is associated with changes in systemic redox status and inflammation markers. Moreover, the intake of polyphenols with antioxidant properties, besides delaying prostate carcinogenesis, may improve the systemic antioxidant defenses and inflammatory response. In vitro studies pointed to a promising antioxidant and anti-inflammatory potential of yellow passion fruit bagasse. However, in vivo studies are scarce. Our results provided information about in vivo impacts of PFBE oral consumption on antioxidant defense and inflammation, indicating its potential as an adjuvant during the initial steps of prostate cancer.

The effect of α-terpineol enantiomers on biomarkers of rats fed a high-fat diet.

Alpha-terpineol is a monoterpenoid found in many essential oils, being widely used in food and household products. In vitro antioxidant and anti-inflammatory activities have already been associated with this alcohol; therefore, this study aimed to check if these properties were also present in vivo, counteracting the oxidant and inflammatory effects of a high-fat diet, as well as if there were differences in the biological activities among the two α-terpineol enantiomers. Thus, this work evaluated the effect of supplementation of α-terpineol enantiomers (at 25, 50 and 100 mg/kg of diet) on biological parameters of diet-induced obese Sprague-Dawley rats. In general, α-terpineol improved the nutritional parameters of rats fed a high-fat diet. The intake of α-terpineol at concentrations ≥50 mg/kg was able to reestablish the insulin sensibility and reduced (p < 0.05) serum levels of pro-inflammatory cytokines TNF-α and IL-1ß, when compared with the control group. The intake of R-(+)- and (-)-α-terpineol decreased the TNF-α level by approximately 1.5 and 3.4 times, respectively, when compared with the high-fat group, regardless of the concentration. Moreover, both enantiomers at 50 mg/kg decreased the levels of serum thiobarbituric acid reactive substances (TBARS) by 2.6-4.2 times, while hepatic TBARS were reduced in approximately 1.6 times, regardless of the compound and concentration tested. Further experiments are suggested to confirm the mechanisms and the security of α-terpineol in different experimental models and more extended exposure experiments.

Brazilian berry extract (Myrciaria jaboticaba): A promising therapy to minimize prostatic inflammation and oxidative stress.

BACKGROUND: Brazilian berry is a fruit popularly known as "Jaboticaba," rich in bioactive compounds with antioxidant and anti-inflammatory properties. Senescence and overweight are increasing worldwide and are considered risk factors to prostatic pathogenesis mainly due to oxidative and inflammatory processes induction. Thus, this study aimed to evaluate the effect of two increasing doses of the patented jaboticaba peel extract (PJE) on oxidative-stress and inflammation in the prostate of aging or high-fat-fed aging mice. METHODS: PJE and/or high-fat diet (HFD) treatments started with 11-month-old mice and lasted 60 days. The levels or the immunoexpression of different inflammatory (nuclear factor κB [NFκB], CD3+, cyclooxygenase 2 [COX-2], toll-like receptor 4 [TLR4], phosphorylated signal transducers and activators of transcription 3 [pSTAT-3], tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and IL-1ß) and oxidative-stress (catalase, superoxide dismutase 2 [SOD2], glutathione reductase [GSR], reduced glutathione, and glutathione peroxidase 3 [GPx3]) related molecules were analyzed by western-blotting, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: Both PJE doses reduced the levels of oxidative-stress-related molecules (GPx3, GSR, catalase), lipid peroxidation (4-hydroxynonenal), inflammatory mediators (COX-2, TNF-α, and pSTAT-3) and CD3+ T cells number, which were associated with the maintenance of the glandular morphological integrity in aging and HFD-fed-aging mice. Nevertheless, only the high PJE dose reduced the NFκB and TLR4 levels in aging mice; and SOD2, IL-6, and IL-1ß levels in HFD-aging mice. Aging itself promoted an oxidative inflammation in the prostate, interfering in the levels of the different oxidative-stress, lipid peroxidation, and inflammatory mediators evaluated, in association with high incidence of prostate epithelial and stromal damages. The HFD intake intensified aging alterations, showing an unfavorable prostatic microenvironment prone to oxidative and inflammatory damages. CONCLUSIONS: PJE exerted a dose-dependent effect controlling inflammation and oxidative-stress in aging and HFD-fed aging mice prostate. This fact contributed to prostate microenvironment balance recovery, preserving the tissue architecture of this gland. Thus, the PJE emerges as a potential therapy to prevent inflammation and oxidative stress in the prostate.

Grape peel powder attenuates the inflammatory and oxidative response of experimental colitis in rats by modulating the NF-κB pathway and activity of antioxidant enzymes.

Most phenolic compounds and dietary fiber reach intact to the colon. We hypothesized that grape peel powder (GPP), a rich source of these bioactive compounds, modulates inflammatory and oxidative pathways collaborating to attenuate colonic damage in experimental colitis. To determine which bioactive fraction would be responsible for this effect, the aim of this study was to evaluate the effect of dietary supplementation with whole GPP or the isolated bioactive-rich fractions from GPP (extractable polyphenols [EP], dietary fiber and fiber-bound polyphenols [NEP-F], and dietary fiber) in rats with experimental colitis. Colitis was induced by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS) after 15 days of dietary supplementation. EP diet did not reverse the decrease in feed intake and indeed worsened colon shortening and increased spleen weight; however, these effects were not observed for the GPP group, which had polyphenols associated to the matrix besides the extractable ones. Colitis impaired the activity of colonic antioxidant enzymes and increased lipid peroxidation, protein oxidation, nitric oxide (NO) levels, and proinflammatory cytokines in serum and in the colon tissue. GPP restored the activity of antioxidant enzymes and decreased colon oxidation and NO levels. All grape peel fractions reduced the protein expression of the inhibitor of kappa kinase beta and NO levels in colon tissue, but only NEP-F reduced the expression of phosphorylated nuclear factor kappa B and myeloperoxidase activity. Results demonstrated that GPP attenuates inflammatory and oxidative response in TNBS-induced colitis by downregulating the nuclear factor kappa B pathway and upregulating antioxidant enzymes, with NEP-F being the fraction most likely associated to these protective effects.

Enhancing the Anticancer Activity and Selectivity of Goniothalamin Using pH-Sensitive Acetalated Dextran (Ac-Dex) Nanoparticles: A Promising Platform for Delivery of Natural Compounds.

Goniothalamin (GTN), a natural compound isolated from Goniothalamus species, has previously demonstrated cytotoxic activity against several cancer cell lines. However, similarly to many natural and synthetic anticancer compounds, GTN presents toxicity toward some healthy cells and low aqueous solubility, decreasing its bioavailability and precluding its application as an antineoplastic drug. In our efforts to improve the pharmacokinetic behavior and selectivity of GTN against cancer cells, we developed a polymeric nanosystem, in which rac-GTN was encapsulated in pH-responsive acetalated dextran (Ac-Dex) nanoparticles (NPs) with high loadings of the bioactive compound. Dynamic light scattering (DLS) analysis showed that the nanoparticles obtained presented a narrow size distribution of around 100 nm in diameter, whereas electron microscopy (EM) images showed nanoparticles with a regular spherical morphology in agreement with the size range obtained by DLS. Stability and release studies indicated that the GTN@Ac-Dex NPs presented high stability under physiological conditions (pH 7.4) and disassembled under slightly acidic conditions (pH 5.5), releasing the rac-GTN in a sustained manner. In vitro assays showed that GTN@Ac-Dex NPs significantly increased cytotoxicity and selectivity against cancer cells when compared with the empty Ac-Dex NPs and the free rac-GNT. Cellular uptake and morphology studies using MCF-7 cells demonstrated that GTN@Ac-Dex NPs are rapidly internalized into the cancer cells, causing cell death. In vivo investigation confirmed the efficient release of rac-GTN from GTN@Ac-Dex NPs, resulting in the delay of prostate cancer progression in transgenic adenocarcinoma of the mouse prostate (TRAMP) model. Furthermore, liver histopathology evaluation after treatment with GTN@Ac-Dex NPs showed no evidence of toxicity. Therefore, the in vitro and in vivo findings suggest that the Ac-Dex NPs are a promising nanosystem for the sustained delivery of rac-GTN into tumors.

High-fat diet effects on the prostatic adenocarcinoma model and jaboticaba peel extract intake: protective response in metabolic disorders and liver histopathology.

Prostate cancer (PCa), overweight and obesity are frequent worldwide health problems. Clinical studies have shown that increased high-fat diet (HFD) consumption is associated with higher incidence of PCa. Brazilian berries, such as Myrciaria jaboticaba (Vell.) Berg, present high polyphenol concentration in the peel and exhibit positive effects on metabolic disorders and hepatic lesions. Therefore, the aim of the study herein was to investigate the patented jaboticaba peel extract effects (PJE) on different metabolic parameters and liver histopathology in the transgenic adenocarcinoma of the mouse prostate model, receiving a either normolipid diet or HFD for 8 weeks. The results showed that PJE reduced insulin resistance and glucose intolerance, decreased hepatic lipid accumulation, and inflammatory markers such as PPARγ and TNFα, respectively. In conclusion, the PJE treatment promoted protective effects in the metabolism of insulin and glucose and liver imbalance caused by HFD intake in the PCa model, suggesting that it may be a good protector against metabolic disorders present in overweight and associated with PCa.

Jaboticaba peel powder and jaboticaba peel aqueous extract reduces obesity, insulin resistance and hepatic fat accumulation in rats.

This study investigated the effects of freeze-dried jaboticaba peel (FJP) and jaboticaba tea (JE) on obesity parameters of diet-induced obese rats. Thirty-six male Wistar rats were distributed into six groups: AIN-93 M feed a normal control diet; HFF (obese control) feed a high-fat and fructose diet; Prevention FJP (P. FJP) and Treatment FJP (T. FJP) feed HFF diet with 2% of FJP powder, for 12 and 6 weeks respectively; Prevention JE (P. JE) and Treatment JE (T. JE) were feed with HFF diet and the water was substituted by JE, for 12 and 6 weeks, respectively. Lipid profile, glucose, adiponectin and leptin were measured. Glucose and insulin tolerance, also pancreatic islet insulin secretion were determined. Liver morphology and fat liver accumulation were evaluated. Results showed that HFF-diet induced weight gain, dyslipidemia, glucose intolerance, insulin resistance and hepatic steatosis. All FJP and JE treatments reduced weight gain, adiposity and improved insulin sensitivity. Twelve weeks supplementation increased HDL-cholesterol and prevented hepatic steatosis. Our results suggest that FJP and JE act as functional foods, being a dietary strategy to prevent or control obesity. FJP and JE 12 weeks supplementation can modulate important parameters of obesity and insulin metabolism, preventing liver steatosis in obese rats.

Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model: A good alternative to study PCa progression and chemoprevention approaches.

The use of genetically modified animals has been studied in scientific research over time as a way to discover new treatments or even a cure for various diseases. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) is a model for prostate cancer (PCa) that develops lesions that range from preneoplastic to metastasis. Its similarity to human PCa brings essential knowledge about disease development as well as making possible to investigate different degrees of the tumor profile. We reviewed the literature regarding five important areas relating to PCa progression in the TRAMP model. We also present some useful PCa models comparing them to TRAMP. Furthermore, we investigated the effect of some therapies related to these areas highlighting the best approaches that can delay PCa progression. The revised studies showed that TRAMP cancer stages are well established from 8 to 30 weeks of age, which makes possible to interfere in specific times of PCa development. Moreover, inflammatory and angiogenic blockage before the appearance of malignant lesions retarded PCa progression and showed better results than therapeutical approaches in other phases in TRAMP mice. Reactive stroma is less studied than other areas, although it has been showing a particular relevance in PCa as a milestone in malignant transformation through the modulation of TGF-ß, vimentin, and αSMA. We concluded that even years after its creation, the TRAMP model is still one of the most essential tools for PCa study, as well as for the development of new strategies to prevent the disease.