Search

Background: Therapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD. Methods: Longitudinal plasma and cross-sectional CSF samples were collected from the YAC128 transgenic mouse model of HD and wild-type (WT) littermate control mice throughout the natural history of disease. Additionally, biofluids were collected from YAC128 mice following intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting the mutant HTT transgene (HTT ASO), at ages both before and after the onset of disease phenotypes. NfL concentrations in plasma and CSF were quantified using ultrasensitive single-molecule array technology. Results: Plasma and CSF NfL concentrations were significantly elevated in YAC128 compared to WT littermate control mice from 9 months of age. Treatment of YAC128 mice with either 15 or 50 µg HTT ASO resulted in a dose-dependent, allele-selective reduction of mHTT throughout the brain at a 3-month interval, which was sustained with high-dose HTT ASO treatment for up to 6 months. Lowering of brain mHTT prior to the onset of regional brain atrophy and HD-like motor deficits in this model had minimal effect on plasma NfL at either dose, but led to a dose-dependent reduction of CSF NfL. In contrast, initiating mHTT lowering in the brain after the onset of neuropathological and behavioural phenotypes in YAC128 mice resulted in a dose-dependent stabilization of NfL increases in both plasma and CSF. Conclusions: Our data provide evidence that the response of NfL in biofluids is influenced by the magnitude of mHTT lowering in the brain and the timing of intervention, suggesting that NfL may serve as a promising exploratory response biomarker for HD. [ABSTRACT FROM AUTHOR]

BackgroundMethodsResultsConclusionThe incidence of osteoarthritis (OA) is increasing, yet its pathogenesis remains largely unknown. Recent studies suggest that abnormal subchondral bone remodeling plays a crucial role in OA development, highlighting a gap in clinical treatments targeting this aspect. Soybean Isoflavone (SI) has shown potential in treating OA, although its mechanisms are not fully understood.This research investigated the effects of SI on subchondral bone remodeling in an OA rat model, assessing joint damage, OARSI scores, and type H vessel formation (CD31hiEmcnhi expression). Additionally, the expression of ALP, OCN, BMP, and TSC1 was evaluated to determine involvement of the mTORC1 pathway. In vitro studies on IL-1β-induced osteoblasts further examined the impact of SI on TSC1/mTORC1 signaling and related markers.SI treatment reduced joint damage and OARSI scores in the rat OA model, significantly decreasing CD31hiEmcnhi expression, indicating a reduction in type H vessel formation. SI also downregulated ALP, OCN, and BMP expression while upregulating TSC1, suggesting inhibition of the mTORC1 signaling pathway and VEGF release. In vitro, SI increased TSC1 expression and decreased mTORC1 signaling, VEGF, ALP, OCN, and BMP levels in IL-1β-induced osteoblasts.SI targets the TSC1/mTORC1 signaling pathway to suppress osteoblast activation and VEGF release, inhibiting type H vessel formation and slowing abnormal subchondral bone remodeling. These findings provide a novel therapeutic approach for OA by focusing on subchondral bone remodeling mechanisms. [ABSTRACT FROM AUTHOR]

Our previous study has demonstrated that sulfated Chinese yam polysaccharide (SCYP) can improve immunomodulatory activity in Raw 264.7 cells. However, its anti‐inflammatory is little known. In this study, the anti‐inflammatory effects of SCYP were systematically investigated via the Lipopolysaccharides (LPS)‐induced Raw264.7 cell model, Caco‐2/Raw264.7 co‐culture system, and acute inflammation mice model. The results suggested SCYP promoted the cell proliferation and have no toxicity in Raw264.7 and Caco‐2 cells at the concentration of 200 µg/mL. Moreover, when treated with SCYP, the production of pro‐inflammatory cytokines (interleukin [IL]‐1β, IL‐6, and tumor necrosis factor‐α) reduced significantly in Raw264.7 via the MAPK/NF‐κB pathway. In the Caco‐2/Raw264.7 co‐cultured system, SCYP could regulate inflammation reaction by improving intestinal barrier, which might prevent systemic inflammation. Further, systemic inflammation was alleviated by SCYP in LPS‐induced acute inflammation mice through MAPK/NF‐κB pathway. Practical Application: These results supported that SCYP may be used as an anti‐inflammation agent in the functional food field. [ABSTRACT FROM AUTHOR]

The accumulation of α-synuclein induces neuronal loss in midbrain nuclei and leads to the disruption of motor circuits, while the pathology of α-synuclein in cortical regions remains elusive. To better characterize cortical synucleinopathy, here we generate a mouse model with the overexpression of human α-synuclein in the primary motor cortex (M1) of mice. A combination of molecular, in vivo recording, and behavioral approaches reveal that cortical expression of human α-synuclein results in the overexcitation of cortical pyramidal neurons (PNs), which are regulated by the decreased inhibitory inputs from parvalbumin-interneurons (PV-INs) to impair complex motor skill learning. Further mechanistic dissections reveal that human α-synuclein aggregation activates ferroptosis, contributing to PV-IN degeneration and motor circuit dysfunction. Taken together, the current study adds more knowledge to the emerging role and pathogenic mechanism of ferroptosis in neurodegenerative diseases. Serially mechanistic studies reveal the role of ferroptosis in disrupting the normal excitatory-inhibitory balance of the motor cortex after overexpressing human α-synuclein. [ABSTRACT FROM AUTHOR]

The secondary injuries following traumatic spinal cord injury (SCI) is a multiphasic and complex process that is difficult to treat. Although methylprednisolone (MP) is the only available pharmacological regime for SCI treatment, its efficacy remains controversial due to its very narrow therapeutic time window and safety concerns associated with high dosage. In this study, we have developed an oil-in-gel type of organohydrogel (OHG) in which the binary oleic-water phases coexist, for the local delivery of MP. This new OHG is fabricated by a glycol chitosan/oxidized hyaluronic acid hydrophilic network that is uniformly embedded with a biocompatible oil phase, and it can be effectively loaded with MP or other hydrophobic compounds. In addition to spatiotemporally control MP release, this biodegradable OHG also provides a brain tissue-mimicking scaffold that can promote tissue regeneration. OHG remarkably decreases the therapeutic dose of MP in animals and extends its treatment course over 21 d, thereby timely manipulating microglia/macrophages and their associated with signaling molecules to restore immune homeostasis, leading to a long-term functional improvement in a complete transection SCI rat model. Thus, this OHG represents a new type of gel for clinical treatment of secondary injuries in SCI. [Display omitted] [ABSTRACT FROM AUTHOR]

Ventral tegmental area (VTA) dopamine (DA) neurons have been found to substantially associate with post-traumatic stress disorder (PTSD) pathology, however, whether and how these DA neurons affect fear memory management in PTSD individuals remains largely unknown. In this study, we utilized auditory conditioned foot-shock to evaluate the fear memory retrieval and retention characteristics in a single prolonged stress-induced PTSD rat model. We employed chemogenetic technology to specifically activate VTA DA neurons to examine the freezing behaviors responding to the conditioned stimuli. In vivo extracellular electrophysiological analyses were used to identify VTA DA neuronal firing alterations due to the chemogenetic activation. The results demonstrated that PTSD model rats showed comparable fear memory retrieval (Day 2 after the conditioned foot-shock), but significant enhancements in fear memory retention (Day 8 after the conditioned foot-shock), compared to normal control rats. Chemogenetic activation of VTA DA neurons markedly diminished the retention of fear memory in PTSD model rats, which appeared concomitantly with increases in the firing activities of the DA neurons. These findings revealed that PTSD induced the persistence of fear memory, which could be attenuated by activation of VTA DA neurons. It is presumed that VTA dopaminergic signals may serve as a prospective option for PTSD treatment. [ABSTRACT FROM AUTHOR]

Background: Spinal cord injury (SCI) presents a major global health challenge, with rising incidence rates and substantial disability. Although progress has been made in understanding SCI's pathophysiology and early management, there is still a lack of effective treatments to mitigate long-term consequences. This study investigates the potential of sovateltide, a selective endothelin B receptor agonist, in improving clinical outcomes in an acute SCI rat model. Methods: Thirty male Sprague–Dawley rats underwent sham surgery (group A) or SCI and treated with vehicle (group B) or sovateltide (group C). Clinical tests, including Basso, Beattie, and Bresnahan scoring, inclined plane, and allodynia testing with von Frey hair, were performed at various time points. Statistical analyses assessed treatment effects. Results: Sovateltide administration significantly improved motor function, reducing neurological deficits and enhancing locomotor recovery compared with vehicle-treated rats, starting from day 7 post injury. Additionally, the allodynic threshold improved, suggesting antinociceptive properties. Notably, the sovateltide group demonstrated sustained recovery, and even reached preinjury performance levels, whereas the vehicle group plateaued. Conclusions: This study suggests that sovateltide may offer neuroprotective effects, enhancing neurogenesis and angiogenesis. Furthermore, it may possess anti-inflammatory and antinociceptive properties. Future clinical trials are needed to validate these findings, but sovateltide shows promise as a potential therapeutic strategy to improve functional outcomes in SCI. Sovateltide, an endothelin B receptor agonist, exhibits neuroprotective properties, enhancing motor recovery and ameliorating hyperalgesia in a rat SCI model. These findings could pave the way for innovative pharmacological interventions for SCI in clinical settings. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to investigate the impact of local windfall gains from the Spanish Christmas lottery on household consumption behavior. Design/methodology/approach: The study applies differences-in-differences to assess permanent income hypothesis (PIH) validity, examining pre- and postlottery consumption effects. Additionally, it also uses an instrumental variable regression, using the lottery shock as an instrument for total expenditures, to estimate the Engel curves. Findings: The paper finds a PIH violation; households in winning region notably increase consumption on durable and nondurable goods compared to nonwinning ones. Moreover, durable goods consumption is responsive to lottery winnings, while nondurable goods consumption are unit-elastic to expenditure shocks. Originality/value: To the best of the author's knowledge, this is the first paper analyzing the effects of winning regions of the Spanish Christmas lottery in all types of consumption goods, testing its consequences in the PIH and estimating its effects in the Engel curves. [ABSTRACT FROM AUTHOR]

Bone loss caused by long-duration spaceflight seriously affects the skeletal health of astronauts. There are many shortcomings in currently available treatments for weightlessness-induced bone loss. The aim of this study was to evaluate the preventive effect of Angelica dahuricae Radix (AR) on simulated microgravity-induced bone loss. Here, we established a hind limb unloading (HLU) mouse model and treated HLU mice with AR (2 g/kg) for 4 weeks. Results indicated that AR significantly inhibited simulated microgravity-induced bone loss. In addition, the components in AR were analyzed using UPLC-MS/MS; results showed that a total of 224 compounds were detected in AR, which mainly contained 7 classes of components. Moreover, the network pharmacological predictions suggested that active ingredients of AR might act on PTGS2 to prevent bone loss. These results elucidate the efficacy of AR in preventing microgravity-induced bone loss and its potential for use in protecting the bone health of astronauts. [ABSTRACT FROM AUTHOR]

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Improvement is needed in the remedies used to control Th2 polarization. Bioengineering approaches have modified immune cells that have immunosuppressive functions. This study aims to generate modified eosinophils (Meos) in vivo and use Meos to balance Th2 polarization and reduce airway allergy. Methods: A cell editor was constructed. The editor contained a peptide carrier, an anti-siglec F antibody, MHC II, ovalbumin, and LgDNA (DNA extracted from a probiotic, Lactobacillus rhamnosus GG). Which was designated as Cedit. Meos are eosinophils modified using Cedits. An airway Th2 polarization mouse model was established used to test the effect of Meos on suppressing airway allergy. Results: The Cedits remained physically and chemically stable in solution (pH7.2) for at least 96 h. Cedits specifically bound to eosinophils, which are designated as Meos. Meos produced programmed death ligand-1 (PD-L1); the latter induced antigen specific CD4+ T cell apoptosis. Administration of Cedits through nasal instillations generated Meos in vivo, which significantly reduced the frequency of antigen specific CD4+ T cells in the airways, and mitigated airway Th2 polarization. Conclusions: We constructed Cedit, which could edit eosinophils into Meos in vivo. Meos could induce antigen specific CD4+ T cell apoptosis, and reconcile airway Th2 polarization. [ABSTRACT FROM AUTHOR]

Copper plays a key role in host-pathogen interaction. We find that during Leishmania major infection, the parasite-harboring macrophage regulates its copper homeostasis pathway in a way to facilitate copper-mediated neutralization of the pathogen. Copper-ATPase ATP7A transports copper to amastigote-harboring phagolysosomes to induce stress on parasites. Leishmania in order to evade the copper stress, utilizes a variety of manipulative measures to lower the host-induced copper stress. It induces deglycosylation and degradation of host-ATP7A and downregulation of copper importer, CTR1 by cysteine oxidation. Additionally, Leishmania induces CTR1 endocytosis that arrests copper uptake. In mouse model of infection, we report an increase in systemic bioavailable copper in infected animals. Heart acts as the major organ for diverting its copper reserves to systemic circulation to fight-off infection by downregulating its CTR1. Our study explores reciprocal mechanism of manipulation of host copper homeostasis pathway by macrophage and Leishmania to gain respective advantages in host-pathogen interaction. Leishmania major alters host copper dynamics. Macrophages utilize copper via ATP7A to stress the pathogen, countered by Leishmania that reduces ATP7A and the copper importer CTR1. Infection elevates mouse systemic copper that aids in its defense. [ABSTRACT FROM AUTHOR]

Alcohol use disorder is highly prevalent worldwide, with characteristically severe pain sensitivity during withdrawal. Here, we established a mouse model of hyperalgesia during ethanol withdrawal (EW) before addiction to investigate the window for onset and underlying mechanisms. Viral tracing with in vivo microendoscopic and two-photon calcium imaging identified a circuit pathway from dorsal hippocampal CA1 glutamatergic neurons (dCA1Glu) to anterior cingulate cortex glutamatergic neurons (ACCGlu) activated in EW mice with hyperalgesia. Chemogenetic inhibition of this pathway can alleviate hyperalgesia in EW mice, whereas artificial activation recapitulates EW-induced hyperalgesia in naïve mice. These findings demonstrate that the dCA1Glu - ACCGlu neuronal pathway participates in driving EW-induced hyperalgesia before ethanol dependence in mice. [ABSTRACT FROM AUTHOR]

AbstractIn this study, the anti-inflammatory, antioxidative, and protective effects of ghrelin were investigated in a fat-fed streptozotocin (STZ) rat model and compared with metformin, diabetes and the healthy control groups. Histopathological evaluations were performed on H&E-stained pancreas and brain sections. Biochemical parameters were investigated by enzyme-linked immunosorbent assay. Blood glucose levels were significantly decreased with ghrelin or metformin treatments than the diabetes group. STZ administration increased brain, renal and pancreatic IL-1β, TNF-α and MDA while decreasing GPX, CAT, SOD, and NGF levels. Ghrelin increased renal GPX, CAT, NGF pancreatic GPX, SOD, CAT, NGF and brain SOD, NGF while it decreased renal, pancreatic and brain IL-1β, TNF-α and MDA levels. Ghrelin reduced neuronal loss and degeneration in the cerebral cortex and hippocampus and greatly ameliorated diabetes-related damage in pancreas. In conclusion, the data suggested that ghrelin is an effective candidate as a protectant for reducing the adverse effects of diabetes. [ABSTRACT FROM AUTHOR]

AbstractThis study aimed to evaluate the anti-inflammatory activity of the combination of Ardisia humilis Vahl. and Curcuma xanthorrhiza Roxb. (AC) extract in monosodium iodoacetate (MIA)-induced osteoarthritis (OA) rat model. AC was administered orally to OA rats (240, 480, and 960 mg/kg bw) for three weeks. The control and model groups comprised OA rats treated with diclofenac sodium and carrier, respectively. AC-treated rats exhibited a significant reduction in oedema volume compared to those of the model group (p < 0.05). Notably, AC, at 960 mg/kg bw, significantly decreased inflammatory cytokines TNF-α and IL-1β, along with matrix metalloproteinase-9 (MMP-9) levels compared to those of the model group (p < 0.05). AC's attenuation of OA progression was also observed through haematoxylin and eosin (H&E) and Safranin O-fast green analysis. A phytochemical study showed AC contained phenolic, flavonoid, curcumin, demethoxycurcumin, and bisdemethoxycurcumin compounds. This study concludes that AC alleviated OA progression through anti-inflammatory effects and depressed MMP-9 levels. [ABSTRACT FROM AUTHOR]

The presence of circulating tumor cells (CTCs) and inadequate immune response limit the therapy effectiveness of tumor metastasis. Epithelial‐mesenchymal transition (EMT), serving as the pivotal initial step in the formation of CTCs, plays a critical role in facilitating tumor metastasis. High expression of CD24 in tumor cells is strongly associated with EMT and immune evasion, but little work has been reported on the inhibitory effect of CD24 blockade on EMT. Here, a nanotherapeutic agent (Au/anti‐CD24@Fu) is fabricated through loading anti‐CD24 antibodies (anti‐CD24) onto Au nanocups, accompanied by surface modification with Fucoidan (Fu). Fu serves as a guide, while Au functions as a controller, jointly facilitating the precise delivery of anti‐CD24 to the tumor site and enabling controlled release. The synergistic collaboration between Fu and anti‐CD24 effectively eliminates the “don't eat me” signal mediated by CD24, thereby augmenting macrophage recognition and phagocytosis. Additionally, it simultaneously obstructs the EMT process facilitated by CD24‐P‐selectin from both ends, consequently impeding the formation of CTCs. Au/anti‐CD24@Fu displays favorable antitumor and anti‐metastasis effect in both 4T1‐bearing mice model and patient‐derived xenografts (PDX) model. This study validates the significance of CD24 blockade in augmenting the antitumor immune response and suppressing the EMT process. [ABSTRACT FROM AUTHOR]

Mouse models are crucial for understanding pulmonary hypertension (PH) mechanisms and developing therapies, but existing mouse models under hypoxia only exhibit mild PH. To address this, we established a double‐hit model combining unilateral pneumonectomy (LPx) or left pulmonary artery ligation (LPAL) with hypoxia exposure in C57BL/6 mice. Our detailed haemodynamic and histological evaluations post‐surgery demonstrated pronounced elevations in right ventricular systolic pressure (RVSP) (LPAL: 41.1 ± 4.63 mmHg, P = 0.005; LPx: 38.4 ± 2.95 mmHg, P = 0.002; Sham: 32.1 ± 2.21 mmHg) and pulmonary vascular wall thickness (LPAL: 56.9 ± 3.34%, P = 0.02; LPx: 54.3 ± 4.65%, P = 0.04; Sham: 44.8 ± 3.76%) compared to hypoxia‐exposed sham‐operated controls, reflecting a more severe PH phenotype. These novel models, which exhibit haemodynamic alterations akin to the established hypoxia with SU5416‐induced PH model as per published data, could offer a substantial contribution to future PH research and therapeutic development. [ABSTRACT FROM AUTHOR]

Pathogenic variants in SF3B4, a component of the U2 snRNP complex important for branchpoint sequence recognition and splicing, are responsible for the acrofacial disorders Nager and Rodriguez Syndrome, also known as SF3B4-related syndromes. Patients exhibit malformations in the head, face, limbs, vertebrae as well as the heart. To uncover the etiology of craniofacial malformations found in SF3B4-related syndromes, mutant mouse lines with homozygous deletion of Sf3b4 in neural crest cells (NCC) were generated. Like in human patients, these embryos had craniofacial and cardiac malformations with variable expressivity and penetrance. The severity and survival of Sf3b4 NCC mutants was modified by the level of Sf3b4 in neighboring non-NCC. RNA sequencing analysis of heads of embryos prior to morphological abnormalities revealed significant changes in expression of genes forming the NCC regulatory network, as well as an increase in exon skipping. Additionally, several key histone modifiers involved in craniofacial and cardiac development showed increased exon skipping. Increased exon skipping was also associated with use of a more proximal branch point, as well as an enrichment in thymidine bases in the 50 bp around the branch points. We propose that decrease in Sf3b4 causes changes in the expression and splicing of transcripts required for proper craniofacial and cardiac development, leading to abnormalities. [ABSTRACT FROM AUTHOR]

Spinal cord ischemic-reperfusion injury (SCIRI) could occurs during surgical procedures without detection, presenting a complex course and an unfavorable prognosis. This may lead to postoperative sensory or motor dysfunction in areas innervated by the spinal cord, and in some cases, permanent paralysis. Timely detection of SCIRI and immediate waring can help surgeons implement remedial intervention to prevent irreversible spinal cord injury. Therefore, it is crucial to develop a precise and effective method for early detection of SCIRI. This study utilized rat models to simulate intraoperative SCIRI and employed somatosensory evoked potentials (SEP) for continuous monitoring during surgery. In this study, SEP signal changes were examined in six groups with varying severities of SCIRI and one normal control group. SEP signal changes were examined during operations in different groups and correlated with postoperative behavioral and histopathological data. The result demonstrated specific changes in SEP signals during SCIRI, termed as time-varying characteristics, which are associated with the duration of ischemia and subsequent reperfusion. Timevarying characteristics in SEP could potentially serve as a new biomarker for the intraoperative detection of SCIRI. This finding is significant for clinical surgeons to identify and guide early intervention of SCIRI timely. Additionally, this measurement is easily translatable to clinical application. [ABSTRACT FROM AUTHOR]

Abstract\nPLAIN LANGUAGE SUMMARYThis study aimed to explore the critical role of FUNDC1 on epithelial cells in model of asthma. Patients with asthma and normal healthy volunteers were obtained from our hospital. The serum of FUNDC1 mRNA expression was down-regulated in patients with asthma. Meanwhile, the serum of FUNDC1 mRNA expression was positive correlation with IgE and anti-HDM IgE protein. FUNDC1 expression in lung tissue of mice model was decreased in mice model of asthma. Sh-FUNDC1 enhanced asthma in mice model of asthma. FUNDC1 up-regulation reduced IL-4, IL-5, IL-10 and IL-13 activity levels in vitro model of asthma.FUNDC1 down-regulation promoted IL-4, IL-5, IL-10 and IL-13 activity levels in vitro model of asthma. FUNDC1 reduced ferroptosis of epithelial cells in model of asthma through the inhibition of mitochondrial damage. FUNDC1 induced FBXL2 and AR protein expression in model of asthma. FUNDC1 interlinked with FBXL2 is modified by SUMO1 at K136. FBXL2, ASN-205, GLN-204, ARG-235, and GLN-237 form hydrogen bonds with FUNDC1's ASP-15, ASP-16, GLU-25, and ARG-29, with lengths of 2.3, 3.1, 2.9, 2.3, and 2.9 Å, respectively. The induction of FBXL2 reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma. The inhibition of AR reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma Overall, FUNDC1 prevents ferroptosis of airway epithelial cells of asthma through FBXL2/AR/GPX4 signaling pathway of SUMO1 at K136. FUNDC1 might benefit the treatment of asthma or other pulmonary disease.FUNDC1 prevents ferroptosis of airway epithelial cells of asthma through FBXL2/AR/GPX4 signaling pathway of SUMO1 at K136. FUNDC1 might benefit the treatment of asthma or other pulmonary disease. [ABSTRACT FROM AUTHOR]

Background: Chiari-like malformation in dogs and Chiari malformation type 1 in humans are conditions characterized by a relatively small caudal cranial fossa, leading to cerebellar herniation. This study aimed to develop a rat model of Chiari-like malformation using surgical techniques based on morphological characteristics observed in dogs. Methods: Endocranial magnetic resonance images of both normal dogs and dogs diagnosed with Chiari-like malformation were retrospectively analyzed. Measurements of the caudal cranial fossa volume, rostral and medial fossa volume, and volume index were taken. The differences in caudal cranial fossa volume and volume index between normal dogs and those diagnosed with Chiari-like malformation were then utilized to create a rat model of Chiari-like malformation through surgical intervention. The measurements were conducted on both the rat Chiari-like malformation models and normal rats, with each measurement taken twice and the mean values calculated. Results: Significant differences were found between normal dogs and dogs diagnosed with Chiari-like malformation in terms of the volume of the caudal cranial fossa (27.62% reduction) and the volume index (23.36% reduction) (p<0.05). These differences were used to develop a rat model, which also showed significant reductions in both caudal cranial fossa volume (29.52%) and volume index (28.30%) compared to normal rats (p<0.05). The condition in the rat model was confirmed through magnetic resonance imaging, which revealed cerebellar herniation into the foramen magnum. Conclusions: The study successfully established a rat model of Chiari-like malformation that accurately reproduces the morphological features observed in dogs. This model potentially serves as a valuable tool for investigating the pathological mechanisms and potential therapeutic approaches for Chiari-like malformation in veterinary medicine. [ABSTRACT FROM AUTHOR]

The use of fibroblast activation protein inhibitors (FAPis) for positron emission tomography (PET) imaging in cancer has garnered significant interest in recent years, yielding promising results in preclinical and clinical settings. FAP is predominantly expressed in pathological conditions such as fibrosis and cancer, making it a compelling target. An optimized approach involves using FAPi homodimers as PET tracers, which enhance tumor uptake and retention, making them more effective candidates for therapy. Here, a UAMC-1110 inhibitor-based homodimer, DOTAGA-Glu(FAPi)2, was synthesized and radiolabeled with gallium-68, and its efficacy was evaluated in vivo for PET imaging in an endogenously FAP-expressing xenografted mouse model, U87MG. Notably, 45 min post-injection, the mean uptake of [68Ga]Ga-DOTAGA-Glu(FAPi)2 was 4.7 ± 0.5% ID/g in the tumor with low off-target accumulation. The ex vivo analysis of the FAP expression in the tumors confirmed the in vivo results. These findings highlight and confirm the tracer's potential for diagnostic imaging of cancer and as a theranostic companion. [ABSTRACT FROM AUTHOR]

A problem of systemic pharmacotherapy is off‐target activity, which causes adverse effects. Outstanding examples include neuroinhibitory medications like antiseizure drugs, which are used against epilepsy and neuropathic pain but cause systemic side effects. There is a need of drugs that inhibit nerve signals locally and on‐demand without affecting other regions of the body. Photopharmacology aims to address this problem with light‐activated drugs and localized illumination in the target organ. Here, we have developed photoswitchable derivatives of the widely prescribed antiseizure drug carbamazepine. For that purpose, we expanded our method of ortho azologization of tricyclic drugs to meta/para and to N‐bridged diazocine. Our results validate the concept of ortho cryptoazologs (uniquely exemplified by Carbazopine‐1) and bring to light Carbadiazocine (8), which can be photoswitched between 400–590 nm light (using violet LEDs and halogen lamps) and shows good drug‐likeness and predicted safety. Both compounds display photoswitchable activity in vitro and in translucent zebrafish larvae. Carbadiazocine (8) also offers in vivo analgesic efficacy (mechanical and thermal stimuli) in a rat model of neuropathic pain and a simple and compelling treatment demonstration with non‐invasive illumination. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the predominant type of end-stage renal disease. Increasing evidence suggests thatglomerular mesangial cell (MC) inflammation is pivotal for cell proliferation and DKD progression. However, the exactmechanism of MC inflammation remains largely unknown. This study aims to elucidate the role of inflammatoryfactor high-mobility group box 1 (Hmgb1) in DKD. Inflammatory factors related to DKD progression are screened viaRNA sequencing (RNA-seq). In vivo and in vitro experiments, including db/db diabetic mice model, CCK-8 assay, EdUassay, flow cytometric analysis, Co-IP, FISH, qRT-PCR, western blot, single cell nuclear RNA sequencing (snRNA-seq),are performed to investigate the effects of Hmgb1 on the inflammatory behavior of MCs in DKD. Here, wedemonstrate that Hmgb1 is significantly upregulated in renal tissues of DKD mice and mesangial cells cultured withhigh glucose, and Hmgb1 cytopasmic accumulation promotes MC inflammation and proliferation. Mechanistically,Hmgb1 cytopasmic accumulation is two-way regulated by MC-specific cyto-lncRNA E130307A14Rik interaction andlactate-mediated acetylated and lactylated Hmgb1 nucleocytoplasmic translocation, and accelerates NFκB signalingpathway activation via directly binding to IκBα. Together, this work reveals the promoting role of Hmgb1 on MCinflammation and proliferation in DKD and helps expound the regulation of Hmgb1 cytopasmic accumulation in twoways. In particular, Hmgb1 may be a promising therapeutic target for DKD. [ABSTRACT FROM AUTHOR]

• Fascia manipulation decrease inflammatory pain. • Caffeine blocks analgesia by fascia manipulation. • Peripheral and spinal adenosine A 1 receptor is involved in the analgesia by fascia manipulation. The role of adenosine receptors in fascial manipulation-induced analgesia has not yet been investigated. The purpose of this study was to evaluate the involvement of the adenosine A 1 receptor (A 1 R) in the antihyperalgesic effect of plantar fascia manipulation (PFM), specifically in mice with peripheral inflammation. Mice injected with Complete Freund's Adjuvant (CFA) underwent behavioral, i.e. mechanical hyperalgesia and edema. The mice underwent PFM for either 3, 9 or 15 min. Response frequency to mechanical stimuli was then assessed at 24 and 96 h after plantar CFA injection. The adenosinergic receptors were assessed by systemic (intraperitoneal, i.p.), central (intrathecal, i.t.), and peripheral (intraplantar, i.pl.) administration of caffeine. The participation of the A 1 R was investigated using the 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), a selective A 1 R subtype antagonist. PFM inhibited mechanical hyperalgesia induced by CFA injection and did not reduce paw edema. Furthermore, the antihyperalgesic effect of PFM was prevented by pretreatment of the animals with caffeine given by i.p., i.pl., and i.t. routes. In addition, i.pl. and i.t. administrations of DPCPX blocked the antihyperalgesia caused by PFM. These observations indicate that adenosine receptors mediate the antihyperalgesic effect of PFM. Caffeine's inhibition of PFM-induced antihyperalgesia suggests that a more precise understanding of how fascia-manipulation and caffeine interact is warranted. [ABSTRACT FROM AUTHOR]

Background: Limited availability and side effects of opioids have led to an increased use of non-opioid analgesia in animal disease models. However, by affecting the immune-inflammatory reactions, analgesia may disrupt the resolution of the host inflammation and modulate the survival in septic animals. This study used a clinically relevant sepsis mouse model of peritoneal contamination and infection (PCI) to investigate the antinociceptive and antiinflammatory properties of two non-opioid analgesics. Methods: Adult C57BL/6Jmicewere intraperitoneally injected with a human feces suspension and received either no analgesics (Non-A), Meloxicam, or Metamizole orally. The mice were monitored for pain and illness. Mortality was assessed at 7 days post-PCI. A separate group of mice was sacrificed 24 hours after infection. Blood, peritoneal lavage fluid (PLF), liver, and spleen were harvested for pathogen load quantification via qPCR, macrophage phenotyping, neutrophil infiltration/activation, and systemic/tissue cytokine release by flow cytometry. Results: Meloxicam but not Metamizole reduced the mortality of septic mice by 31% on day 7 compared to the Non-A group. Both analgesics effectively alleviated pain but did not affect illness severity, body weight, and temperature. Meloxicam quadrupled the bacterial burden in the blood and PLF. In high IL-6 responders, Meloxicam treatment was associated with reduced circulating IL-10 and IL-1b compared to the Non-A septic group. In low IL-6 responders, Meloxicam increased circulating MCP-1 levels and decreased PGE2 levels compared to Non-A septic mice. Notably, Meloxicam reduced spleen neutrophil infiltration by 20% compared to two other sepsis groups. Conclusion: Metamizole and Meloxicam effectively relieved pain and increased the animals' basal activity in the PCI sepsis model. Meloxicam prolonged survival yet triggered maladaptive responses due to its immunosuppressive features that decreased tissue bacterial clearance during sepsis. In contrast, Metamizole constitutes a safe and effective non-opioid alternative for analgesic control in the non-surgical PCI sepsis model. [ABSTRACT FROM AUTHOR]

Post‐stroke depression is a common complication that imposes significant burdens and challenges on patients. The occurrence of depression is often associated with frontal lobe hemorrhage, however, current understanding of the underlying mechanisms remains limited. Here, the pathogenic mechanisms associated with the circuitry connectivity, electrophysiological alterations, and molecular characteristics are investigated related to the frontal lobe in adult male mice following unilateral injection of blood in the medial prefrontal cortex (mPFC). It is demonstrated that depression is a specific neurological complication in the unilateral hematoma model of the mPFC, and the ventral tegmental area (VTA) shows a higher percentage of connectivity disruption compared to the lateral habenula (LHb) and striatum (STR). Additionally, long‐range projections originating from the frontal lobe demonstrate higher damage percentages within the connections between each region and the mPFC. mPFC neurons reveal reduced neuronal excitability and altered synaptic communication. Furthermore, transcriptomic analysis identifies the involvement of the Janus Kinase‐Signal Transducer and Activator of Transcription (JAK‐STAT) signaling pathway, and targeting the JAK‐STAT pathway significantly alleviates the severity of depressive symptoms. These findings improve the understanding of post‐hemorrhagic depression and may guide the development of efficient treatments. [ABSTRACT FROM AUTHOR]

Failure rate after chronic rotator cuff repair is considerably high. Moreover, diabetes mellitus is known as a compromising factor of rotator cuff tear. The effect of Polydeoxyribonucleotide (PDRN) and polynucleotide (PN) on tendon healing and fatty infiltration is unclear as tissue regeneration activator in diabetic state. Therefore, a diabetic rat model with chronic rotator cuff tear was made for mechanical, histologic and blood tests. In the animal study using a diabetic rat cuff repair model, the administration of PDRN and PN increased the load to failure of repaired cuffs and improved tendon healing and decreased fatty infiltration. Also, the plasma levels of vascular endothelial growth factor and fibroblast growth factor were elevated in PDRN and PN administrated groups. We concluded that PDRN and PN appear to boost tendon recovery and reduce the presence of fatty infiltration following cuff repair in diabetic state. Also, PN showed a later onset and a longer duration than PDRN associated with the mean plasma growth factors. [ABSTRACT FROM AUTHOR]

Background: Dolutegravir (DTG), an integrase strand inhibitor, is currently used as the first-line treatment for HIV. Despite relatively poor tissue penetration, the risk of adverse effects in metabolic and excretory systems should be considered. The trace aminergic system and trace amines are emerging as relevant role players in many chronic diseases that are commonly diagnosed but poorly understood. Trace amines are biogenic amines that are endogenously produced and can also be ingested by the intake of trace amine-rich food. Trace amines are known to differentially regulate inflammatory and neurological outcome. Objective: This study investigated the effects of DTG on the trace amine profile in a wistar rat model. Methods: A total of 24 healthy wistar rats were randomly divided into four experimental groups: male and female controls and male and female DTG-treated. Blood and tissue samples were collected following a 12-week DTG administration study. Liquid chromatography-tandem mass spectroscopy (LC-MS/MS) was used to determine trace amine concentrations in urine, plasma, brain, and gastrointestinal tissue. Results: Current data illustrate that polyamines differ significantly (p < 0.05) between males and females in various matrices. DTG significantly (p < 0.05) reduced jejunal tyramine and urinary synephrine levels. Conclusion: Data do not raise major concerns about DTG in the context of the trace amine profile. However, given the importance of the dysregulated trace amine profile in various diseased states, including HIV, current data warrant clinical investigation to further evaluate the significance of DTG-associated effects on the trace amine profile. [ABSTRACT FROM AUTHOR]

Attention deficits are frequently reported within the clinical autism population. Despite not being a core diagnostic feature, some aetiological theories place atypical attention at the centre of autism development. Drugs used to treat attention dysfunction are therefore increasingly prescribed to autistic patients, though currently off‐label with uncertain efficacy. We utilised a rodent‐translated touchscreen test of sustained attention in mice carrying an autism‐associated R451C mutation in the neuroligin‐3 gene (Nlgn3R451C). In doing so, we replicated their cautious but accurate response profile and probed it using two widely prescribed attention‐modulating drugs: methylphenidate (MPH) and atomoxetine (ATO). In wild‐type mice, acute administration of MPH (3 mg/kg) promoted impulsive responding at the expense of accuracy, while ATO (3 mg/kg) broadly reduced impulsive responding. These drug effects were absent in Nlgn3R451C mice, other than a small reduction in blank touches to the screen following ATO administration. The absence of drug effects in Nlgn3R451C mice likely arises from their altered behavioural baseline and underlying neurobiology, highlighting caveats to the use of classic attention‐modulating drugs across disorders and autism subsets. It further suggests that altered dopaminergic and/or norepinephrinergic systems may drive behavioural differences in the Nlgn3R451C mouse model of autism, supporting further targeted investigation. [ABSTRACT FROM AUTHOR]

Fear overgeneralization is widely accepted as a pathogenic marker of post‐traumatic stress disorder (PTSD). Recently, GABAergic interneurons have been regarded as key players in the regulation of fear memory. The role of hippocampal GABAergic interneurons in contextual fear generalization of PTSD remains incompletely understood. In the present study, we established a rat model of PTSD with inescapable foot shocks (IFS) and observed the loss of GABAergic interneuron phenotype in the hippocampal cornu ammonis‐1 (CA1) subfield. To determine whether the loss of GABAergic interneuron phenotype was associated with fear generalization in PTSD rats, we used adeno‐associated virus (AAV) to reduce the expression of GAD67 in CA1 and observed its effect on fear generalization. The results showed that the reduction of GAD67 in CA1 enhanced contextual fear generalization in rats. We investigated whether the PERK pathway was involved in the GABAergic interneuron injury. Increased expression of p‐PERK, CHOP, and Caspase12 in GABAergic interneurons of PTSD rats was observed. Then, we used salubrinal, an endoplasmic reticulum stress inhibitor, to modulate the PERK pathway. The salubrinal treatment significantly protected the GABAergic interneurons and relieved fear generalization in PTSD rats. In addition, the results showed that salubrinal down‐regulated the expression of CHOP and Caspase12 in GABAergic interneurons of PTSD rats. In conclusion, this study provided evidence that the loss of GABAergic interneuron phenotype in CA1 may contribute to contextual fear generalization in PTSD. The PERK pathway is involved in the GABAergic interneuron injury of PTSD rats and modulating it can protect GABAergic interneurons and constrain contextual fear generalization. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a chronic condition that causes permanent disability, particularly cognitive impairment resulting from glial scar formation. Minocycline treatment inhibits glial scar formation through the Ciliary Neurotropic Factor (CNTF) pathway in multiple sclerosis. We hypothesized that minocycline could also inhibit CNTF, which would play a role in the inhibition of glial scar formation in TBI. The objective was to evaluate the role of minocycline in inhibiting glial scar formation through the CNTF signaling pathway and ameliorating cognitive impairment in TBI model rats. Male Sprague Dawley rats (n = 16) were divided into 4 groups (n = 4/group). TBI through the weight drop model is performed on day 0, followed by minocycline treatment of 25 mg/kg (MNO1 group), 50 mg/kg (MNO2 group) and 100 mg/kg (MNO3 group) given for 14 days. The NOR test is performed on day 15, followed by immunofluorescence double staining on day 16. Minocycline plays a role in inhibiting glial scar formation in TBI model rats. Minocycline inhibits the formation of CNTF with an effect proportion of 66.3 %, which plays a role in inhibiting glial scar in the perilesional area in TBI model rats. Inhibition of glial scar improves cognitive function impairment in TBI model rats. Administration of minocycline improves cognitive function in TBI model rats with an effect proportion of 46.7 %. It can be concluded that minocycline inhibits glial scar through the inhibition of CNTF expression and ameliorates cognitive impairment in a rat model of TBI. [ABSTRACT FROM AUTHOR]

Fibromyalgia (FM) is a widespread musculoskeletal pain associated with psychological disturbances, the etiopathogenesis of which is still not clear. One hypothesis implicates inflammatory cytokines in increasing central and peripheral sensitization along with neuroinflammation, leading to an elevation in pro-inflammatory cytokines, e.g., interleukin-17A (IL-17A), enhanced in FM patients and animal models. The intermittent cold stress (ICS)-induced FM-like model in C57BL/6 mice has been developed since 2008 and proved to have features which mimic the clinical pattern in FM patients such as mechanical allodynia, hyperalgesia, and female predominance of pain. Electroacupuncture (EA) is an effective treatment for relieving pain in FM patients, but its mechanism is not totally clear. It was reported as attenuating pain-like behaviors in the ICS mice model through the transient receptor potential vanilloid 1 (TRPV1) pathway. Limited information indicates that TRPV1-positive neurons trigger IL-17A-mediated inflammation. Therefore, we hypothesized that the IL-17A would be inactivated by EA and TRPV1 deletion in the ICS-induced FM-like model in mice. We distributed mice into a control (CON) group, ICS-induced FM model (FM) group, FM model with EA treatment (EA) group, FM model with sham EA treatment (Sham) group, and TRPV1 gene deletion (Trpv1−/−) group. In the result, ICS-induced mechanical and thermal hyperalgesia increased pro-inflammatory cytokines including IL-6, IL-17, TNFα, and IFNγ in the plasma, as well as TRPV1, IL-17RA, pPI3K, pAkt, pERK, pp38, pJNK, and NF-κB in the somatosensory cortex (SSC) and cerebellum (CB) lobes V, VI, and VII. Moreover, EA and Trpv1−/− but not sham EA countered these effects significantly. The molecular mechanism may involve the pro-inflammatory cytokines, including IL-6, IL-17, TNFα, and IFNγ. IL-17A–IL-17RA play a crucial role in peripheral and central sensitization as well as neuroinflammation and cannot be activated without TRPV1 in the ICS mice model. EA alleviated FM-pain-like behaviors, possibly by abolishing the TRPV1- and IL-17A-related pathways. It suggests that EA is an effective and potential therapeutic strategy in FM. [ABSTRACT FROM AUTHOR]

Introduction: Porokeratosis (PK) is an autoinflammatory keratinization disease (AIKD) characterized by circular or annular skin lesions with a hyperkeratotic rim, pathologically shown as the cornoid lamella. Four genes that cause PK are associated with the mevalonate (MV) pathway. In Chinese PK patients, mevalonate diphosphate decarboxylase (MVD) is the most common causative gene. The lack of an animal model has greatly limited research on PK pathogenesis. Materials and Methods: In this research, we constructed K14‐CreERT2‐Mvdfl/fl mice using the Cre‐LoxP system to create a mouse model for in‐depth studies of PK. The Epidermal Mvd gene was knocked out by intraperitoneal injection of Tamoxifen (TAM). Pathology, immunohistochemistry, RNA‐seq, and Western Blot analysis were performed. Results: Skin lesions appeared following Mvd deficiency, and pathological examination revealed the characteristic cornoid lamella, as well as cutaneous inflammation. Furthermore, we observed elevated levels of IL‐17A and IL‐1β, and a decreased Loricrin level in epidermal Mvd‐deficient mice. Compared with the wild‐type (WT) group, Mvd deficiency activated the expression of lipid metabolism‐related proteins. Conclusion: We developed the first mouse model for PK research, enabling further studies on disease development and treatment approaches. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte hyperproliferation, inflammation, and aberrant differentiation. Imiquimod-induced psoriasis in rodent models has been widely used to study the pathogenesis of the disease and evaluate potential therapeutic interventions. In this study, we investigated the efficacy of two commonly used treatments, Clobetasol and Tacrolimus, in ameliorating psoriatic symptoms in an Imiquimod-induced psoriasis Wistar rat model. Interestingly, rat models are poorly evaluated in the literature despite rats displaying several advantages in evaluating pharmacological substances. Psoriasis-like skin lesions were induced by topical application of Imiquimod cream on shaved dorsal skin for seven consecutive days. Following induction, rats in the treatment groups received either a Clobetasol or Tacrolimus ointment once daily for one week, while the control group did not receive any application. Disease severity was assessed using clinical scoring, histological examination, and measurement of proinflammatory cytokine levels. Both Clobetasol and Tacrolimus treatments significantly reduced psoriatic lesion severity compared to the control group. Clinical scoring revealed a decrease in erythema, scaling, transepidermal water loss, and thickness of skin lesions in both treatment groups with a more marked effect with Clobetasol. Histological analysis demonstrated reduced epidermal hyperplasia in treated animals compared to controls. Furthermore, Clobetasol led to a significant reduction in the expression levels of the interleukin-17 (IL-17a and IL-17f) proinflammatory cytokines in lesioned skin. Overall, our findings demonstrated the therapeutic efficacy of both Clobetasol and, in a modest manner, Tacrolimus in attenuating Imiquimod-induced psoriasis-like symptoms in a rat model. These results support the clinical use of these agents in the management of psoriasis and mitigating psoriatic inflammation. They also provide insights into the use of rats as a relevant species for the Imiquimod-induced psoriasis model. [ABSTRACT FROM AUTHOR]

Chronic subdural hematoma (cSDH), a condition that develops over time, is characterized by inflammation, angiogenesis, and membrane development. As the population's average age increases, the incidence of cSDH is expected to grow. While surgery is the primary treatment technique, medicinal therapy options are being explored for high-risk patients. Currently, the most effective therapy combination is dexamethasone (Dex) and atorvastatin (Ato); however, it is associated with an increased risk of mortality. This study explored the effects of bevacizumab (Bev), a vascular endothelial growth factor antagonist, on cSDH. Ninety-five rats were divided into four groups (n = 18): sham, control hematoma, Dex-Ato, and Bev. Two separate autologous blood injections into the subdural space were used as the model. Weight was monitored for all rats to assess changes in their overall health. The control group was given i.p. saline, the Dex-Ato treatment was given by gavage, and the Bev treatment was given i.p. On seventh, 14th and 21st days six rats from each group were sacrificed and analyzed, while 23 rats were excluded from the experiment. The maximum immunological response to cSDH was observed on day 14. Hematoma volume decreased over time in all groups. Dex-Ato and Bev were both found effective, while Dex-Ato caused weight loss. Bev had similar effects to the Dex-Ato group and was well tolerated by rats. Given that cSDH is a disease of the elderly and vulnerable populations, Bev may be a viable alternative that can shed light on the disease's etiology for future research. [ABSTRACT FROM AUTHOR]

Background: Myocardial infarction (MI) is known worldwide for its important disabling features, including myocarditis and cardiomyocyte apoptosis. It is believed that microRNA (miRNA) has a role in the cellular processes of apoptosis and myocarditis, and miR-219a-5p has been found to suppress the inflammatory response. However, unknown is the precise mechanism by which miR-219a-5p contributes to MI. Methods: We measured the expression of miR-219a-5p and evaluated its effects on target proteins, inflammatory factors, and apoptosis in a mouse model of MI. Echocardiography was utilized to examine the MI clinical index, and triphenyl tetrazolium chloride staining was employed to analyze the infarcted region. Enzyme-linked immunosorbent assay and Western blotting measured serum and molecular markers in heart tissues. To quantify the association with miR-219a-5p and ATPase sarcoplasmic/endoplasmic reticulum Ca2+transporting 2 (ATP2A2), the luciferase activity assay and Pearson's correlation analysis were employed. Results: MiR-219a-5p exhibited low expression in a mouse model of MI, and its amplification prevented both apoptotic and inflammatory reactions. Specifically, miR-219a-5p targeted ATP2A2. Conclusion: In a mouse model of MI, miR-219a-5p exerted a potent protective effect via direct targeting of ATP2A2. [ABSTRACT FROM AUTHOR]

Multiple studies have shown that astrocytes in the medullary dorsal horn (MDH) play an important role in the development of pathologic pain. However, little is known about the structural reorganization of the peripheral astrocytic processes (PAP), the main functional part of the astrocyte, in MDH in neuropathic state. For this, we investigated the structural relationship between PAP and their adjacent presynaptic axon terminals and postsynaptic dendrites in the superficial laminae of the MDH using electron microscopical immunohistochemistry for ezrin, a marker for PAP, and quantitative analysis in a rat model of neuropathic pain following chronic constriction injury of the infraorbital nerve (CCI-ION). We found that, compared to controls, in rats with CCI-ION, (1) the number, % area, surface density, and volume fraction of ezrin-positive (+) PAP, as well as the fraction of synaptic edge apposed by ezrin + PAP and the degree of its coverage of presynaptic axon terminals and postsynaptic dendrites increased significantly, (2) these effects were abolished by administration of the mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP). These findings indicate that PAP undergoes structural reorganization around the central synapses of sensory afferents following nerve injury, suggest that it may be mediated by mGluR5, and may represent the structural basis for enhancing astrocyte-neuron interaction in neuropathic pain. [ABSTRACT FROM AUTHOR]

The main purpose of the present study was to evaluate the therapeutic efficacy of Aloe vera-coated curcumin encapsulated nanoparticles in mitigating Alzheimer's disease progression in mice, by examining behavioural changes, biochemical markers, and histopathological alterations, thus elucidating its potential as a treatment strategy. The green synthesis method was used to synthesise this nanoformulation, which was then characterised using a variety of techniques, including percentage encapsulation efficacy, UV-visible spectroscopy, DLS, FT-IR, FESEM, and EDX. Several in-vivo assessments, including behavioural evaluations, dose optimisation studies, oxidative stress marker estimation, and histological studies, were conducted to determine the potential therapeutic impact of nanoformulation on the Alzheimer-induced mice model. The synthesised nanoparticles show a mean diameter of 76.12 nm ±1.23, a PDI of 0.313 ± 0.02, a zeta potential of 6.27 ± 0.65 mV, and the percentage encapsulation efficiency between 90% and 95% indicating good stability of synthesised nanoformulation. With the help of Morris water maze, Y-maze, and novel object recognition assay, the learning capacity and memory were assessed, and the results show that the synthesised nanoformulation significantly decreased the transfer latency to reach baited arm or to the hidden platform within 7 days. The formulation demonstrated significant biochemical benefits and remarkable cognitive advantages, establishing it as a prospective therapeutic intervention option that is both safe and effective. [ABSTRACT FROM AUTHOR]

Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis. In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used. After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior. Only rodent models of depression were used, and human samples were not included. The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression. • miR-29a-5p is downregulated by chronic stress. • Upregulation of miR-29a-5p improved depression-like behavior. • miR-29a-5p deficits in prefrontal cortex mediate microglial anomalies. • miR-29a-5p and TMEM33 are potential therapeutic targets for depression treatment. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the pathogenesis of CLCN6‐related disease and to assess whether its Cl−/H+‐exchange activity is crucial for the biological role of ClC‐6. Methods: We performed whole‐exome sequencing on a girl with development delay, intractable epilepsy, behavioral abnormities, retinal dysfunction, progressive brain atrophy, suggestive of neuronal ceroid lipofuscinoses (NCLs). We generated and analyzed the first knock‐in mouse model of a patient variant (p.E200A) and compared it with a Clcn6−/− mouse model. Additional functional tests were performed with heterologous expression of mutant ClC‐6. Results: We identified a de novo heterozygous p.E200A variant in the proband. Expression of disease‐causing ClC‐6E200A or ClC‐6Y553C mutants blocked autophagic flux and activated transcription factors EB (TFEB) and E3 (TFE3), leading to autophagic vesicle and cholesterol accumulation. Such alterations were absent with a transport‐deficient ClC‐6E267A mutant. Clcn6E200A/+ mice developed severe neurodegeneration with typical features of NCLs. Mutant ClC‐6E200A, but not loss of ClC‐6 in Clcn6−/− mice, increased lysosomal biogenesis by suppressing mTORC1‐TFEB signaling, blocked autophagic flux through impairing lysosomal function, and increased apoptosis. Carbohydrate and lipid deposits accumulated in Clcn6E200A/+ brain, while only lipid storage was found in Clcn6−/− brain. Lysosome dysfunction, autophagy defects, and gliosis were early pathogenic events preceding neuron loss. Interpretation: CLCN6 is a novel genetic cause of NCLs, highlighting the importance of considering CLCN6 mutations in the diagnostic workup for molecularly undefined forms of NCLs. Uncoupling of Cl− transport from H+ countertransport in the E200A mutant has a dominant effect on the autophagic/lysosomal pathway. ANN NEUROL 2024;96:608–624 [ABSTRACT FROM AUTHOR]

Diabetes mellitus (DM) is a prevalent metabolic disorder often accompanied by oxidative stress, which contributes to various diabetic complications. Investigating the antioxidant activity of linalool (LIN) is crucial as it may offer a natural therapeutic approach to mitigate oxidative damage in DM. The aim of the present study was to investigate the antioxidant activity of LIN in a DM rat model. A total of 40 male Wistar albino rats (age, 8 weeks; weight, 250-300 g) were used. CONTROL and DM groups were administered physiological saline solution by oral gavage for 21 days. In rats in the DM + LIN and LIN groups, 100 mg/kg LIN was administered intragastrically after streptozotocin injection (n=10 per group). In the first (48 h after STZ injection), second (1 week later), third (2 weeks later), and fourth (3 weeks later) blood glucose measurements, a statistically significant increase was found in the blood glucose values of the DM and DM + LIN groups compared with those of the CONTROL group. During the 21-day experimental period, there was no reduction in blood glucose levels of the DM + LIN group. Consequently, no discernible anti-hyperglycemic effect of LIN was observed. Catalase enzyme activity, superoxide dismutase (SOD) enzyme activity, malondialdehyde (MDA) levels and glutathione (GSH) levels were measured spectrophotometrically. All assays were conducted according to the protocols provided in the respective kits. The results were analyzed to assess the oxidative status and antioxidant capacity in the experimental groups. Catalase (CAT) activity was decreased in the DM group compared with that in the CONTROL group in both the serum and liver. However, LIN administration restored CAT activity in the DM + LIN group to the level of the CONTROL group. In the liver, the DM + LIN-treated group showed a notable reduction in malondialdehyde (MDA) levels compared with those in the DM group. In conclusion, the present results suggest that the antioxidant properties of LIN may have a regulatory effect on the oxidative status in diabetes-affected systems, potentially offering therapeutic benefits in managing oxidative stress associated with diabetes. [ABSTRACT FROM AUTHOR]

Despite the great progress in developing wound dressings, delayed wound closure still remains a global challenge. Thus, developing novel wound dressings and employing advanced strategies, including tissue engineering, are urgently desired. The carboxylated cellulose was developed through the in situ synthesis method and further reinforced by incorporating pal-KTTKS to stimulate collagen synthesis and improve wound healing. The developed composites supported cell adhesion and proliferation and showed good biocompatibility. To boost wound-healing performance, adipose-derived mesenchymal stem cells (MSC) were seeded on the pal-KTTKS-enriched composites to be implanted in a rat model of burn wound healing. Healthy male rats were randomly divided into four groups and wound-healing performance of Vaseline gauze (control), carboxylated cellulose (CBC), pal-KTTKS-enriched CBC (KTTKS-CBC), and MSCs seeded on the KTTKS-CBC composites (MSC-KTTKS-CBC) were evaluated on days 3, 7, and 14 post-implantation. In each group, the designed therapeutic dressings were renewed every 5 days to increase wound-healing performance. We found that KTTKS-CBC and MSC-KTTKS-CBC composites exhibited significantly better wound healing capability, as evidenced by significantly alleviated inflammation, increased collagen deposition, improved angiogenesis, and considerably accelerated wound closure. Nevertheless, the best wound-healing performance was observed in the MSC-KTTKS-CBC groups among all four groups. This research suggests that the MSC-KTTKS-CBC composite offers a great deal of promise as a wound dressing to enhance wound regeneration and expedite wound closure in the clinic. [ABSTRACT FROM AUTHOR]

The primary function of the skin is to form a mechanical, permeability, antimicrobial, and ultraviolet radiation barrier, which is essential for maintaining physiological homeostasis. Our previous studies demonstrated that cutaneous pigmentation could promote skin barrier function in addition to providing anti‐ultraviolet irradiation defense. The present study aimed to develop a new regimen that enhances skin barrier function by regulating skin pigmentation using low‐concentration imiquimod. Results showed that topical application of low‐concentration imiquimod effectively induced skin hyperpigmentation in the dorsal skin and external ear of mice without inducing inflammatory cell infiltration. An in vitro study also revealed that low‐concentration imiquimod did not induce any cytotoxic effects on melanoma cells but triggered excessive melanin synthesis. In coculture systems, low‐concentration imiquimod was noted to increase tyrosinase activity in a broader cellular context, revealing the potential role of neighboring cells in melanin production. The next‐generation sequencing result indicated that PKCη and Dnm3 might regulate melanin synthesis and release during imiquimod treatment. Overall, our study presents new insights into the regulation of melanin production by low‐concentration imiquimod, both in a mice model and cultured cells. Furthermore, our study highlights the potential benefits of imiquimod in promoting melanin synthesis without causing skin disruptions or inducing inflammation, validating its potential to serve as a method for enhancing skin barrier functions by regulating the epidermal melanization reaction. [ABSTRACT FROM AUTHOR]

Patients with non-obstructive azoospermia (NOA) are unable to have their children. Therefore, there is an urgent need for additional treatment alternatives for these patients. Recently, novel treatments based on the exosomes derived from mesenchymal stem cells (MSCs) as the agents responsible for exerting the paracrine effects and consequently biological functions of MSCs are proposed. Besides, platelet-rich plasma (PRP) as a significant blood byproduct has been therapeutically applied in several male infertility studies. In this study, we compared the effects of PRP and exosome treatment on spermatogenesis restoration in NOA rat models. Exosomes and PRP were isolated from the adipose tissue-derived MSCs (AD-MSCs) collected from conditioned medium and peripheral blood of human volunteers, respectively. Non-obstructive azoospermia (NOA) induction was done through two doses of busulfan at a 21-day interval. Thirty-five days after NOA induction, intratesticular injection of AD-MSCs-derived exosome (AD-Exo), PRP, and PBS was performed. The control group did not receive any treatment. Two months later, the rats were euthanized for further analysis. Our results revealed that both AD-Exo and PRP treatments improved the size and weight of testis, modulated the expression level of Dazl, Ddx4, Stra8, Pwil1, and Ccna1, and ameliorated the serum level of LDH, SOD, and GR enzymes in NOA rats. Moreover, the AD-Exo group showed improved testosterone, GPx, MAD, and CAT serum levels, sperm motility, and protein levels of DAZL and DDX4. This investigation verified the more efficient effects of AD-Exo treatment in comparison to PRP in ameliorating busulfan-induced NOA rat models. [ABSTRACT FROM AUTHOR]

Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant transformation. To investigate acute inflammation, we employed an in vitro model by subjecting Caco‐2 cells to various inflammatory stimuli (IL‐1β, TNF‐α, or LPS) individually or in combination. The successful induction of inflammation was confirmed by robust increases in IL‐6 and NO production. Notably, inflamed Caco‐2 cells exhibited significantly diminished levels of ABCB1 and ABCG2, while the expression of ABCC2 was upregulated. For chronic inflammation induction in vivo, we employed the well‐established AOM/DSS mouse model known for its association with colitis‐driven tumorigenesis. Persistent inflammation was effectively monitored throughout the experiment via elevated IL‐6 and NO levels. The sequential stages of tumorigenesis were confirmed through Ki‐67 immunohistochemistry. Intriguingly, we observed gradual alterations in the expression patterns of the studied drug transporters during stepwise induction, with ABCB1, ABCG2, and ABCC1 showing downregulation and ABCC2 exhibiting upregulation. Immunohistochemistry further revealed dynamic changes in the expression of ABCB1 and ABCC2 during the induction cycles, closely paralleling the gradual increase in Ki‐67 expression observed during the development of precancerous lesions. Collectively, our findings underscore the significant impact of inflammation on drug transporter expression, potentially influencing the process of malignant transformation of the colon. [ABSTRACT FROM AUTHOR]

Allergic contact dermatitis (ACD), a prevalent inflammatory skin disease, is elicited upon repeated skin contact with protein-reactive chemicals through a complex and poorly characterized cellular network between immune cells and skin resident cells. Here, single-cell transcriptomic analysis of the murine hapten-elicited model of ACD reveals that upon elicitation of ACD, infiltrated CD4+ or CD8+ lymphocytes were primarily the IFNγ-producing type 1 central memory phenotype. In contrast, type 2 cytokines (IL4 and IL13) were dominantly expressed by basophils, IL17A was primarily expressed by δγ T cells, and IL1β was identified as the primary cytokine expressed by activated neutrophils/monocytes and macrophages. Furthermore, analysis of skin resident cells identified a sub-cluster of dermal fibroblasts with preadipocyte signature as a prominent target for IFNγ+ lymphocytes and dermal source for key T cell chemokines CXCL9/10. IFNγ treatment shifted dermal fibroblasts from collagen-producing to CXCL9/10-producing, which promoted T cell polarization toward the type-1 phenotype through a CXCR3-dependent mechanism. Furthermore, targeted deletion of Ifngr1 in dermal fibroblasts in mice reduced Cxcl9/10 expression, dermal infiltration of CD8+ T cell, and alleviated ACD inflammation in mice. Finally, we showed that IFNγ+ CD8+ T cells and CXCL10-producing dermal fibroblasts co-enriched in the dermis of human ACD skin. Together, our results define the cell type-specific immune responses in ACD, and recognize an indispensable role of dermal fibroblasts in shaping the development of type-1 skin inflammation through the IFNGR-CXCR3 signaling circuit during ACD pathogenesis. [ABSTRACT FROM AUTHOR]

BACKGROUND: With the increasing popularity of plant protein‐based diets, soy proteins are favored as the most important source of plant protein worldwide. However, potential food allergy risks limit their use in the food industry. This work aims to reveal the mechanism of β‐conglycinin‐induced food allergy, and to explore the regulatory mechanism of heat treatment and high hydrostatic pressure (HHP) treatment in a BALB/c mouse model. RESULTS: Our results showed that oral administration of β‐conglycinin induced severe allergic symptoms in BALB/c mice, but these symptoms were effectively alleviated through heat treatment and HHP treatment. Moreover, β‐conglycinin stimulated lymphocyte proliferation and differentiation; a large number of cytokines interleukin (IL)‐4, IL‐5, IL‐10, IL‐12 and IL‐13 were released and interferon γ secretion was inhibited, which disrupted the Th1/Th2 immune balance and promoted the differentiation and proliferation of naive T cells into Th2‐type cells. CONCLUSION: Heat/non‐heat treatment altered the conformation of soybean protein, which significantly reduced allergic reactions in mice. This regulatory mechanism may be associated with Th1/Th2 immune balance. Our results provide data support for understanding the changes in allergenicity of soybean protein within the food industry. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Objective: Gastrointestinal dysfunction are often associated with type 2 diabetes mellitus (T2DM), a complicated metabolic illness. Contributing factors have been proposed, including genetic predisposition, gene environmental, and lifestyle interactions, but the pathophysiology remains unknown. Methods: We aim to explore the possible causes behind gastrointestinal dysfunction caused by type 2 diabetes in this study. A comprehensive analysis of the gastric sinus metabolome, transcriptome, and proteome in db/db mice with gastrointestinal dysfunction was conducted. Results: The model group of mice had considerably lower small intestine propulsion and gastric emptying rates, higher blood glucose levels, and were significantly obese compared to the control group. We identified 297 genes, 350 proteins, and 1,001 metabolites exhibiting significant differences between db/db and control mice (p < 0.05). Moreover, multi-omics analysis revealed that the genes, proteins, and metabolites in the T2DM-induced gastroenteropathy mice group were involved in arachidonic acid metabolism, glycerophospholipid metabolism and vitamin digestion and absorption. Specifically, Cbr3, Etnppl, and Apob were the major mRNAs associated with T2DM-induced gastrointestinal dysfunction, while Cyp2b10, Cyp2b19, Pgs1, Gpat3, Apoa4, and Tcn2 were the major proteins associated with T2DM-induced gastrointestinal injury, and 16(R)-HET, 5-HETE, LysoPC (22:0), and Pantothenic acid were the major metabolites associated with T2DM-induced gastrointestinal disorders. Conclusion: The mechanism of action of diabetic gastroenteropathy may be related to vitamin digestion and absorption, glycerophospholipid metabolism, and arachidonic acid metabolism. [ABSTRACT FROM AUTHOR]

Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, and COVID-19 remains incompletely understood. This study aimed to elucidate the age-related COVID19 pathogenesis using an Hutchinson-Gilford progeria syndrome (HGPS) mouse model, a premature aging disease model, with humanized ACE2 receptors. Pathological features were compared between young, aged, and HGPS hACE2 mice following SARS-CoV-2 challenge. We demonstrated that young mice display robust interferon response and antiviral activity, whereas this response is attenuated in aged mice. Viral infection in aged mice results in severe respiratory tract hemorrhage, likely contributing a higher mortality rate. In contrast, HGPS hACE2 mice exhibit milder disease manifestations characterized by minor immune cell infiltration and dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared and unique gene expression dynamics among different mouse groups. Collectively, our studies evaluated the impact of SARS-CoV-2 infection on progeroid syndromes using a HGPS hACE2 mouse model, which holds promise as a useful tool for investigating COVID-19 pathogenesis in individuals with premature aging. [ABSTRACT FROM AUTHOR]