Mouse Model Of Disease Research Articles

Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease

BackgroundAmyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS. MethodsPrp-TDP-43A315T mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43A315T mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43A315T mice with or without SLCP were determined. ResultsWe found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43A315T mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43A315T mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes. ConclusionsOur results showed that Prp-TDP-43A315T mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.

Associations between Renin-Angiotensin System and Abnormal Renal Energy Metabolism in a Mouse Model of Diabetic Kidney Disease

Associations between Renin-Angiotensin System and Abnormal Renal Energy Metabolism in a Mouse Model of Diabetic Kidney Disease

Loss of ARL13B's Guanine Nucleotide Exchange Factor Activity for ARL3 in Cilia Suppresses Cystogenesis in Adult Mouse Models of Polycystic Kidney Disease

Loss of ARL13B's Guanine Nucleotide Exchange Factor Activity for ARL3 in Cilia Suppresses Cystogenesis in Adult Mouse Models of Polycystic Kidney Disease

Intranasal administration of dextran-pramlintide polyelectrolyte complex-coated nanoemulsions improves cognitive impairments in a mouse model of Alzheimer's disease

Nasal delivery has emerged as a non-invasive route to administer drugs for brain delivery. In particular, polyelectrolyte complexes-based nanocarriers have been demonstrated to be advantageous for nasal delivery of peptide drugs and vaccines. Pramlintide (Pram) is a peptide that emerges as a novel neuroprotective strategy to modify the pathogenesis of Alzheimer's disease (AD). In this study, we examined the effects of the intranasal administration of dextran-pramlintide polyelectrolyte complex-coated nanoemulsions (PEC-NEDexS/Pram) in an experimental model of AD induced by intracerebroventricular (i.c.v.) infusion of amyloid-beta (Aβ1–42) peptide in mice. PEC-NEDexS/Pram displayed droplet size lower than 200 nm and a negatively charged surface. The locomotor activity of the animals was not affected by the i.c.v. Aβ1–42 injection or Pram treatment. On the other hand, the intranasal administration of PEC-NEDexS/Pram at a dose of 100 μg/day for 14 consecutive days restored the impairment induced by Aβ1–42 injection in the discriminative learning and the short-term spatial reference memory of mice. However, Pram treatment did not alter the Aβ1–42-induced anhedonic behavior, oxidative stress parameters, or the pre-synaptic SNAP-25 and post-synaptic PSD-95 levels in the hippocampus and prefrontal cortex. These findings indicate cognitive-enhancing properties of intranasal Pram administration in an animal model of AD.

Adeno-Associated Virus 1 (AAV1) CFTR Gene Therapy Successfully Reduces Cysts in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Adeno-Associated Virus 1 (AAV1) CFTR Gene Therapy Successfully Reduces Cysts in a Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Vagus nerve stimulation with a small total charge transfer improves motor behavior and reduces neuroinflammation in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a common neurodegenerative disease characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Conventional treatments are ineffective in reversing disease progression. Recently, the therapeutic and rehabilitation potential of vagus nerve stimulation (VNS) in PD has been explored. However, the underlying mechanisms remain largely unknown. In this study, we investigated the neuroprotective effects of VNS in a lateral lesioned mice model of PD. Excluding controls, experimental mice received cuff electrode implantation on the left vagus nerve and 6-hydroxydopamine administration into the bilateral striatum. After ten days, electrical stimulation was delivered for 11 consecutive days onto PD animals. Behavioral tests were performed after stimulation. The expression of TH, Iba-1, GFAP, adrenergic receptors and cytokines in the SN and striatum was detected by immunofluorescence or western blotting. The activity of noradrenergic neurons in the locus coeruleus (LC) was also measured. Our results suggest that VNS improved behavioral performance in rod rotation, open field tests and pole-climbing tests in PD mice, accompanied by a decrease in the loss of dopaminergic neurons in the SN and increased TH expression in the striatum. Neuroinflammation-related factors, such as GFAP, Iba-1, TNF-α and IL-1β were also suppressed in PD mice after VNS compared to those without treatment. Furthermore, the proportion of c-Fos-positive noradrenergic neurons in the LC increased when animals received VNS. Additionally, the expression of the adrenergic receptor of α1BR was also upregulated after VNS compared to PD mice. In conclusion, VNS has potential as a novel PD therapy for neuroprotective effects, and indicate that activation of norepinephric neurons in LC may plays an important role in VNS treatment for PD.

Pharmacological inhibition of PLK2 kinase activity mitigates cognitive decline but aggravates APP pathology in a sex-dependent manner in APP/PS1 mouse model of Alzheimer's disease

Converging evidence from clinical and experimental studies suggest the potential significance of Polo-like kinase 2 (PLK2) in regulating the phosphorylation and toxicity of the Alzheimer's disease (AD)-related protein, amyloid precursor protein (APP). These findings have prompted various experimental trials aimed at inhibiting PLK2 kinase activity in different transgenic mouse models of AD. While positive impacts on cognitive decline were reported in these studies, the cellular effects remained controversial. In the present study, we sought to assess the cognitive and cellular consequences of chronic PLK2 inhibitor treatment in the APP/PS1 transgenic mouse model of AD. First, we confirmed that inhibiting PLK2 prevented cognitive decline in a sex-dependent manner, particularly by enhancing working memory in male APP/PS1 mice. Surprisingly, cellular analysis revealed that treatment with PLK2 inhibitor increased the load of amyloid plaques and elevated levels of soluble amyloid β (Aβ) 40 and Aβ42 in the cortex, as well as insoluble Aβ42 in the hippocampus of female mice, without affecting APP pathology in males. These results underscore the potential of PLK2 inhibition to mitigate cognitive symptoms in males. However, paradoxically, it intensifies amyloid pathology in females by enhancing APP amyloidogenic processing, creating a controversial aspect to its therapeutic impact. Overall, these data highlight the sex-dependent nature of the effects of PLK2 inhibition, which may also be influenced by the genetic background of the transgenic mouse model utilized.

Early Treatment with 2-Deoxy-D-Glucose Reduces Proliferative Proteins in the Kidney and Slows Cyst Growth in a Hypomorphic Pkd1 Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Early Treatment with 2-Deoxy-D-Glucose Reduces Proliferative Proteins in the Kidney and Slows Cyst Growth in a Hypomorphic Pkd1 Mouse Model of Autosomal Dominant Polycystic Kidney Disease

Atractylenolide-I Ameliorates Motor Deficits and Reduces Inflammation of the Spinal Cord by SIRT1/PGC-1α Pathway in MPTP Subacute Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder that impacts various systems, including the substantia nigra (SN) par compacta (SNpc) and extranigral regions like the spinal cord. The presence of persistent inflammation in the SN and spinal cord is associated with movement difficulties in PD. Atractylenolide-I (ATR-I) is a natural sesquiterpene recognized for its anti-inflammatory and neuroprotective effects. This research aimed to assess the impact of ATR-I treatment on motor function and inflammation in MPTP-induced subacute PD mice, particularly focusing on the role of ATR-I in spinal cord inflammation. The motor functions of the mice were assessed using suspension and gait tests. Dopaminergic neuronal loss in the SNpc and microglial activation in both the SNpc and spinal cord were evaluated through immunofluorescence staining. The levels of inflammatory mediators in the spinal cord were measured using RT-qPCR analysis. The expressions of SIRT1 and PGC-1α in the spinal cord were analyzed through Western blotting and RT-qPCR. ATR-I treatment improved motor deficits in MPTP-induced mice. Moreover, ATR-I reduced the loss of dopamine neurons and microglial activation in the SNpc of MPTP-induced mice. Additionally, ATR-I suppressed spinal cord inflammation by decreasing microglial activation and the mRNA expression of TNF-α, IL-1β, and iNOS in MPTP-induced mice. Interestingly, ATR-I also upregulated SIRT1 and PGC-1α levels in the spinal cord of MPTP-induced mice. These findings suggest that ATR-I exhibits anti-inflammatory and neuroprotective properties in PD. The attenuation of spinal cord inflammation via the SIRT1/PGC-1α pathway may contribute to enhancing motor function, highlighting ATR-I as a potential therapeutic avenue for PD.

Deletion of the Homeobox Gene Cux1 Decreases Ciliogenesis in a Mouse Model of Polycystic Kidney Disease

Deletion of the Homeobox Gene Cux1 Decreases Ciliogenesis in a Mouse Model of Polycystic Kidney Disease

Early intervention using long-term rhythmic pulsed magnetic stimulation alleviates cognitive decline in a 5xFAD mouse model of Alzheimer's disease

BackgroundAlzheimer's disease (AD) is the most prevalent form of dementia, but no effective therapeutic strategy is available to date. Rhythmic magnetic stimulation is an attractive means of neuron modulation that could be beneficial for restoring learning and memory abilities. ObjectiveTo assess the effect of a compound pulsed rhythmic magnetic field (cPMF) on cognition during AD progression and to explore the appropriate cPMF intervention period. MethodsFemale 5xFAD mice aged 10 weeks and 18 weeks were exposed to cPMF with a carrier frequency of 40 Hz, repeated at 5 Hz for 1 h/d for 8 consecutive weeks. The Morris water maze (MWM) test was used for cognitive behavioral assessment. Furthermore, changes in molecular pathology within the brain were detected using immunofluorescence staining and real-time PCR. Results10-week-old AD mice treated with cPMF explored the target quadrant more frequently than sham-exposed AD mice in MWM test, exhibiting improved learning and memory abilities. Additionally, cPMF exposure alleviated Aβ plaque deposition and astrogliosis in the AD brain. Moreover, neurotrophic factor fibroblast growth factor 1 (FGF1) in the AD brain was upregulated by cPMF treatment. However, in 18-week-old AD mice treated with cPMF, cognitive performance and Fgf1 gene expression were not significantly improved, although Aβ plaque deposition and astrogliosis were alleviated. ConclusionEarly intervention via long-term rhythmic cPMF stimulation may alleviate the histopathological features and enhance neuroprotective gene Fgf1 expression, thereby improving the cognitive performance of 5xFAD mice, which should provide promising insight for the clinical treatment of patients with AD.

Shisandra Decoction Alleviates Parkinson's Disease Symptoms in a Mouse Model Through PI3K/AKT/mTOR Signalling Pathway.

The present study aimed to characterize neuroprotective effects of Schisandra Decoction (Sch D) treatment in a mouse model of Parkinson's disease (PD), and to explore underlying mechanisms focused on the mammalian target of rapamycin (mTOR) signaling pathway. 50 male C57 BL/6 mice were randomly assigned to either control (n = 10) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model (n = 40) groups. PD mice were further divided into four groups of ten mice each: MPTP group, LY294002 group, Sch D group, and LY2940002 + Sch D group. Mice from each group were assessed in pole climbing, rotary rod and open field tests. Brain Tyrosine hydroxylase (TH) protein was observed using immunohistochemistry. mRNA levels of PTEN, PI3K and LC3 in brain tissue were measured using RT-PCR. Protein levels of PTEN, PI3K, Akt, p-Akt, mTOR, p-mTOR, p70s6K, p62, LC3II / I, α-synuclein (α-syn), TH in brain tissue were assessed by Western blotting (WB). In behavioral tests, PD mice treated with Sch D showed reduced pole climbing time, longer rotarod duration, and greater distance traveled. In terms of neuroprotection, PD mice in the Sch D group exhibited higher levels of TH protein and enhanced α-syn clearance. Regarding autophagy, compared to the control group, mice in the MPTP group had elevated PTEN protein expression, which inhibited PI3K, p-AKT/AKT, and p-mTOR/mTOR protein levels, decreased LC3II/I protein expression, and increased P62 protein expression. Treatment with Sch D reversed these effects. Sch D reduces α-syn aggregation in the brains of MPTP-induced PD model mice, exerts neuroprotective effects, and improves motor function. Additionally, Sch D inhibits autophagy through the PI3K/AKT/mTOR pathway. The neuroprotective effect of Sch D may involve the suppression of abnormal autophagy and its antioxidant properties, which indirectly reduces α-syn accumulation. Future studies should assess the impact of Sch D on oxidative stress markers to evaluate its antioxidant effects.

TFEB agonist clomiphene citrate activates the autophagy-lysosomal pathway and ameliorates Alzheimer's disease symptoms in mice

Autophagy is a conserved eukaryotic cellular clearance and recycling process through the lysosome-mediated degradation of damaged organelles and protein aggregates to maintain homeostasis. Impairment of the autophagy-lysosomal pathway is implicated in the pathogenesis of Alzheimer’s disease (AD). Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Therefore, activating TFEB and autophagy provides a novel strategy for AD treatment. We previously described that clomiphene citrate (CC) promotes nuclear translocation of TFEB and increases autophagy and lysosomal biogenesis. In this study, 7 and 3-month-old APP/PS1 mice were treated with TFEB agonist CC and assessed. The behavioral tests were performed using Morris water maze and open field test. Additional changes in Aβ pathology, autophagy and inflammatory response were determined. We found that CC activated TFEB and the autophagy-lysosomal pathway in neuronal cells. Moreover, using mouse model of Alzheimer's disease, CC treatment promoted clearance of Aβ plaques and ameliorated cognitive function in both 7 and 3-month-old APP/PS1 mice. The CC-induced activation of TFEB occurs by promoting acetylation of TFEB for nuclear translocation. These findings provide a molecular mechanism for the TFEB-mediated activation of the autophagy-lysosome pathway by CC, which has the potential to be repurposed and applied in the treatment or prevention of AD.

Activation of Apelin Receptor Inhibits Cystogenesis in a Mouse Model of Polycystic Kidney Disease

Activation of Apelin Receptor Inhibits Cystogenesis in a Mouse Model of Polycystic Kidney Disease

Renal Cell Type-Associated Therapeutic Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Renal Cell Type-Associated Therapeutic Effects of Semaglutide in a Mouse Model of Hypertension-Accelerated Diabetic Kidney Disease

Elongation factor 1A1 inhibition elicits changes in lipid droplet size, the bulk transcriptome, and cell type-associated gene expression in MASLD mouse liver.

Eukaryotic elongation factor 1A1 (EEF1A1), originally identified for its role in protein synthesis, has additional functions in diverse cellular processes. Of note, we previously discovered a role for EEF1A1 in hepatocyte lipotoxicity. We also demonstrated that a 2-wk intervention with the EEF1A1 inhibitor didemnin B (DB) (50 µg/kg) decreased liver steatosis in a mouse model of obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) [129S6/SvEvTac mice fed Western diet (42% fat) for 26 wk]. Here, we further characterized the hepatic changes occurring in these mice by assessing lipid droplet (LD) size, bulk differential expression, and cell type-associated alterations in gene expression. Consistent with the previously demonstrated decrease in hepatic steatosis, we observed decreased median LD size in response to DB. Bulk RNA sequencing (RNA-Seq) followed by gene set enrichment analysis revealed alterations in pathways related to energy metabolism and proteostasis in DB-treated mouse livers. Deconvolution of bulk data identified decreased cell type association scores for cholangiocytes, mononuclear phagocytes, and mesenchymal cells in response to DB. Overrepresentation analyses of bulk data using cell type marker gene sets further identified hepatocytes and cholangiocytes as the primary contributors to bulk differential expression in response to DB. Thus, we show that chemical inhibition of EEF1A1 decreases hepatic LD size and decreases gene expression signatures associated with several liver cell types implicated in MASLD progression. Furthermore, changes in hepatic gene expression were primarily attributable to hepatocytes and cholangiocytes. This work demonstrates that EEF1A1 inhibition may be a viable strategy to target aspects of liver biology implicated in MASLD progression.NEW & NOTEWORTHY Chemical inhibition of EEF1A1 decreases hepatic lipid droplet size and decreases gene expression signatures associated with liver cell types that contribute to MASLD progression. Furthermore, changes in hepatic gene expression are primarily attributable to hepatocytes and cholangiocytes. This work highlights the therapeutic potential of targeting EEF1A1 in the setting of MASLD, and the utility of RNA-Seq deconvolution to reveal valuable information about tissue cell type composition and cell type-associated gene expression from bulk RNA-Seq data.

Atractylenolide-I Ameliorates Motor Deficits and Reduces Inflammation of the Spinal Cord by SIRT1/PGC-1α Pathway in MPTP Subacute Mouse Model of Parkinson's Disease [Letter

Atractylenolide-I Ameliorates Motor Deficits and Reduces Inflammation of the Spinal Cord by SIRT1/PGC-1α Pathway in MPTP Subacute Mouse Model of Parkinson's Disease [Letter

Exploring the Mechanism of Action of Sericin in Ameliorating non-Alcoholic Fatty Liver Disease in Mice Based on the Nrf2- GPX4/ NF-κB p65 Pathway

Objective: To explore the ameliorative effect and mechanism of action of sericin on liver injury in Non-Alcoholic Fatty Liver Disease (NAFLD) model mice. Methods: Mice were fed a high-fat diet for 8 weeks to establish NAFLD model mice. The NAFLD mice were then randomly divided into 6 groups and given 0, 250, 500, and 1000 mg/kg body weight of sericin, 1000 mg/kg sericin + ML385 (a protein inhibitor of Nrf2), and Zhibitai Capsules (a positive drug), by gavage, respectively. The levels of TC, TG, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) in mouse serum and the levels of MDA, GSH, SOD, TNF-α, and IL-6 in liver tissues were measured. Pathological changes in liver tissues were evaluated using hematoxylin-eosin (HE) and Oil Red O staining. Protein expression of Nrf2, Keap1, HO-1, GPX4, and NF-κB p65 in liver tissues was detected by Western blotting, and the expression level of GPX4 in the liver was examined by immunohistochemistry. Results: Sericin and Zhibitai Capsules improved hepatic steatosis and lipid accumulation in NAFLD model mice. TC, TG, LDL-C, MDA, and TNF-α, IL-6 levels were down-regulated, and HDL-C and SOD levels were up-regulated. There was no significant difference in the expression of AST and ALT in all the groups. In addition, Sericin and Zhibitai Capsules upregulated the expression levels of Nrf2, keap1, HO-1, and GPX4 proteins and inhibited the expression of NF-κB p65 in the liver of NAFLD model mice. There was no significant difference in serum lipids and liver indices between the 1000 mg/kg sericin + ML385 group and the sericin dose groups. Conclusion: Sericin has an ameliorative effect on liver injury in NAFLD model mice by alleviating oxidative stress and inflammatory responses in liver injury. It remains to be explored whether this effect is regulated through the Nrf2- GPX4/ NF-κB p65 signaling pathway.

Chondroitin sulfate modulates oxidative stress and inflammation in the substantia nigra via gut microbiota regulation: Mechanistic insights into Parkinson's disease treatment

Hydrogen sulfide (H2S) is a bioactive gas with potential neuroprotective properties. This study explores the therapeutic efficacy of chondroitin sulfate (CS) in a Parkinson's disease (PD) mouse model by evaluating its impact on behavior, gut microbiota composition, substantia nigra (SN) pathology, oxidative stress, and inflammation. Behavioral tests indicate that CS improves cognitive function and learning abilities in PD mice. Gut microbiota analysis and fecal H2S content measurement reveal that CS fosters the growth of Desulfovibrio and boosts H2S production, respectively. Further examination shows that CS treatment enhances antioxidant defenses, reduces inducible nitric oxide synthase (iNOS)-mediated inflammation, and alleviates PD-related pathology and α-synuclein overexpression in the SN. These findings suggest that CS modulates the gut microbiota and its metabolic product, H2S, potentially improving PD symptoms through the gut-brain axis.

Small Molecule APOL1 Channel Inhibitor Reduces Proteinuria, Rescues Podocyte Injury, and Reverses eGFR Decline in an APOL1-Mediated Kidney Disease Mouse Model

Small Molecule APOL1 Channel Inhibitor Reduces Proteinuria, Rescues Podocyte Injury, and Reverses eGFR Decline in an APOL1-Mediated Kidney Disease Mouse Model