Selpercatinib attenuates bleomycin-induced pulmonary fibrosis by inhibiting the TGF-ß1 signaling pathway.

IPF is a chronic, progressive, interstitial lung disease with high mortality. Current drugs have limited efficacy in curbing disease progression and improving quality of life. Selpercatinib, a highly selective inhibitor of receptor tyrosine kinase RET (rearranged during transfection), was approved in 2020 for the treatment of a variety of solid tumors with RET mutations. In this study, the action and mechanism of Selpercatinib in pulmonary fibrosis were evaluated in vivo and in vitro. In vivo experiments demonstrated that Selpercatinib significantly ameliorated bleomycin (BLM)-induced pulmonary fibrosis in mice. In vitro, Selpercatinib inhibited the proliferation, migration, activation and extracellular matrix deposition of fibroblasts by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathway, and suppressed epithelial-mesenchymal transition (EMT) like process of lung epithelial cells via inhibiting TGF-ß1/Smad pathway. The results of in vivo pharmacological tests corroborated the results obtained from the in vitro experiments. Further studies revealed that Selpercatinib inhibited abnormal phenotypes of lung fibroblasts and epithelial cells in part by regulating its target RET. In short, Selpercatinib inhibited the activation of fibroblasts and EMT-like process of lung epithelial cells by inhibiting TGF-ß1/Smad and TGF-ß1/non-Smad pathways, thus alleviating BLM-induced pulmonary fibrosis in mice.

Positron emission tomography guided synergistic treatment of melanoma using multifunctional zirconium-hematoporphyrin nanosonosensitizers.

Sonodynamic therapy (SDT) has emerged as a useful approach for tumor treatment. However, its widespread application is impeded by poor pharmacokinetics of existing sonosensitizers. Here we developed a metal-organic nanoplatform, wherein a small-molecule sonosensitizer (hematoporphyrin monomethyl ether, HMME) was ingeniously coordinated with zirconium, resulting in a multifunctional nanosonosensitizer termed Zr-HMME. Through post-synthetic modifications involving PEGylation and tumor-targeting peptide (F3) linkage, a nanoplatform capable of homing on melanoma was produced, which could elicit robust immune responses to suppress tumor lung metastasis in the host organism. Importantly, after seamless incorporation of positron-emitting 89Zr into this nanosonosensitizer, positron emission tomography (PET) could be used to monitor its in vivo pharmacokinetics. PET imaging studies revealed that this nanoplatform exhibited potent tumor accumulation and strong in vivo stability. Using intrinsic fluorescence from HMME, a dual-modal diagnostic capability (fluorescence and PET) was confirmed for this nanosonosensitizer. In addition, the mechanisms of how this nanoplatform interacted with immune system were also investigated. The collective data proved that the coordination structure between small-molecule drug cargos and metals may enhance the functions of each other while mitigating their weaknesses. This straightforward approach can expand the potential applications of suitable drug molecules.

Preventive effect of Cleome spinosa against cucumber Fusarium wilt and improvement on cucumber growth and physiology.

Cucumber wilt is an important soil borne disease in cucumber production, which seriously affects the development of the cucumber industry. Cleome spinosa also has pharmacological effects such as antibacterial, analgesic, anti-inflammatory, and insect repellent. To study the control effect and mechanism of Cleome spinosa fumigation on cucumber wilt disease, different concentrations of Cleome spinosa fragments were applied on cucumber plants infected with Fusarium oxysporum. Cleome spinosa fumigation significantly reduced the incidence rate of cucumber Fusarium wilt. Under the fumigation treatment of 7.5 g kg-1 Cleome spinosa fragments, the preventive effects were 74.7%. Cleome spinosa fragments fumigation can promote cucumber growth and synthesis of photosynthetic pigments, thereby improving individual plant yield and fruit quality. At 7.5 g kg-1 Cleome spinosa fragments fumigation treatment, the plant height and individual plant yield of cucumber increased by 20.3% and 34.3%, respectively. Cleome spinosa fumigation can enhance the activity of antioxidant enzymes in cucumber, maintain a balance of reactive oxygen species metabolism, and enhance the plant disease resistance. Moreover, Cleome spinosa can also regulate the activities of Mg2+-ATPase and Ca2+-ATPase, enhancing its resistance to Fusarium oxysporum. Moreover, number of bacteria and fungi significantly decreased under Cleome spinosa fumigation. Those results suggested that Cleome spinosa could effectively restrain cucumber Fusarium wilt. This study will provide a new idea for the further use of biological fumigation to prevent soil-borne diseases.

Physiological mechanism beneath the inhibition of Cleome spinosa against the morphology and reproduction of Fusarium oxysporum.

Fusarium oxysporum is a soil-borne plant pathogen that can cause various plant diseases including cucumber wilt. An experiment was conducted to explore the physiological mechanism underlying the inhibitory activity of Cleome spinosa against the morphology and reproduction of F. oxysporum. Different concentrations of C. spinosa extracts. -0 (Z0), 5 (Z5), 15 (Z15), 30 (Z30), 45 (Z45), and 60 (Z60) mg·mL-1 were applied to F. oxysporum. Cleome spinosa extract significantly reduced the colony diameter (89.7 %) and dry mass (78.9 %) of F. oxysporum under the Z45 treatment. Moreover, spore formation was also significantly inhibited by C. spinosa extract. The spore number and germination rate decreased by 73.5 % and 83.0 %, respectively, under the Z45 treatment. The number of mycelia in the unit field of view was significantly reduced, and the mycelia were wizened with rough surfaces and more bends under the Z45 treatment. Hence, C. spinosa extracts severely damaged the morphology of F. oxysporum mycelia. Additionally, F. oxysporum could not adjust to the osmotic changes caused by C. spinosa extract, leading to membrane injury and electrolyte leakage. Finally, they impaired the antioxidant system in F. oxysporum, resulting in cell membrane injury.

Nanosized Shikonin-Fe(III) Coordination Material for Synergistic Wound Treatment: An Initial Explorative Study.

Shikonin (Shik), a natural pigment, has received growing interest in various biomedical fields due to its anti-inflammatory, antitumor, antimicrobial, and antioxidant ability. However, some inherent characteristics of Shik, such as its virulence, low bioavailability, and poor solubility, have limited its biomedical applicability. Here, we reported a facile synthetic method to produce the Shik-iron (III) nanoparticles (Shik-Fe NPs), which could overcome these limitations of Shik. The synthesized Shik-Fe NPs possessed a uniform size range of 110 ± 10 nm, negative surface charges, good water dispersity, and high safety. Iron distributed uniformly inside Shik-Fe NPs, and iron constituted 20% of total mass in PEGylated Shik-Fe NPs. When interacting with activated macrophages, Shik-Fe NPs significantly reduced the level of cellular inflammatory factors, for example, iNOS, IL-1ß, and TNF-α. Furthermore, the Shik-Fe NPs demonstrated synergistic anti-inflammation and anti-bacterial properties in vivo, since they could release Fe3+ and Shik to eradicate bacteria (Staphylococcus aureus and P. aeruginosa were used as model microbes here) during wound infections and provide full recovery for scald wounds. Collectively, the study established a dual-functional Shik-derived nanoplatform, which could be useful for the treatment of various inflammation-involved diseases.

Kruppel like factor 16 promotes lung adenocarcinoma progression by upregulating lamin B2.

Lung cancer is one of the most common causes of cancer-related death. In the past decade, the treatment and diagnosis of lung cancer have progressed significantly in early efforts to promote the survival of lung cancer patients. Kruppel like factor 16 (KLF16) is a zinc finger transcription factor that regulates a diverse array of developmental events and cellular processes. KLF16 is involved in the progression of various cancer types. However, the role of KLF16 in the development of lung cancer remains unknown. In this study, KLF16 was overexpressed in lung cancer samples. KLF16 downregulation inhibited lung cancer cell proliferation and migration. Conversely, KLF16 overexpression promoted lung cancer cell growth and invasion. Mechanistically, the expression level LMNB2 was suppressed by KLF16 knockdown and was promoted by KLF16 overexpression. The overall survival of patients with high LMNB2 levels was poor. Luciferase assays showed that KLF16 promoted the transcription activity of LMNB2 gene. Concomitantly, the expression level of LMNB2 was also higher in lung adenocarcinoma (LUAD) than in normal tissues, and its knockdown or overexpression can reverse the effect of KLF16 overexpression or knockdown on lung cancer cell proliferation, migration, and even tumorigenesis, indicating that LMNB2 also functions as an oncogene. In conclusion, KLF16 can be used as a potential therapeutic and preventive biomarker in lung cancer treatment and prognosis by actively regulating the expression of LMNB2.

Involvement of O2·- release in zearalenone-induced hormesis of intestinal porcine enterocytes: An electrochemical sensor-based analysis.

Relationship between mycotoxin-induced hormesis and reactive oxygen species (ROS) has not been systematically investigated due to the lack of an effective analysis method. To monitor cellular release and intracellular level of O2·-, carboxymethyl cellulose-Mn3(PO4)2 nanocomposite was synthesized to fabricate an electrochemical biosensor, which selectively detects O2·- over the range of 57.50 nM âˆ¼ 2.95 µM (R2 = 0.99) with the sensitivity of 78.67 µA µM-1 cm-2 and the detection limit of 8.47 nM. Transient exposure to zearalenone (ZEA) induces the enhancement on cell viability, immediate O2·- release from cells, and reduction of intracellular O2·- level. After post-treatment culture, intracellular O2·- initially increases to a high level and then decreases to the normal level. Concurrently, the ZEA-induced hormesis disappears. Based on the findings, we propose a mechanism, involving the ROS release, increase of succinate dehydrogenase activity and recovery of intracellular ROS, to explain the occurrence and disappearance of hormesis in intestinal porcine enterocytes.

Ultrasound (US)-activated redox dyshomeostasis therapy reinforced by immunogenic cell death (ICD) through a mitochondrial targeting liposomal nanosystem.

Introduction: An imbalance in redox homeostasis consistently inhibits tumor cell proliferation and further causes tumor regression. Thus, synchronous glutaminolysis inhibition and intracellular reactive oxygen (ROS) accumulation cause severe redox dyshomeostasis, which may potentially become a new therapeutic strategy to effectively combat cancer. Methods: Mitochondrial-targeting liposomal nanoparticles (abbreviated MLipRIR NPs) are synthesized by the encapsulation of R162 (inhibitor of glutamate dehydrogenase 1 [GDH1]) and IR780 (a hydrophobic sonosensitizer) within the lipid bilayer, which are exploited for ultrasound (US)-activated tumor dyshomeostasis therapy reinforced by immunogenic cell death (ICD). Results: R162 released from MLipRIR NPs disrupts the glutaminolysis pathway in mitochondria, resulting in downregulated enzymatic activity of glutathione peroxidase (GPx). In addition, loaded IR780 can generate high levels of ROS under US irradiation, which not only interrupts mitochondrial respiration to induce apoptosis but also consumes local glutathione (GSH). GSH depletion accompanied by GPx deactivation causes severe ferroptosis of tumor cells through the accumulation of lipid peroxides. Such intracellular redox dyshomeostasis effectively triggers immunogenic cell death (ICD), which can activate antitumor immunity for the suppression of both primary and distant tumors with the aid of immune checkpoint blockade. Conclusions: Taking advantage of multimodal imaging for therapy guidance, this nanoplatform may potentiate systemic tumor eradication with high certainty. Taken together, this state-of-the-art paradigm may provide useful insights for cancer management by disrupting redox homeostasis.

Reduced Granule Cell Proliferation and Molecular Dysregulation in the Cerebellum of Lysosomal Acid Phosphatase 2 (ACP2) Mutant Mice.

Lysosomal acid phosphatase 2 (Acp2) mutant mice (naked-ataxia, nax) have a severe cerebellar cortex defect with a striking reduction in the number of granule cells. Using a combination of in vivo and in vitro immunohistochemistry, Western blotting, BrdU assays, and RT-qPCR, we show downregulation of MYCN and dysregulation of the SHH signaling pathway in the nax cerebellum. MYCN protein expression is significantly reduced at P10, but not at the peak of proliferation at around P6 when the number of granule cells is strikingly reduced in the nax cerebellum. Despite the significant role of the SHH-MycN pathway in granule cell proliferation, our study suggests that a broader molecular pathway and additional mechanisms regulating granule cell development during the clonal expansion period are impaired in the nax cerebellum. In particular, our results indicate that downregulation of the protein synthesis machinery may contribute to the reduced number of granule cells in the nax cerebellum.

Engineering oxygen-deficient ZrO2-x nanoplatform as therapy-activated "immunogenic cell death (ICD)" inducer to synergize photothermal-augmented sonodynamic tumor elimination in NIR-II biological window.

Nano-zirconia, as an amphoteric semiconductor, has been industrially exploited in photocatalytic reactions and as piezoelectric sensors. However, its biomedical applications, especially in antitumor therapeutics, have been seldom investigated to date. Here, oxygen-deficient zirconia (ZrO2-x)-based nanoplatform with surface PEGylation and cyclic-Arg-Gly-Asp (cRGD) peptide functionalization (ZrO2-x@PEG/cRGD, abbreviated as ZPR) was rationally designed and established for the first time, which was utilized as therapy-activated "immunogenic cell death (ICD)" inducer to boost photothermal-augmented sonodynamic tumor elimination in NIR-II biological window. As-synthesized ZPR nanoparticles (NPs) exhibited intense optical absorbance in the wavelength range of 900-1100 nm, which endowed ZPR NPs with a photothermal conversion efficiency as high as 45.8% for photothermal therapy (PTT). Moreover, owing to the abundant surface oxygen defects, ZPR NPs can serve as a category of high-performance nano-sonosensitizer based on the strengthened separation of electron (e-)/hole (h+) pairs from the energy band under external ultrasound (US) activation. More importantly, cytotoxic reactive oxygen species (ROS) generated from sonodynamic therapy (SDT) can effectively induce immunogenic cell death (ICD), which is regarded to be significant to boost systemic anti-tumor immunity for rendering a complete tumor eradication post-treatment. In vivo experiments on tumor xenografts demonstrated the high therapeutic efficacy upon photothermal-augmented sonodynamic therapy, with the aid of photoacoustic (PA) imaging navigation. Remarkably, the level of inflammatory cytokines, including type I interferon (IFN), tumor necrosis factor α (TNF-α) as well as interleukin (IL-6) were systemically upgraded after NIR-II/US irradiation, verifying the promotion of immunogenicity. Taken together, this study delivers useful insights for extending the applications of zirconia as promising translational medicine for tumor theranostics in the near future.

Upregulation of Neural Cell Adhesion Molecule 1 and Excessive Migration of Purkinje Cells in Cerebellar Cortex.

Purkinje cells (PCs) are large GABAergic projection neurons of the cerebellar cortex, endowed with elaborate dendrites that receive a multitude of excitatory inputs. Being the only efferent neuron of the cerebellar cortex, PCs project to cerebellar nuclei and control behaviors ranging from movement to cognition and social interaction. Neural cell adhesion molecule 1 (NCAM1) is widely expressed in the embryonic and postnatal development of the brain and plays essential roles in neuronal migration, axon pathfinding and synapse assembly. However, despite its high expression levels in cerebellum, little is known to date regarding the role(s) of NCAM1 in PCs development. Among other aspects, elucidating how the expression of NCAM1 in PCs could impact their postnatal migration would be a significant achievement. We analyzed the Acp2 mutant mouse (nax: naked and ataxia), which displays excessive PC migration into the molecular layer, and investigated how the excessive migration of PCs along Bergmann glia could correlate to NCAM1 expression pattern in early postnatal days. Our Western blot and RT-qPCR analysis of the whole cerebellum show that the protein and mRNA of NCAM1 in wild type are not different during PC dispersal from the cluster stage to monolayer formation. However, RT-qPCR analysis from FACS-based isolated PCs shows that Ncam1 is significantly upregulated when PCs fail to align and instead overmigrate into the molecular layer. Our results suggest two alternative interpretations: (1) NCAM1 promotes excessive PC migration along Bergmann glia, or (2) NCAM1 upregulation is an attempt to prevent PCs from invading the molecular layer. If the latter scenario proves true, NCAM1 may play a key role in PC monolayer formation.

Mutations in the Reelin pathway are associated with abnormal expression of microglial IgG FC receptors in the cerebellar cortex.

Microglia are the immune cells of the central nervous system involved in a variety of developmental processes, such as regulation of cell death and survival, spatial patterning, and contribute to the development of Purkinje cells (PCs) during migration. Microglia express immunoglobulin G Fc receptors (FcgRs). In this report, we describe microglial FcgR expression and its relation to abnormal PC migration in the cerebellum during development. To detect microglial FcgR, the direct anti-IgG (secondary antisera) and high concentrations of Triton X-100 were applied as a method for labeling microglial cells without the use of any specific primary antiserum. By using Acp2-/- mice, which show an excessive PC migration into the molecular layer (ml), and 3 different types of mice with a null to alter the Reelin pathway (Reeler-, Dab1 (SCM)-, and Apoer mutant mice), we studied the location of PCs and the expression of FcgRs. Wild type littermates were used as controls in all studies. We show that the expression of microglial FcgRs was absent and PCs were ectopically located in the white matter in the cerebella of all mutant mice, except for the Acp2-/- mice (PCs were located in the ml). These results suggest a role for FcgRs in the Reelin signaling pathway, not in regulating PC migration, but rather in the adaptation to an environment with a relatively large number of ectopically located PCs. However, the exact correlation between the ectopic location of PCs and lack of FcgRs in Reeler, SCM, and Apoer-/- mice and the presence of FcgRs and directed PC location in the ml in Acp2-/- mice are yet to be determined.

Alteration of the Dopamine Receptors' Expression in the Cerebellum of the Lysosomal Acid Phosphatase 2 Mutant (Naked-Ataxia (NAX)) Mouse.

A spontaneous mutation in the lysosomal acid phosphatase (Acp2) enzyme (nax: naked-ataxia) in experimental mice results in delayed hair appearance and severe cytoarchitectural impairments of the cerebellum, such as a Purkinje cell (PC) migration defect. In our previous investigation, our team showed that Acp2 expression plans a significant role in cerebellar development. On the other hand, the dopaminergic system is also a player in central nervous system (CNS) development, including cerebellar structure and function. In the current investigation, we have explored how Acp2 can be involved in the regulation of the dopaminergic pathway in the cerebellum via the regulation of dopamine receptor expression and patterning. We provided evidence about the distribution of different dopamine receptors in the developing cerebellum by comparing the expression of dopamine receptors on postnatal days (P) 5 and 17 between nax mice and wild-type (wt) littermates. To this aim, immunohistochemistry and Western blot analysis were conducted using five antibodies against dopamine receptors (DRD1, -2, -3, -4, and -5) accompanied by RNAseq data. Our results revealed that DRD1, -3, and -4 gene expressions significantly increased in nax cerebella but not in wt, while gene expressions of all 5 receptors were evident in PCs of both wt and nax cerebella. DRD3 was strongly expressed in the PCs' somata and cerebellar nuclei neurons at P17 in nax mice, which was comparable to the expression levels in the cerebella of wt littermates. In addition, DRD3 was expressed in scattered cells in a granular layer reminiscent of Golgi cells and was observed in the wt cerebella but not in nax mice. DRD4 was expressed in a subset of PCs and appeared to align with the unique parasagittal stripes pattern. This study contributes to our understanding of alterations in the expression pattern of DRDs in the cerebellum of nax mice in comparison to their wt littermates, and it highlights the role of Acp2 in regulating the dopaminergic system.

Rational design of oxygen deficient TiO2-x nanoparticles conjugated with chlorin e6 (Ce6) for photoacoustic imaging-guided photothermal/photodynamic dual therapy of cancer.

Oxygen deficient TiO2-x nanoparticles (NPs) have been recognized as a category of new-fashioned photothermal agents to offer safer PTT. However, the surface of TiO2-x NPs is deficient in free active groups or radicals to conjugate functional therapeutic molecules, which seriously impedes their in-depth development for versatile medical applications. In this study, surface activation of TiO2-x NPs was realized by the facile conjugation of (3-aminopropyl)triethoxysilane (APTES) through the formation of a stable Si-O-Ti bond, and photosensitizer chlorin e6 (Ce6) was successfully modified onto the TiO2-x NP surface and with a considerably high loading content. The resultant TiO2-x@APTES/Ce6 (TAC) NPs displayed decent biosafety, rapid tumor enrichment and outstanding performance in photoacoustic (PA) imaging. Taking advantage of the intense photo-absorption in the near-infrared (NIR) region and high dose of conjugated Ce6, a powerful antitumor effect was realized based on the combination of hyperthermia-induced cell ablation and cytotoxic reactive oxygen species (ROS)-triggered apoptosis both in vitro and in vivo. Moreover, PA imaging guidance was exceptionally useful for locating the tumor position and optimizing the treatment regimens. Apart from Ce6, this elaborate modification strategy for TiO2-x is believed to be universal for steadily binding more versatile therapeutic agents, which would definitely favor the development of multifunctional TiO2-x-based nanocomplexes for enhanced tumor treatment.

Primary Culture of Neurons Isolated from Embryonic Mouse Cerebellum.

The use of primary cell cultures has become one of the major tools to study the nervous system in vitro. The ultimate goal of using this simplified model system is to provide a controlled microenvironment and maintain the high survival rate and the natural features of dissociated neuronal and nonneuronal cells as much as possible under in vitro conditions. In this article, we demonstrate a method of isolating primary neurons from the developing mouse cerebellum, placing them in an in vitro environment, establishing their growth, and monitoring their viability and differentiation for several weeks. This method is applicable to embryonic neurons dissociated from cerebellum between embryonic days 12-18.

Novel Oxygen-Deficient Zirconia (ZrO2-x) for Fluorescence/Photoacoustic Imaging-Guided Photothermal/Photodynamic Therapy for Cancer.

Theranostic nanoplatforms that integrate therapy and diagnosis in a single composite have become increasingly attractive in the field of precise and efficient tumor treatment. Herein, a novel oxygen-deficient zirconia (ZrO2-x) nanosystem based on the conjugation of thiol-polyethylene glycol-amine (SH-PEG-NH2) and chlorin e6 (Ce6) was elaborately designed and established for efficacious photothermal/photodynamic therapy (PTT/PDT) and fluorescence/photoacoustic (FL/PA) bimodal imaging for the first time. The crystalline-disordered, PEGylated ZrO2-x nanoparticles (ZP NPs) displayed strong optical absorption in the near-infrared (NIR) window and were featured with significant photothermal conversion capacity. The ZP NPs were further covalently conjugated with Ce6 to form ZrO2-x@PEG/Ce6 (ZPC) NPs, which displayed a long circulatory half-life, efficient tumor accumulation, and outstanding FL/PA imaging performance. Moreover, the nanocomposites effectively generated cytotoxic intracellular reactive oxygen species (ROS) responsive to laser activation. Both cell studies and animal experiments explicitly demonstrated that ZPC NPs mediated remarkable tumor ablation with minimal systemic toxicity thanks to their tumor-specific PTT/PDT effect. Collectively, these findings may open up new avenues to broaden the application of oxygen-deficient ZrO2-x nanostructures as high-performance photothermal agents in tumor theranostics through rational design and accurate control of their physiochemical properties.

Zebrin II Is Ectopically Expressed in Microglia in the Cerebellum of Neurogenin 2 Null Mice.

Zebrin II/aldolase C expression in the normal cerebellum is restricted to a Purkinje cell subset and is the canonical marker for stripes and zones. This spatial restriction has been confirmed in over 30 species of mammals, birds, fish, etc. In a transgenic mouse model in which the Neurogenin 2 gene has been disrupted (Neurog2-/-), the cerebellum is smaller than normal and Purkinje cell dendrites are disordered, but the basic zone and stripe architecture is preserved. Here, we show that in the Neurog2-/- mouse, in addition to the normal Purkinje cell expression, zebrin II is also expressed in a population of cells with a morphology characteristic of microglia. This identity was confirmed by double immunohistochemistry for zebrin II and the microglial marker, Iba1. The expression of zebrin II in cerebellar microglia is not restricted by zone or stripe or lamina. A second zone and stripe marker, PLCß4, does not show the same ectopic expression. When microglia are compared in control vs. Neurog2-/- mice, no difference is seen in apparent number or distribution, suggesting that the ectopic zebrin II immunoreactivity in Neurog2-/- cerebellum reflects an ectopic expression rather than the invasion of a new population of microglia from the periphery. This ectopic expression of zebrin II in microglia is unique as it is not seen in numerous other models of cerebellar disruption, such as in Acp2-/- mice and in human pontocerebellar hypoplasia. The upregulation of zebrin II in microglia is thus specific to the disruption of Neurog2 downstream pathways, rather than a generic response to a cerebellar disruption.

Overexpression of Human SOD1 Leads to Discrete Defects in the Cerebellar Architecture in the Mouse.

The human superoxide dismutase 1 (SOD1) gene is responsible for neutralizing supercharged oxygen radicals within the cell. Mutation in SOD1 gene causes amyotrophic lateral sclerosis (ALS). Recent studies have shown involvement of the cerebellum in ALS, although the cerebellar contribution in SOD1 transgenic mice remains unclear. Using immunohistopathology, we investigated the Purkinje cell phenotype in the vermis of the SOD1 transgenic mice cerebellum. Calbindin 1 (Calb1) and three well-known zone and stripe markers, zebrin II, HSP25, and PLCß4 have been used to explore possible alteration in zone and stripe. Here we show that Calb1 expression is significantly reduced in a subset of the Purkinje cells that is almost aligned with the cerebellar zones and stripes pattern. The Purkinje cells of SOD1 transgenic mice display a pattern of Calb1 down-regulation, which seems to proceed to Purkinje cell degeneration as the mice age. The onset of Calb1 down-regulation in Purkinje cells begins from the central zone and continues into the nodular zone, however it has not been observed in the anterior and posterior zones. In a subgroup of SOD1 transgenic mice in which gait unsteadiness was apparent, down-regulation of Calb1 is seen in a subset of PLCß4+ Purkinje cells in the anterior zone. These observations suggest that the Calb1- subset of Purkinje cells in the anterior zone, which receives somatosensory input, causes unsteady gait. Our data suggest that human SOD1 overexpression leads to Calb1 down-regulation in the zone and strip pattern and raise the question of whether SOD1 overexpression leads to Purkinje cells degeneration.

Mevalonate Cascade and Neurodevelopmental and Neurodegenerative Diseases: Future Targets for Therapeutic Application.

The mevalonate cascade is a key metabolic pathway that regulates a variety of cellular functions and is thereby implicated in the pathophysiology of most brain diseases, including neurodevelopmental and neurodegenerative disorders. Emerging lines of evidence suggest that statins and Rho GTPase inhibitors are efficacious and have advantageous properties in treatment of different pathologic conditions that are relevant to the central nervous system. Beyond the original role of statins in lowering cholesterol synthesis, they have anti-inflammatory, antioxidant and modulatory effects on signaling pathways. Additionally, Rho GTPase inhibitors and statins share the mevalonate pathway as a common target of their therapeutic actions. In this review, we discuss potential mechanisms through which these drugs, via their role in the mevalonate pathway, exert their neuroprotective effects in neurodegenerative and neurodevelopmental disorders.