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Patients with type 2 diabetes (T2D) are threatened by excessive cardiovascular morbidity and mortality. While accelerated arterial stiffening may represent a critical mechanistic factor driving cardiovascular risk in T2D, specific therapies to contain the underlying diabetic arterial remodeling have been elusive. The present translational study investigates the role of microRNA-29b (miR-29b) as a driver and therapeutic target of diabetic aortic remodeling and stiffening. Using a murine model (db/db mice), as well as human aortic tissue samples, we find that diabetic aortic remodeling and stiffening is associated with medial fibrosis, as well as fragmentation of aortic elastic layers. miR-29b is significantly downregulated in T2D and miR-29b repression is sufficient to induce both aortic medial fibrosis and elastin breakdown through upregulation of its direct target genes COL1A1 and MMP2 thereby increasing aortic stiffness. Moreover, antioxidant treatment restores aortic miR-29b levels and counteracts diabetic aortic remodeling. Concluding, we identify miR-29b as a comprehensive—and therefore powerful—regulator of aortic remodeling and stiffening in T2D that moreover qualifies as a (redox-sensitive) target for therapeutic intervention.

Objectives: Flies have been implicated in the dispersal of medically important bacteria including members of the genus Klebsiella between different environmental compartments. The aim of this study was to retrieve and characterize antibiotic-resistant bacteria from flies collected near to hospitals. Methods: Flies were collected in the vicinity of medical facilities and examined for bacteria demonstrating phenotypic resistance to ceftriaxone, followed by determination of phenotypic and genotypic resistance profiles. In addition, whole genome sequencing followed by phylogenetic analysis and resistance genotyping were performed with the multidrug-resistant (MDR) strain Lemef23, identified as Klebsiella quasipneumoniae subsp. similipneumoniae. Results: The strain Lemef23, classified by multiple locus sequence typing as novel ST 3397, harboured numerous resistance genes. The blaNDM was located on a Tn3000 element, a common genetic platform for the carriage of this gene in Brazil. Inference of phylogenetic orthology of strain Lemef23 and other clinical isolates suggested an anthropogenic origin. Conclusions: The findings of this study support the role of flies as vectors of MDR bacteria of clinical importance and provide the first record of blaNDM-1 and blaCTXM-15 in a Brazilian isolate of K. quasipneumoniae subsp. similipneumoniae, demonstrating the value of surveying insects as reservoirs of antibiotic resistance.

Antimicrobial photodynamic therapy (aPDT) has been explored as an innovative therapeutic approach because it can be used to inactivate a variety of microbial forms (vegetative forms and spores) without causing significant damage to host tissues, and without the development of resistance to the photosensitization process. This study assesses the photodynamic antifungal/sporicidal activity of tetra- and octasubstituted phthalocyanine (Pc) dyes with ammonium groups. Tetra- and octasubstituted zinc(II) phthalocyanines (1 and 2) were prepared and tested as photosensitizers (PSs) on Fusarium oxysporum conidia. Photoinactivation (PDI) tests were conducted with photosensitizer (PS) concentrations of 20, 40, and 60 µM under white-light exposure at an irradiance of 135 mW·cm–2, applied during 30 and 60 min (light doses of 243 and 486 J·cm−2). High PDI efficiency corresponding to the inactivation process until the detection limit was observed for both PSs. The tetrasubstituted PS was the most effective, requiring the lowest concentration and the shortest irradiation time for the complete inactivation of conidia (40 µM, 30 min, 243 J·cm−2). Complete inactivation was also achieved with PS 2, but a longer irradiation time and a higher concentration (60 µM, 60 min, 486 J·cm−2) were necessary. Because of the low concentrations and moderate energy doses required to inactivate resistant biological forms such as fungal conidia, these phthalocyanines can be considered potent antifungal photodynamic drugs.

Multifaceted changes in the mechanobiological environment of skeletal joints, at multiple length scales, are central to the development of diseases-like osteoarthritis (OA). Recent evidence demonstrates related mechanical alterations in both bone and cartilage tissues, with crosstalk between the tissues being an important factor in acute and chronic degenerative processes. However, recapitulating multicellular tissue systems in the laboratory to study the entire osteochondral unit remains challenging. Thus, the development of accurate and reproducible OA model systems and the selection of the most suitable model for individual experimental approaches are critical. This review first discusses recent progress in understanding mechanosensory processes in healthy and osteoarthritic joints. Subsequently, we review advancements in the development of in vitro and ex vivo model systems ranging from 2D monocultures through to joint organ-on-a-chip models. Use of these systems allows for the study of multiple cell types in controlled, reproducible, and dynamic environments, which can incorporate precisely controlled mechanical and biochemical stimuli, and biophysical cues. The way in which these models have, and will continue to, improve our ability to recapitulate complex mechanical/paracrine signaling pathways in osteochondral tissues is then discussed. As the accuracy of model systems advances, they will have a significant impact on both our understanding of the pathobiology of OA and in identifying and screening therapeutic targets to improve treatment of this complex disease.

Abstract Astrocytes play crucial and diverse roles in brain health and disease. The ability to selectively control astrocytes provides a valuable tool for understanding their function and has the therapeutic potential to correct dysfunction. Existing technologies such as optogenetics and chemogenetics require the introduction of foreign proteins, which adds a layer of complication and hinders their clinical translation. A novel technique, magnetomechanical stimulation (MMS), that enables remote and selective control of astrocytes without genetic modification is described here. MMS exploits the mechanosensitivity of astrocytes and triggers mechanogated Ca2+ and adenosine triphosphate (ATP) signaling by applying a magnetic field to antibody‐functionalized magnetic particles that are targeted to astrocytes. Using purpose‐built magnetic devices, the mechanosensory threshold of astrocytes is determined, a sub‐micrometer particle for effective MMS is identified, the in vivo fate of the particles is established, and cardiovascular responses are induced in rats after particles are delivered to specific brainstem astrocytes. By eliminating the need for device implantation and genetic modification, MMS is a method for controlling astroglial activity with an improved prospect for clinical application than existing technologies.

The brain receives 20% of cardiac output, but in accord with the current knowledge lacks a specialized sensor of its own blood flow. Here, the authors show that brain astrocytes detect drops in perfusion and trigger compensatory increases in arterial pressure and heart rate to preserve brain blood flow and oxygen delivery.

Medicinal plant species contain vast and unexploited riches of chemical substances with high medical potential making these plant species valuable as biomedicine sources. Cassia fistula L is an important medicinal plant used in many traditional medicinal systems including Ayurveda and Chinese Traditional Medicine. It is a deciduous medium sized tree with elongated and rod-shaped fruits having pulp and have bright yellow flowers, earning the name ‘Yellow Shower’. The present review provides a version of updated information on its botanical description and pharmacological properties including antioxidant, antimicrobial, anti-inflammatory, antidiabetic, antitumor, hepatoprotective among other activities. Pharmacological reviews on medicinal plants will provide valuable information; thus, Cassia fistula L can provide important discoveries of valuable bioactive natural products facilitating in developing novel pharmaceuticals products.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). DM can lead to multiple cardiovascular complications, including coronary artery disease (CAD), cardiac hypertrophy, and heart failure (HF). HF represents one of the most common causes of death in patients with DM and results from DM-induced CAD and diabetic cardiomyopathy. Oxidative stress is closely associated with the pathogenesis of DM and results from overproduction of reactive oxygen species (ROS). ROS overproduction is associated with hyperglycemia and metabolic disorders, such as impaired antioxidant function in conjunction with impaired antioxidant activity. Long-term exposure to oxidative stress in DM induces chronic inflammation and fibrosis in a range of tissues, leading to formation and progression of disease states in these tissues. Indeed, markers for oxidative stress are overexpressed in patients with DM, suggesting that increased ROS may be primarily responsible for the development of diabetic complications. Therefore, an understanding of the pathophysiological mechanisms mediated by oxidative stress is crucial to the prevention and treatment of diabetes-induced CVD. The current review focuses on the relationship between diabetes-induced CVD and oxidative stress, while highlighting the latest insights into this relationship from findings on diabetic heart and vascular disease.

The Leishmania developmental cycle comprises three main life forms in two hosts, indicating that the parasite is continually challenged due to drastic environmental changes. The disruption of this cycle is critical for discovering new therapies to eradicate leishmaniasis, a neglected disease that affects millions worldwide. Telomeres, the physical ends of chromosomes, maintain genome stability and cell proliferation and are potential antiparasitic drug targets. Therefore, understanding how telomere length is regulated during parasite development is vital. Here, we show that telomeres form clusters spread in the nucleoplasm of the three parasite life forms. We also observed that amastigotes telomeres are shorter than metacyclic and procyclic promastigotes and that in parasites with continuous in vitro passages, telomere length increases over time. These observed differences in telomere length among parasite’s life stages were not due to lack/inhibition of telomerase since enzyme activity was detected in all parasite life stages, although the catalysis was temperature-dependent. These data led us to test if, similar to other eukaryotes, parasite telomere length maintenance could be regulated by Hsp83, the ortholog of Hsp90 in trypanosomatids, and Leishmania (LHsp90). Parasites were then treated with the Hsp90 inhibitor 17AAG. The results showed that 17AAG disturbed parasite growth, induced accumulation into G2/M phases, and telomere shortening in a time-dependent manner. It has also inhibited procyclic promastigote’s telomerase activity. Besides, LHsp90 interacts with the telomerase TERT component as shown by immunoprecipitation, strongly suggesting a new role for LHsp90 as a parasite telomerase component involved in controlling telomere length maintenance and parasite life span.

(1) Background: Vaccination of dogs against leptospirosis is of paramount importance, as they ideally must provide not only long-term protection, but also against the renal carrier state of leptospires. This study assessed the post-vaccine humoral response against Leptospira in naturally exposed dogs and effects on renal carrier status. (2) Methods: A total of 118 dogs were studied for 365 days, separated into Group A (vaccinated, n = 94) and Group B (non-vaccinated, n = 24). Group A was subdivided into three groups: A1 with 32 dogs immunized with the vaccine #1; A2 by 32 dogs with #2; and A3 30 dogs with #3. Serology (MAT and IgG-ELISA) and urinary PCR were conducted. (3) Results: Seroreactivity increased at D15 post-vaccination and, regardless of vaccine brand, remained high up to D180, with antibody switch to IgG after D30. A total of 46.8% of animals from Group A were PCR-positive at least once, in contrast to 75% in Group B, regardless of vaccine brand (p < 0.05; OR: 0.3). (4) Conclusions: All commercial vaccines succeeded at eliciting a long-term IgG-based response and were partially effective at protecting against kidney infection.

New technologies have greatly shaped the scientific and medical landscape within the last years. The unprecedented expansion of data and information on RNA biology has led to the discovery of new RNA classes with unique functions and unexpected modifications. Today, the biggest challenge is to transfer the large number of findings in basic RNA biology into corresponding clinical RNA-based therapeutics. Lately, this research begins to yield positive outcomes. RNA drugs advance to the final phases of clinical trials or even receive FDA approval. Furthermore, the introduction of the RNA-guided gene-editing technology CRISPR and advances in the delivery of messenger RNAs have triggered a major progression in the field of RNA-therapeutics. Especially short interfering RNAs and antisense oligonucleotides are promising examples for novel categories of therapeutics. However, several issues need to be addressed including intracellular delivery, toxicity, and immune responses before utilizing RNAs in a clinical setting. In this review, we provide an overview on opportunities and challenges for clinical translation of RNA-based therapeutics, with an emphasis on advances in novel delivery technologies and abdominal aortic aneurysm disease where non-coding RNAs have been shown to play a crucial regulatory role.