New Mediators in the Crosstalk between Different Adipose Tissues.

Adipose tissue is a multifunctional organ that regulates many physiological processes such as energy homeostasis, nutrition, the regulation of insulin sensitivity, body temperature, and immune response. In this review, we highlight the relevance of the different mediators that control adipose tissue activity through a systematic review of the main players present in white and brown adipose tissues. Among them, inflammatory mediators secreted by the adipose tissue, such as classical adipokines and more recent ones, elements of the immune system infiltrated into the adipose tissue (certain cell types and interleukins), as well as the role of intestinal microbiota and derived metabolites, have been reviewed. Furthermore, anti-obesity mediators that promote the activation of beige adipose tissue, e.g., myokines, thyroid hormones, amino acids, and both long and micro RNAs, are exhaustively examined. Finally, we also analyze therapeutic strategies based on those mediators that have been described to date. In conclusion, novel regulators of obesity, such as microRNAs or microbiota, are being characterized and are promising tools to treat obesity in the future.

Use of rivaroxaban attenuates renal function impairment in patients with atrial fibrillation: insights of the EMIR study.

BACKGROUND: In atrial fibrillation (AF) patients on vitamin K antagonists, a progressive deterioration of renal function is common but there is limited evidence with long-term use of rivaroxaban. Herein, we investigated the change in renal function in AF patients after 2 years of rivaroxaban treatment. METHODS: The EMIR registry is an observational and multicentre study including AF patients treated with rivaroxaban for at least 6 months prior to inclusion. Changes in analytical parameters were recorded during 2 years of follow-up. Renal function was estimated using the Cockroft-Gault equation. RESULTS: 1433 patients (638, 44.5% women, mean age of 74.2 ± 9.7 years) were included. Creatinine clearance (CrCl) was available at baseline and at 2 years in 1085 patients. At inclusion, 33.2% of patients had impaired renal function (CrCl <60 ml/min). At 2 years, we were not able to find changes in the proportion of patients with impaired renal function, which increased to 34.6% (p = 0.290). However, the baseline mean CrCl was 76.0 ± 30.5 ml/min and slightly improved at 2 years (77.0 ± 31.8 ml/min; p = 0.014). Overall, the proportion of patients with CrCl <60 ml/min at baseline that had CrCl ≥60 ml/min at 2 years was significantly higher compared to that of patients with CrCl ≥60 ml/min at baseline and CrCl <60 ml/min after (22.2% vs. 13.1%; p < 0.001) CONCLUSIONS: In AF patients on long-term rivaroxaban therapy, a decrease in renal function was not observed. We even observed a slight improvement in the patients with renal impairment. These results reinforce the idea that rivaroxaban may be a safe option even in patients with renal impairment.

Latin American Older people and neuropsychiatric symptoms: a mini-systematic review of effects of COVID-19 Pandemic.

BACKGROUND: Ending December 2019, the world had to face to COVID-19. Latin America and the Caribbean suffered the effects where the contiguous and the number of deaths has been significant. Studies indicate that older adults with some degree of cognitive impairment are at greater risk of worsening their cognitive status and mental health, for this reason it's exposed that social isolation and loneliness has harmful effects on the health of this population. This mini-review inquires on the effects of COVID-19 due to social isolation on neuropsychiatric symptoms (NPS) in Latin American older adults with and without dementia. METHOD: A search was carried out in PubMed, SCOPUS, and ScienceDirect identifying all articles published up to July 31, 2021 using the keywords "social isolation", "lockdown", "quarantine", "COVID-19",, "neuropsychiatric symptoms ", "neurobehavioral", "dementia"," mild cognitive impairment "," Older People ", "aging", "elderly". Two independent reviewers screened and selected appropriate articles and a third researcher helped resolve disagreements. The selected articles met the following criteria: written in English, Spanish or Portuguese, original article; focused on elderly subjects, articles that provided information on the NPS effects in Latin American populations during the COVID-19 pandemic. The review was based on the PRISMA Statement and used the SIGN criteria. RESULT: From 61 articles recovered from electronic databases (PubMed, Science Direct and Scopus) 10 of them were chosen for this review. The majority of the articles reported in a general way a negative impact on the mental health of the population in Latin America. They referred to a significant increase in the anxiety and depression symptoms. The majority of the articles were studies developed in Brazil, Argentina and Chile. CONCLUSION: The COVID-19 has shown a negative impact on the mental health of older adults. Latin America is a region with important socio-sanitary problems which increase the impact of the pandemic in SNP, especially in older adults. It's necessary to increase the studies in Latin America that glimpse the real situation in the region.

99mTc Stearyl 6-(benzylidenehydrazinyl) nicotinamide Liposomes as Tumor Permeability Evaluation Tracer.

Nanomedicine is a highly demanded discipline. Liposomes have seen an increased attention due to their physicochemical properties that allow them to act as nanocarriers of drugs and also of radioisotopes that can be used to diagnose and treat cancer. In order to obtain a novel permeability cancer imaging agent based on 99mTc-labeled liposomes, we describe microwave-assisted synthesis of stearyl 6-(benzylidenehydrazinyl) nicotinamide lipid, which was included in two formulations: nanometric hydrazinonicotinic acid (HYNIC) liposome and its PEGylated coated analogue, HYNIC-PEG liposome. Radiolabeling with 99mTc via stearyl 6-(benzylidenehydrazinyl) nicotinamide was found to be easy, reproducible, and stable, revealing high radiochemical purity (94 ± 1.7%) for both liposomal formulations. Biodistribution at 4 h and 24 h and scintigraphic images at 4 h were performed in normal and melanoma-bearing C57BL/6 mice. Biodistribution studies at 4 h showed tumor uptake of 99mTc-HYNIC liposome and 99mTc-HYNIC-PEG liposome (1.1 ± 0.6 and 2.5 ± 0.4, respectively) and also at 24 h p.i. (1.8 ± 0.5 and 3.0 ± 1.1, respectively). Scintigraphic images showed appreciable tumor uptake in melanoma tumor-bearing mice with both liposomal formulations. Our results show that 99mTc stearyl 6-(benzylidenehydrazinyl) nicotinamide liposomes can be used as diagnostic noninvasive in vivo tumor-targeting agents capable of evaluating tumor permeability and development who can be used in personalized chemotherapy planning.

The ECHO model proved to be a useful tool to increase clinicians' self-effectiveness for care of patients with Hepatitis C in Argentina.

The ECHO model was developed to expand access to medical care for populations with HCV infection in underserved areas. We aimed to compare HCV treatment outcomes in community-based clinics with the Austral University Hospital (AUH) and to assess improvement in physician knowledge and skills. In October 2015, we established an HCV ECHO clinic at the AUH in Buenos Aires. To evaluate the impact of this programme, we conducted a prospective cohort study comparing treatment for HCV infection at the AUH with healthcare providers from different Argentinean provinces. A survey evaluating skills and competence in HCV care was administered, and results were compared. The primary endpoint was sustained virologic response (SVR) and under direct-acting antivirals. Since the implementation of ECHO clinics, a total of 25 physicians participated in at least one session (median 10.0; IQR 3.0-18.0). SVR rates (n = 437 patients) were 94.2% (95% CI 90.4-96.8) in patients treated at AUH clinic (n = 227/242) and 96.4% (95% CI 92.7-98.5) in those treated at ECHO sites (n = 188/195), with a nonsignificant difference between sites, 2.2% SVR difference (95% CI -0.24-0.06; P = 0.4). We also found a significant improvement in all the evaluated skills and abilities. Replicating the ECHO model helped to improve participants' skills in the management of HCV achieving similar SVR rates. ECHO model was demonstrated to be an effective intervention able to multiply and expand HCV treatment, a critical barrier to access to care that needs to be solved if we are committed with WHO goals to eliminate HCV by 2030.

Efficacy and safety of pop-titrated versus fixed-energy trans-scleral diode laser cyclophotocoagulation for refractory glaucoma.

PURPOSE: To compare the efficacy and safety of pop-titrated versus fixed-energy diode laser trans-scleral cyclophotocoagulation (DLTSC) for refractory glaucoma. METHODS: This is a prospective, interventional, longitudinal, and comparative case-control study. Patients with refractory glaucoma treated with pop-titrated DLTSC were compared to a fixed-energy DLTSC control group. Variables analyzed included: age, gender, diagnosis, pre- and post-treatment intraocular pressure (IOP). Success rate, anti-glaucoma medications reduction, and complications were analyzed at day 90 post-treatment. Primary success criterion consisted of eyes with a postoperative IOP ≤ 22 mmHg or a 30% reduction of pre-treatment IOP and managed with topical anti-glaucoma medications only. RESULTS: A total of 68 eyes from 67 patients were included for analysis: 30 in the pop-titrated group and 38 in the fixed-energy group. Therapeutic success was achieved in 56-72% of the pop-titrated group versus 47-52% in the fixed-energy group considering the 3 different criteria analyzed (p = 0.23-0.4). There was a 22% (from 4.1 to 3.2 drugs) reduction of anti-glaucoma medications in the pop-titrated group, compared to 32% (from 3.5 to 2.4 drugs) in the fixed-energy group (p = 0.42). Five eyes (13.1%) developed hypotony, all of which belonged to the fixed-energy group (p = 0.048). CONCLUSIONS: Pop-titrated DLTSC represents an effective and safe option for the management of refractory glaucoma. We found no statistically significant difference in success rates among both groups. However, there was a significantly higher risk of hypotony in eyes treated with the fixed-energy protocol.

Synthesis of hydrophilic HYNIC-[1,2,4,5]tetrazine conjugates and their use in antibody pretargeting with 99mTc.

Pretargeted imaging, based on the highly reactive process between [1,2,4,5]tetrazines with trans-cyclooctene (TCO), appears as an attractive strategy to overcome disadvantages associated with traditional radioimmunoconjugates. To be successful, the radiolabeled component should react in vivo with the conjugated antibody and the non reactive excess clear fast from the organism. Herein, we explore the in vivo effects of hydrophilic linker incorporation into [1,2,4,5]tetrazine systems bearing a 6-hydrazinonicotinyl (HYNIC) moiety for technetium-99m coordination. Incorporation of a polypeptide chain containing hydrophilic aminoacids, resulted in a derivative with renal clearance. Pretargeted bevacizumab imaging was used as proof of concept.

Increased hepatitis C virus co-infection and injection drug use in HIV-infected fishermen in Myanmar.

BACKGROUND: In Southeast Asia, though fishermen are known to be a key population at high risk of HIV, little is known about their co-infection rates with Hepatitis C virus (HCV), or how illness and risk behaviors vary by occupation or type of fishermen. In Myanmar, this lack of knowledge is particularly acute, despite the fact that much of the country's border is coastline. METHODS: We conducted a retrospective analysis to assess clinical, demographic, and risk characteristics of HIV-infected, ≥15-year-old males under HIV care from 2004 to 2014. Subgroups of fishermen were categorized according to the location of fishing activities, boat ownership, and length of time at sea. Generalized linear models assessed odds of high risk behaviors, including MSM (men who have sex with men), transactional sex, injection drug use (IDU), and HCV co-infection among international, local subsistence, and national migrant fishermen. RESULTS: Of 2798 adult males who enrolled in HIV care between 2004 and 2014, 41.9% (n = 1172) were fishermen. Among these, migrants had the highest odds of engaging in risk behaviors such as sex work (Myanmar national migrants: OR 3.26 95% CI: 2.20 to 4.83), and injecting drugs (international migrants: OR 2.93, 95% CI: 1.22 to 3.87) when compared to the general male HIV clinic population. 15.9% of all fishermen reported past or current IDU (23.0% of international migrants). 22.8% of all fishermen were also co-infected with HCV, and though predictably injectors had the highest odds (OR 20.1, 95% CI: 13.7 to 29.5), even after controlling for other risk factors, fishermen retained higher odds (OR 2.37 95% CI: 1.70 to 3.32). CONCLUSIONS: HIV positive fishermen in Myanmar had higher odds of HCV co-infection. They also disproportionally injected drugs and engaged in transactional sex more than other patients. This is especially pronounced among international migrant fishermen. HIV-infected fishermen should be counseled on high risk activities, screened for HCV, and targeted by harm reduction programs.

Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products.

Many fungal quinazolinone metabolites, which contain the methyl-indole pyrazino [1,2-b]quinazoline-3,6-dione core, have been found to possess promising antitumor activity. The purpose of this work was to synthesize the enantiomeric pairs of two members of this quinazolinone family, to explore their potential as antitumor and their ability to revert multidrug resistance. The marine natural product fiscalin B (4c), and antienantiomers (4b, 5b, and 5c) were synthesized via a one-pot approach, while the syn enantiomers (4a, 4d, 5a, and 5d) were synthetized by a multi-step procedure. These strategies used anthranilic acid (i), chiral N-protected α-amino acids (ii), and tryptophan methyl esters (iii) to form the core ring of pyrazino[2,1-b]quinazoline-3,6-dione scaffold. Four enantiomeric pairs, with different enantiomeric purities, were obtained with overall yields ranging from 7 to 40%. Compounds 4a⁻d and 5a⁻d were evaluated for their growth inhibitory effect against two tumor cell lines. Differences between enantiomeric pairs were noted and 5a⁻d displayed GI50 values ranging from 31 to 52 µM, which are lower than those of 4a⁻d. Nevertheless, no effect on P-glycoprotein (P-gp) modulation was observed for all compounds. This study disclosed new data for fiscalin B (4c), as well as for its analogues for a future development of novel anticancer drug leads.

Technetium-99m- or Cy7-Labeled Rituximab as an Imaging Agent for Non-Hodgkin Lymphoma.

INTRODUCTION: Rituximab was the first monoclonal antibody approved for the treatment of B-cell non-Hodgkin lymphoma (NHL) expressing CD20 antigen. This antibody has also the potential to be used as a specific fluorescent and radiolabel agent for targeting NHL. OBJECTIVE: To radiolabel rituximab with technetium-99m (99mTc) or Cy7 and evaluate both probes as potential imaging agents for NHL. METHODS: Rituximab was derivatized with the trifluoroacetyl hydrazino protected form of succinimidyl ester of HYNIC and radiolabeled with 99mTc. Radiochemical stability and in vitro cell assays were evaluated. Biodistribution and single-photon emission computed tomography/computed tomography (SPECT/CT) were performed. Raji cells were transfected with luciferase for bioluminescent NHL imaging up to 21 days. Rituximab was labeled with Cy7 for in vivo noninvasive fluorescence imaging up to 96 h. RESULTS: Radiolabeling was carried out in a fast, reproducible, easy, and stable way with high radiochemical purity and did not interfere with epitope recognition. Biodistribution and SPECT/CT studies showed high liver and discrete tumor uptake. Bioluminescence and fluorescence studies helped us evaluate rituximab-Cy7 in Raji subcutaneous engraftment in BALB/c nude mice. CONCLUSIONS: Our results support the potential use of rituximab labeled either with 99mTc or Cy7 as a molecular imaging tool for staging, restaging, and guiding surgical excision of tumors, which merits further evaluation.

Development of new PTK7-targeting aptamer-fluorescent and -radiolabelled probes for evaluation as molecular imaging agents: Lymphoma and melanoma in vivo proof of concept.

Aptamers are single-stranded oligonucleotides that recognize molecular targets with high affinity and specificity. Aptamer that selectively bind to the protein tyrosine kinase-7 (PTK7) receptor, overexpressed on many cancers, has been labelled as probes for molecular imaging of cancer. Two new PTK7-targeting aptamer probes were developed by coupling frameworks from the fluorescent dye AlexaFluor647 or the 6-hydrazinonicotinamide (HYNIC) chelator-labelled to 99mTc. The derivatizations via a 5'-aminohexyl terminal linker were done at room temperature and under mild buffer conditions. Physicochemical and biological controls for both imaging agents were performed verifying the integrity of the aptamer-conjugates by HPLC. Recognition of melanoma (B16F1) and lymphoma (A20) mouse cell lines by the aptamer was studied using cell binding, flow cytometry and confocal microscopy. Finally, in vivo imaging studies in tumour-bearing mice were performed. The new probes were able to bind to melanoma and lymphoma cell lines in vitro, the in vivo imaging in tumour-bearing mice showed different uptake behaviours showing for the fluorescent conjugate good uptake by B cell lymphoma while the radiolabelled conjugate did not display tumour uptake due to its high extravascular distribution, and both showed rapid clearance properties in tumour-bearing mice.

Clinical Experience with Ivabradine in Acute Heart Failure.

OBJECTIVE: Ivabradine has been shown to improve symptoms and to reduce rehospitalization and mortality in patients with severe chronic heart failure (HF). Its indication in acute HF is not clear. Acute HF patients could also benefit from HR reduction, as myocardial consumption and oxidative stress are related to tachycardia. Moreover, beta-blockers are contraindicated in cardiogenic shock and should not be initiated with congestive signs. Accordingly, we evaluated the role of ivabradine in acute HF patients. METHODS: This was a retrospective analysis of 29 consecutive patients treated for acute HF in the Cardiac ICU, and for whom ivabradine was initiated during hospitalization between January 2011 and January 2014. All patients were in sinus rhythm and had a heart rate (HR) >70 bpm. Catecholamine use was necessary in 16 patients (57.1%) during the hospitalization, in 14 (87.5%) of these before ivabradine treatment. RESULTS: Systolic blood pressure showed no variation during the first 24 h of ivabradine administration or at discharge. HR showed an absolute reduction of 10 bpm at 6 h (p < 0.001), 11 bpm at 24 h (p = 0.004) and 19 bpm (p < 0.001) at discharge. No episodes of significant bradycardia or hypotension were recorded after starting the drug. CONCLUSIONS: HR reduction with ivabradine in acute HF is well tolerated. It represents an attractive option, especially when there is excessive catecholamine-related tachycardia; this should be appropriately evaluated in randomized trials.

In vitro and in vivo uptake studies of PAMAM G4.5 dendrimers in breast cancer.

BACKGROUND: Breast cancer is the second leading cause of cancer death worldwide. Nanotechnology approaches can overcome the side effects of chemotherapy as well as improve the efficacy of drugs. Dendrimers are nanometric size polymers which are suitable as drug delivery systems. To the best of our knowledge, studies on the application of PAMAM G4.5 (polyamidoamine half generation 4) dendrimers as potential drug delivery systems in breast cancer have not been reported. In this work we developed a PAMAM G4.5 dendrimer containing FITC (fluorescein isothiocyanate) dye to study their uptake by murine breast cancer cells and BALB/c mice breast tumors. RESULTS: We performed a reaction between FITC and PAMAM G4.5 dendrimers which were previously derivatized with piperazine (linker molecule), characterized them by (1)H NMR (proton nuclear magnetic resonance) spectroscopy and MALDI-TOF (matrix-assisted laser desorption/ionization- time-of-flight) mass spectrometry. The experimental data indicated that 2 FITC molecules could be bound covalently at the PAMAM G4.5 dendrimer surface, with 17 FITC molecules probably occluded in PAMAM dendrimers cavity. PAMAM-FITC dendrimer (PAMAM G4.5-piperazinyl-FITC dendrimer) size distribution was evaluated by DLS (dynamic light scattering) and TEM (transmission electron microscopy). The nanoparticle hydrodynamic size was 96.3 ± 1.4 nm with a PdI (polydispersion index) of 0.0296 ± 0.0171, and the size distribution measured by TEM was 44.2 ± 9.2 nm. PAMAM-FITC dendrimers were neither cytotoxic in 4T1 cells nor hemolytic up to 24 h of incubation. In addition, they were uptaken in vitro by 4T1 cells and in vivo by BALB/c mice breast tumors. PAMAM G4.5-piperazinyl-FITC dendrimer intracellular distribution was observed through histologic analysis of the tumor by laser confocal microscopy. CONCLUSION: These results indicate that PAMAM G4.5 dendrimers enter tumor tissue cells, being good candidates to be used as antitumor drug delivery systems for breast cancer treatment and diagnosis.

Identification of a new amide-containing thiazole as a drug candidate for treatment of Chagas' disease.

Although the parasitic infection Chagas' disease was described over 100 years ago, even now there are not suitable drugs. The available drugs nifurtimox and benznidazole have limited efficacies and tolerances, with proven mutagenic effects. Attempting to find appropriate drugs to deal with this problem, here we report on the development and pharmacological characterization of new amide-containing thiazoles. In the present study, we evaluated the in vitro and in vivo effects of new candidates against Trypanosoma cruzi, the etiological agent of Chagas' disease. The lead amide-containing thiazole derivative had potent in vitro activity, an absence of both in vitro mutagenic and in vivo clastogenic effects, and excellent in vitro selectivity and in vivo tolerance. The compound suppressed parasitemia in mice, modifying the anti-T. cruzi antibodies like the reference drug, benznidazole, and displayed the lowest mortality among the tested drugs. The present evidence suggests that this compound is a promising anti-T. cruzi agent surpassing the lead optimization stage in drug development and leading to a candidate for preclinical study.

Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis.

BACKGROUND: Tuberculosis remains an important cause of death among patients infected with the human immunodeficiency virus (HIV). Robust data are lacking with regard to the timing for the initiation of antiretroviral therapy (ART) in relation to the start of antituberculosis therapy. METHODS: We tested the hypothesis that the timing of ART initiation would significantly affect mortality among adults not previously exposed to antiretroviral drugs who had newly diagnosed tuberculosis and CD4+ T-cell counts of 200 per cubic millimeter or lower. After beginning the standard, 6-month treatment for tuberculosis, patients were randomly assigned to either earlier treatment (2 weeks after beginning tuberculosis treatment) or later treatment (8 weeks after) with stavudine, lamivudine, and efavirenz. The primary end point was survival. RESULTS: A total of 661 patients were enrolled and were followed for a median of 25 months. The median CD4+ T-cell count was 25 per cubic millimeter, and the median viral load was 5.64 log(10) copies per milliliter. The risk of death was significantly reduced in the group that received ART earlier, with 59 deaths among 332 patients (18%), as compared with 90 deaths among 329 patients (27%) in the later-ART group (hazard ratio, 0.62; 95% confidence interval [CI]; 0.44 to 0.86; P=0.006). The risk of tuberculosis-associated immune reconstitution inflammatory syndrome was significantly increased in the earlier-ART group (hazard ratio, 2.51; 95% CI, 1.78 to 3.59; P<0.001). Irrespective of the study group, the median gain in the CD4+ T-cell count was 114 per cubic millimeter, and the viral load was undetectable at week 50 in 96.5% of the patients. CONCLUSIONS: Initiating ART 2 weeks after the start of tuberculosis treatment significantly improved survival among HIV-infected adults with CD4+ T-cell counts of 200 per cubic millimeter or lower. (Funded by the French National Agency for Research on AIDS and Viral Hepatitis and the National Institutes of Health; CAMELIA ClinicalTrials.gov number, NCT01300481.).

Natural killer cell degranulation capacity predicts early onset of the immune reconstitution inflammatory syndrome (IRIS) in HIV-infected patients with tuberculosis.

Immune reconstitution inflammatory syndrome (IRIS) is a common and potentially serious complication occurring in HIV-infected patients being treated for tuberculosis (TB) using combined antiretroviral treatment. A role of adaptive immunity has been suggested in the onset of IRIS, whereas the role of natural killer (NK) cells has not yet been explored. The present study sought to examine the involvement of NK cells in the onset of IRIS in HIV-infected patients with TB and to identify predictive markers of IRIS. A total of 128 HIV-infected patients with TB from the Cambodian Early versus Late Introduction of Antiretroviral Drugs (CAMELIA) trial were enrolled in Cambodia. Thirty-seven of the 128 patients developed IRIS. At inclusion, patients had low CD4 cell counts (27 cells/mm(3)) and high plasma viral load (5.76 and 5.50 log/mL in IRIS and non-IRIS patients, respectively). At baseline, NK-cell degranulation capacity was significantly higher in IRIS patients than in non-IRIS patients (9.6% vs 6.38%, P < .005). At IRIS onset, degranulation capacity did not differ between patients, whereas activating receptor expression was lower in IRIS patients. Patients with degranulation levels > 10.84% had a higher risk of IRIS (P = .002 by log-rank test). Degranulation level at baseline was the most important IRIS predictor (hazard ratio = 4.41; 95% confidence interval, 1.60-12.16). We conclude that NK-degranulation levels identify higher IRIS risk in HIV-infected patients with TB.

Enhanced Tumor Targeting of Radiolabeled Mouse/Human Chimeric Anti-Tn Antibody in Losartan-Treated Mice Bearing Tn-Expressing Lung Tumors.

Aim: ChiTn, a mouse/human chimeric anti-Tn monoclonal antibody, was radiolabeled with iodine-131 (131I) and technetium-99m (99mTc) to assess its biodistribution and internalization in Tn-expressing (Tn+) and wild-type (Tn-) LL/2 lung cancer cells. Results: Selective accumulation and gradual internalization of ChiTn were observed in Tn+ cells. Biodistribution in mice with both Tn+ or Tn- lung tumors indicated that the uptake of radiolabeled ChiTn within tumors increased over time. Dual-labeling experiments with 99mTc and 131I showed different biodistribution patterns, with 99mTc exhibiting higher values in the liver, spleen, and kidneys, while 131I showed higher uptake in the thyroid and stomach. However, tumor uptake did not significantly differ between Tn+ and Tn- tumors. To improve tumor targeting, Losartan, an antihypertensive drug known to enhance tumor perfusion and drug delivery, was investigated. Biodistribution studies in Losartan-treated mice revealed significantly higher radiolabeled ChiTn uptake in Tn+ tumors. No significant changes were observed in the uptake of the control molecule IgG-HYNIC™99mTc. Conclusions: These findings demonstrate the enhanced tumor targeting of radiolabeled ChiTn in Losartan-treated mice with Tn-expressing lung tumors. They highlight the potential of ChiTn as a theranostic agent for cancer treatment and emphasize the importance of Losartan as an adjunctive treatment to improve tumor perfusion and drug delivery.

Synergistic Effect of a Flavonoid-Rich Cocoa-Carob Blend and Metformin in Preserving Pancreatic Beta Cells in Zucker Diabetic Fatty Rats.

The loss of functional beta-cell mass in diabetes is directly linked to the development of diabetic complications. Although dietary flavonoids have demonstrated antidiabetic properties, their potential effects on pancreatic beta-cell preservation and their synergistic benefits with antidiabetic drugs remain underexplored. We have developed a potential functional food enriched in flavonoids by combining cocoa powder and carob flour (CCB), which has shown antidiabetic effects. Here, we investigated the ability of the CCB, alone or in combination with metformin, to preserve pancreatic beta cells in an established diabetic context and their potential synergistic effect. Zucker diabetic fatty rats (ZDF) were fed a CCB-rich diet or a control diet, with or without metformin, for 12 weeks. Markers of pancreatic oxidative stress and inflammation, as well as relative beta-cell mass and beta-cell apoptosis, were analyzed. Results demonstrated that CCB feeding counteracted pancreatic oxidative stress by enhancing the antioxidant defense and reducing reactive oxygen species. Moreover, the CCB suppressed islet inflammation by preventing macrophage infiltration into islets and overproduction of pro-inflammatory cytokines, along with the inactivation of nuclear factor kappa B (NFκB). As a result, the CCB supplementation prevented beta-cell apoptosis and the loss of beta cells in ZDF diabetic animals. The observed additive effect when combining the CCB with metformin underscores its potential as an adjuvant therapy to delay the progression of type 2 diabetes.