Search

Stimuli-responsive nanomaterials have emerged as a promising strategy for inclusion in anticancer therapy. In particular, pH-responsive silica nanocarriers have been studied to provide controlled drug delivery in acidic tumor microenvironments. However, the intracellular microenvironment that the nanosystem must face has an impact on the anticancer effect; therefore, the design of the nanocarrier and the mechanisms that govern drug release play a crucial role in optimizing efficacy. Here, we synthesized and characterized mesoporous silica nanoparticles with transferrin conjugated on their surface via a pH-sensitive imine bond (MSN-Tf) to assess camptothecin (CPT) loading and release. The results showed that CPT-loaded MSN-Tf (MSN-Tf@CPT) had a size of ca. 90 nm, a zeta potential of -18.9 mV, and a loaded content of 13.4%. The release kinetic data best fit a first-order model, and the predominant mechanism was Fickian diffusion. Additionally, a three-parameter model demonstrated the drug-matrix interaction and impact of transferrin in controlling the release of CPT from the nanocarrier. Taken together, these results provide new insights into the behavior of a hydrophobic drug released from a pH-sensitive nanosystem.

Fibrin, derived from proteins involved in blood clotting (fibrinogen and thrombin), is a biopolymer with different applications in the health area since it has hemostasis, biocompatible and three-dimensional physical structure properties, and can be used as scaffolds in tissue regeneration or drug delivery system for cells and/or growth factors. Fibrin alone or together with other biomaterials, has been indicated for use as a biological support to promote the regeneration of stem cells, bone, peripheral nerves, and other injured tissues. In its diversity of forms of application and constitution, there are platelet-rich fibrin (PRF), Leukocyte- and platelet-rich fibrin (L-PRF), fibrin glue or fibrin sealant, and hydrogels. In order to increase fibrin properties, adjuvant therapies can be combined to favor tissue repair, such as photobiomodulation (PBM), by low-level laser therapy (LLLT) or LEDs (Light Emitting Diode). Therefore, this systematic review aimed to evaluate the relationship between PBM and the use of fibrin compounds, referring to the results of previous studies published in PubMed/MEDLINE, Scopus and Web of Science databases. The descriptors "fibrin AND low-level laser therapy" and "fibrin AND photobiomodulation" were used, without restriction on publication time. The bibliographic search found 44 articles in PubMed/MEDLINE, of which 26 were excluded due to duplicity or being outside the eligibility criteria. We also found 40 articles in Web of Science and selected 1 article, 152 articles in Scopus and no article selected, totaling 19 articles for qualitative analysis. The fibrin type most used in combination with PBM was fibrin sealant, mainly heterologous, followed by PRF or L-PRF. In PBM, the gallium-aluminum-arsenide (GaAlAs) laser prevailed, with a wavelength of 830 nm, followed by 810 nm. Among the preclinical studies, the most researched association of fibrin and PBM was the use of fibrin sealants in bone or nerve injuries; in clinical studies, the association of PBM with medication-related treatments osteonecrosis of the jaw (MRONJ). Therefore, there is scientific evidence of the contribution of PBM on fibrin composites, constituting a supporting therapy that acts by stimulating cell activity, angiogenesis, osteoblast activation, axonal growth, anti-inflammatory and anti-edema action, increased collagen synthesis and its maturation, as well as biomolecules.

There are several treatment methods available for bone repair, although the effectiveness becomes limited in cases of large defects. The objective of this pre-clinical protocol was to evaluate the grafting of hydroxyapatite/tricalcium phosphate (BCP) ceramic biomaterial (B; QualyBone BCP ® , QualyLive, Amadora, Portugal) together with the heterologous fibrin biopolymer (FB; CEVAP/UNESP Botucatu, Brazil) and with photobiomodulation (PBM; Laserpulse ® , Ibramed, Amparo, Brazil) in the repair process of bone defects. Fifty-six rats were randomly divided into four groups of seven animals each: the biomaterial group (G1/B), the biomaterial plus FB group (G2/BFB); the biomaterial plus PBM group (G3/B + PBM), and the biomaterial plus FB plus PBM group (G4/BFB + PBM). After anesthesia, a critical defect was performed in the center of the rats' parietal bones, then filled and treated according to their respective groups. The rats were euthanized at 14 and 42 postoperative days. Histomorphologically, at 42 days, the G4/BFB + PBM group showed a more advanced maturation transition, with more organized and mature bone areas forming concentric lamellae. A birefringence analysis of collagen fibers also showed a more advanced degree of maturation for the G4/BFB + PBM group. In the comparison between the groups, in the two experimental periods (14 and 42 days), in relation to the percentage of formation of new bone tissue, a significant difference was found between all groups (G1/B (5.42 ± 1.12; 21.49 ± 4.74), G2/BFB (5.00 ± 0.94; 21.77 ± 2.83), G3/B + PBM (12.65 ± 1.78; 29.29 ± 2.93), and G4/BFB + PBM (12.65 ± 2.32; 31.38 ± 2.89)). It was concluded that the use of PBM with low-level laser therapy (LLLT) positively interfered in the repair process of bone defects previously filled with the biocomplex formed by the heterologous fibrin biopolymer associated with the synthetic ceramic of hydroxyapatite and tricalcium phosphate.

Flavonoids are natural phytochemicals that have therapeutic effects and act in the prevention of several pathologies. These phytochemicals can be found in seeds, grains, tea, coffee, wine, chocolate, cocoa, vegetables and, mainly, in citrus fruits. Neohesperidin, hesperidin and hesperetin are citrus flavonoids from the flavanones subclass that have anti-inflammatory and antioxidant potential. Neohesperidin, in the form of neohesperidin dihydrochalcone (NHDC), also has dietary properties as a sweetener. In general, these flavanones have been investigated as a strategy to control bone diseases, such as osteoporosis and osteoarthritis. In this literature review, we compiled studies that investigated the effects of neohesperidin, hesperidin and its aglycone, hesperetin, on bone health. In vitro studies showed that these flavanones exerted an antiosteoclastic and anti- inflammatory effects, inhibiting the expression of osteoclastic markers and reducing the levels of reactive oxygen species, proinflammatory cytokines and matrix metalloproteinase levels. Similarly, such studies favored the osteogenic potential of preosteoblastic cells and induced the overexpression of osteogenic markers. In vivo, these flavanones favored the regeneration of bone defects and minimized inflammation in arthritis- and periodontitis-induced models. Additionally, they exerted a significant anticatabolic effect in ovariectomy models, reducing trabecular bone loss and increasing bone mineral density. Although research should advance to the clinical field, these flavanones may have therapeutic potential for controlling the progression of metabolic, autoimmune or inflammatory bone diseases.

Cell-based therapy is a promising treatment to favor tissue healing through less invasive strategies. Mesenchymal stem cells (MSCs) highlighted as potential candidates due to their angiogenic, anti-apoptotic and immunomodulatory properties, in addition to their ability to differentiate into several specialized cell lines. Cells can be carried through a biological delivery system, such as fibrin glue, which acts as a temporary matrix that favors cell-matrix interactions and allows local and paracrine functions of MSCs. Thus, the aim of this systematic review was to evaluate the potential of fibrin glue combined with MSCs in nerve regeneration. The bibliographic search was performed in the PubMed/MEDLINE, Web of Science and Embase databases, using the descriptors ("fibrin sealant" OR "fibrin glue") AND "stem cells" AND "nerve regeneration", considering articles published until 2021. To compose this review, 13 in vivo studies were selected, according to the eligibility criteria. MSCs favored axonal regeneration, remyelination of nerve fibers, as well as promoted an increase in the number of myelinated fibers, myelin sheath thickness, number of axons and expression of growth factors, with significant improvement in motor function recovery. This systematic review showed clear evidence that fibrin glue combined with MSCs has the potential to regenerate nervous system lesions.

Cell therapy strategies using mesenchymal stem cells (MSCs) carried in fibrin glue have shown promising results in regenerative medicine. MSCs are crucial for tissue healing because they have angiogenic, anti-apoptotic and immunomodulatory properties, in addition to the ability to differentiate into several specialized cell lines. Fibrin sealant or fibrin glue is a natural polymer involved in the coagulation process. Fibrin glue provides a temporary structure that favors angiogenesis, extracellular matrix deposition and cell-matrix interactions. Additionally, fibrin glue maintains the local and paracrine functions of MSCs, providing tissue regeneration through less invasive clinical procedures. Thus, the objective of this systematic review was to assess the potential of fibrin glue combined with MSCs in bone or cartilage regeneration. The bibliographic search was performed in the PubMed/MEDLINE, LILACS and Embase databases, using the descriptors ("fibrin sealant" OR "fibrin glue") AND "stem cells" AND "bone regeneration", considering articles published until 2021. In this case, 12 preclinical and five clinical studies were selected to compose this review, according to the eligibility criteria. In preclinical studies, fibrin glue loaded with MSCs, alone or associated with bone substitute, significantly favored bone defects regeneration compared to scaffold without cells. Similarly, fibrin glue loaded with MSCs presented considerable potential to regenerate joint cartilage injuries and multiple bone fractures, with significant improvement in clinical parameters and absence of postoperative complications. Therefore, there is clear evidence in the literature that fibrin glue loaded with MSCs, alone or combined with bone substitute, is a promising strategy for treating lesions in bone or cartilaginous tissue.

Lipid nanocarriers have a great potential for improving the physicochemical characteristics and behavior of poorly water-soluble drugs, such as aqueous dispersibility and oral bioavailability. This investigation presents a novel nanostructured lipid carrier (NLC) based on a mixture of solid lipid glycerides, fatty acid esters of PEG 1500 (Gelucire ® 44/14), and an oil mix composed of capric and caprylic triglycerides (Miglyol ® 812). These NLCs were developed by a simple low-energy method based on melt emulsification to yield highly encapsulating and narrowly distributed nanoparticles (~100 nm, PdI = 0.1, and zeta potential = ~-10 mV). Rhodamine 123 was selected as a poorly water-soluble drug model and owing to its spectroscopic properties. The novel NLCs were characterized by dynamic light scattering (DLS), zeta potential, nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and colloidal stability. The drug release was determined through a dialysis bag and vertical Franzs' cells to provide insights about the methods' suitability, revealing similar performance regardless of their different fluid dynamics. Rhodamine 123 followed a characteristic biphasic release profile owing to the swelling of the hydrophilic polymer coating and diffusion process from the lipid core as revealed by the Korsmeyers-Peppas kinetic modeling. Moreover, to elucidate the formation and incorporation of Rhodamine 123 into the NLC core, several molecular dynamics simulations were conducted. The temperature was shown to be an important condition to improve the formation of the nanoparticles. In addition, the liquid lipid incorporation to the formulation forms nanoparticles with imperfect centers, in contrast to nanoparticles without it. Moreover, Miglyol ® 812 improves hydrophobic molecule solubility. These results suggest the potential of novel NLC as a drug delivery system for poorly water-soluble drugs.

Age-related macular degeneration (AMD) is the leading cause of central vision loss and severe blindness among the elderly population. Recently, we reported on the association of the SGCD gene (encoding for δ-sarcoglycan) polymorphisms with AMD. However, the functional consequence of Sgcd alterations in retinal degeneration is not known. Herein, we characterized changes in the retina of the Sgcd knocked-out mouse (KO, Sgcd -/- ). At baseline, we analyzed the retina structure of three-month-old wild-type (WT, Sgcd +/+ ) and Sgcd -/- mice by hematoxylin and eosin (H&E) staining, assessed the Sgcd-protein complex (α-, β-, γ-, and ε-sarcoglycan, and sarcospan) by immunofluorescence (IF) and Western blot (WB), and performed electroretinography. Compared to the WT, Sgcd -/- mice are five times more likely to have retinal ruptures. Additionally, all the retinal layers are significantly thinner, more so in the inner plexiform layer (IPL). In addition, the number of nuclei in the KO versus the WT is ever so slightly increased. WT mice express Sgcd-protein partners in specific retinal layers, and as expected, KO mice have decreased or no protein expression, with a significant increase in the α subunit. At three months of age, there were no significant differences in the scotopic electroretinographic responses, regarding both a- and b-waves. According to our data, Sgcd -/- has a phenotype that is compatible with retinal degeneration.

CFH and HTRA1 genes are traditional markers of increased risk of age-related macular degeneration (AMD) across populations. Recent findings suggest that additional genes-for instance, in the dystrophin-associated protein complex-might be promising markers for AMD. Here, we performed a case-control study to assess the effect of SGCD single nucleotide polymorphisms (SNPs), a member of this protein family, on AMD diagnosis and phenotype. We performed a case-control study of an under-studied population from Hispanics in Mexico City, with 134 cases with 134 unpaired controls. Cases were 60 years or older (Clinical Age-Related Maculopathy Staging (CARMS) grade 4⁻5, as assessed by experienced ophthalmologists following the American Association of Ophthalmology (AAO) guidelines), without other retinal disease or history of vitreous-retinal surgery. Controls were outpatients aged 60 years or older, with no drusen or retinal pigment epithelium (RPE) changes on a fundus exam and a negative family history of AMD. We examined SNPs in the SGCD gene (rs931798, rs140617, rs140616, and rs970476) by sequencing and real-time PCR. Genotyping quality checks and univariate analyses were performed with PLINK v1.90b3.42. Furthermore, logistic regression models were done in SAS v.9.4 and haplotype configurations in R v.3.3.1. After adjusting for clinical covariates, the G/A genotype of the SGCD gene (rs931798) significantly increases the odds of being diagnosed with AMD in 81% of cases (1.81; 95% CI 1.06⁻3.14; p = 0.031), especially the geographic atrophy phenotype (1.82; 95% CI 1.03⁻3.21; p = 0.038) compared to the G/G homozygous genotype. Moreover, the GATT haplotype in this gene (rs931798, rs140617, rs140616, and rs970476) is associated with lower odds of AMD (adjusted odds ratio (OR) 0.13; 95% CI 0.02⁻0.91; p = 0.041). SGCD is a promising gene for AMD research. Further corroboration in other populations is warranted, especially among other Hispanic ethnicities., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; final the writing of the manuscript; or in the decision to publish the results.

Although data from both animals and humans suggests that adult cocaine use can have long term effects on behavior, it is unknown if prior cocaine use affects future maternal behavior in nulliparous females. In the current study, cocaine or saline was administered to adult female rats for 10 days, the animals were withdrawn from cocaine for 7 days, and the females were then exposed to donor pups to induce the expression of maternal behavior. Nulliparous females sensitized to cocaine were more likely to retrieve pups, spent more time caring for the pups, and were more likely to express full maternal behavior on day 8 of pup exposure. The fMRI data revealed significant effects of pup exposure in the hippocampal CA1 region, and effects of cocaine in the anterior thalamus and periaqueductal gray. Prior adult cocaine use may have lasting effects on offspring care, and this effect is not dependent on pup mediated effects or the endocrine changes of gestation and lactation. The present findings provide support for the hypothesis that maternal motivation to exhibit maternal behavior is enhanced by prior cocaine sensitization, possibly due to cross sensitization between cocaine and the natural reward of maternal behavior.