Comparative Analysis of the Antioxidative and Hepatoprotective Activities of Dimethyl Diphenyl Bicarboxylate in Four Animal Models of Hepatic Injury

As a well-known hepatoprotective and antioxidant agent, dimethyl diphenyl bicarboxylate (DDB) has frequently been employed to remedy various liver diseases. However, it is still uncertain whether DDB exerts consistent hepatoprotective and antioxidative activities against varying degrees of hepatic damage. Therefore, DDB (100, 25, 5, or 50 mg/kg depending on the model) was administered to animals in four representative models of liver injury (CCl4 chemical acute model, DMN subchronic model, TAA chronic model, and restraint stress psychological acute model). Horizontal comparative analysis indicated that DDB significantly lowered the excess serum AST and ALT levels in the CCl4 and DMN models but not in the TAA and restraint stress models. In accordance with this result, DDB markedly reduced oxidative stress indices (hepatic MDA and ROS) but restored five main antioxidant components (GSH content, GSH-peroxidase, GSH-reductase, SOD, and catalase activity) in the CCl4 and DMN models. DDB failed to normalize oxidative stressors in the restraint stress-induced injury model and restore these five antioxidant components in the TAA model. Overall, our results produced a comprehensive overview of the effects of DDB on oxidative stressors and the main antioxidative components using four animal models. These findings will provide valuable clues to guide therapeutic clinical applications.

Should We Open Fire on Microglia? Depletion Models as Tools to Elucidate Microglial Role in Health and Alzheimer’s Disease

Microglia play a critical role in both homeostasis and disease, displaying a wide variety in terms of density, functional markers and transcriptomic profiles along the different brain regions as well as under injury or pathological conditions, such as Alzheimer’s disease (AD). The generation of reliable models to study into a dysfunctional microglia context could provide new knowledge towards the contribution of these cells in AD. In this work, we included an overview of different microglial depletion approaches. We also reported unpublished data from our genetic microglial depletion model, Cx3cr1CreER/Csf1rflx/flx, in which we temporally controlled microglia depletion by either intraperitoneal (acute model) or oral (chronic model) tamoxifen administration. Our results reported a clear microglial repopulation, then pointing out that our model would mimic a context of microglial replacement instead of microglial dysfunction. Next, we evaluated the origin and pattern of microglial repopulation. Additionally, we also reviewed previous works assessing the effects of microglial depletion in the progression of Aβ and Tau pathologies, where controversial data are found, probably due to the heterogeneous and time-varying microglial phenotypes observed in AD. Despite that, microglial depletion represents a promising tool to assess microglial role in AD and design therapeutic strategies.

Design and Synthesis In Silico Drug-like Prediction and Pharmacological Evaluation of Cyclopolymethylenic Homologous of LASSBio-1514

Acylhydrazones are still an important framework to the design of new bioactive compounds. As treatment of chronic pain represents a clinical challenge, we decided to modify the structure of LASSBio-1514 (1), previously described as anti-inflammatory and analgesic prototype. Applying the homologation as a strategy for molecular modification, we designed a series of cyclopentyl- (2a–e), cyclobutyl- (3a–e), and cyclopropylacylhydrazones (4a–e) that were synthetized and evaluated in murine models of inflammation and pain. A comparison of their in silico physicochemical and drug-like profile was conducted, as well as their anti-inflammatory and analgesic effect. Compounds 4a (LASSBio-1755) and 4e (LASSBio-1757) displayed excellent in silico drug-like profiles and were identified as new analgesic lead-candidates in acute and chronic model of pain, through oral administration.

Distribution and Afferent Effects of Transplanted mESCs on Cochlea in Acute and Chronic Neural Hearing Loss Models

Hearing loss is a sensory deprivation that can affect the quality of life. Currently, only rehabilitation devices such as hearing aids and cochlear implants are used, without a definitive cure. However, in chronic hearing-deprived patients, in whom secondary auditory neural degeneration is expected, a relatively poor rehabilitation prognosis is projected. Stem cell therapy for cochlear neural structures would be an easier and feasible strategy compared with cochlear sensory cells. Considering the highly developed cochlear implantation technology, improving cochlear neural health has significant medical and social effects. Stem cell delivery to Rosenthal’s canal in an acutely damaged mouse model has been performed and showed cell survival and the possibility of differentiation. The results of stem cell transplantation in chronic auditory neural hearing loss should be evaluated because neural stem cell replacement therapy for chronic (long-term) sensorineural hearing loss is a major target in clinics. In the present study, we established a mouse model that mimicked chronic auditory neural hearing loss (secondary degeneration of auditory neurons after loss of sensory input). Then, mouse embryonic stem cells (mESCs) were transplanted into the scala tympani and survival and distribution of transplanted cells were compared between the acute and chronic auditory neural hearing loss models induced by ouabain or kanamycin (KM), respectively. The mESC survival was similar to the acute model, and perilymphatic distribution of cell aggregates was more predominant in the chronic model. Lastly, the effects of mESC transplantation on neural signal transduction observed in the cochlear nucleus (CN) were compared and a statistical increase was observed in the chronic model compared with other models. These results indicated that after transplantation, mESCs survived in the cochlea and increased the neural signaling toward the central auditory pathway, even in the chronic (secondary) hearing loss mouse model.

Glycine/NMDA Receptor Pathway Mediates the Rapid-onset Antidepressant Effect of Alkaloids From Trichilia Monadelpha

Introduction: Major depressive disorder is often associated with suicidal tendencies, and this condition accentuates the need for rapid-acting antidepressants. We previously reported that Alkaloids (ALK) from Trichilia monadelpha possess antidepressant action in acute animal models of depression and that this effect is mediated through the monoamine and L-arginine-NO-cGMP pathways. This study investigated the possible rapid-onset antidepressant effect of ALK from T. monadelpha and its connection with the glycine/NMDA receptor pathway. Methods: The onset of ALK action from T. monadelpha was evaluated using the Open Space Swim Test (OSST), a chronic model of depression. The modified forced swimming and tail suspension tests were used to assess the effect of the ALK on the glycine/NMDA receptor pathway. The Instutute of Cancer Research (ICR) mice were treated with either ALK (30–300 mg/kg, orally [PO]), imipramine (3–30 mg/kg, PO), fluoxetine (3–30 mg/kg, PO), or saline. To identify the role of glycine/NMDA receptor pathway in the effect of ALK, we pretreated mice with a partial agonist of the glycine/NMDA receptor, D-cycloserine (2.5 mg/kg, intraperitoneally [IP]), and an agonist of glycine/NMDA receptor, D-serine (600 mg/kg, IP), before ALK administration. Results: ALK reversed immobility in mice after the second day of drug treatment in the OSST. In contrast, there was a delay in the effects induced by fluoxetine and imipramine. ALK also increased mean swimming and climbing scores in mice. ALK was more efficacious than imipramine and fluoxetine in reducing immobility and increasing distance traveled. It is noteworthy that ALK was less potent than fluoxetine and imipramine. D-cycloserine potentiated mobility observed in the ALK- and fluoxetine-treated mice. In contrast, D-serine decreased mobility in the ALK-treated mice. Conclusion: The study results suggest that ALK from T. monadelpha exhibits rapid antidepressant action in mice, and the glycine/NMDA receptor pathway possibly mediates the observed effect.

MicroRNA-874-3p/ADAM (A Disintegrin and Metalloprotease) 19 Mediates Macrophage Activation and Renal Fibrosis After Acute Kidney Injury

Inflammation and maladaptive repair play a crucial role in the development of chronic kidney disease and hypertension after acute kidney injury. To study the mechanisms involved in acute kidney injury-to-chronic kidney disease transition, we established a chronic renal fibrosis mouse model that was triggered by an initial ischemia/reperfusion–induced acute kidney injury (acute-chronic model). Downregulation of microRNA-874-3p during renal fibrosis was identified by a genome-wide RNA-sequencing and was further confirmed in cell-based assays, mouse models, and human samples. Overexpression of microRNA-874-3p in the kidneys markedly alleviated renal fibrosis, accompanied with decreased infiltrated macrophages and expression of α-smooth muscle actin, type I collagen, fibronectin, CCL (C-C motif chemokine ligand) 2, and ADAM (A Disintegrin and Metalloprotease) 19. ADAM19 is a target gene of microRNA-874-3p as shown by luciferase reporter assays and was upregulated in the acute-chronic model. Overexpression of ADAM19 directly induced the expression of fibrotic genes, CCL2, and macrophage infiltration in vivo. Depletion of macrophages using clodronate liposomes ameliorated the fibrogenic effects of ADAM19. Overexpression of ADAM19 also induced accumulation of the Notch1 intracellular domain, an upstream regulator of CCL2 expression, whereas Notch1 pathway antagonist N-(N-[3,5-difluorophenacetyl]-L-alanyl)-S-phenylglycine t-butyl ester reduced CCL2 level in ADAM19-overexpressed cells. Collectively, microRNA-874-3p/ADAM19 mediates renal fibrosis after acute kidney injury by increasing macrophage infiltration via the Notch1/CCL2 pathway.

Chronic mild and acute severe glaucomatous neurodegeneration derived from silicone oil-induced ocular hypertension

Recently, we established silicone oil-induced ocular hypertension (SOHU) mouse model with significant glaucomatous neurodegeneration. Here we characterize two additional variations of this model that simulate two distinct glaucoma types. The first is a chronic model produced by high frequency (HF) pupillary dilation after SO-induced pupillary block, which shows sustained moderate IOP elevation and corresponding slow, mild glaucomatous neurodegeneration. We also demonstrate that although SO removal quickly returns IOP to normal, the glaucomatous neurodegeneration continues to advance to a similar degree as in the HF group without SO removal. The second, an acute model created by no pupillary dilation (ND), shows a greatly elevated IOP and severe inner retina degeneration at an early time point. Therefore, by a straightforward dilation scheme, we extend our original SOHU model to recapitulate phenotypes of two major glaucoma forms, which will be invaluable for selecting neuroprotectants and elucidating their molecular mechanisms.