The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis.

The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.

SRT1720 inhibits bladder cancer cell progression by impairing autophagic flux.

Bladder cancer (BC) is the most common cancer of the urinary tract, with poor survival, high recurrence rates, and lacking of targeted drugs. In this study, we constructed a library to screen compounds inhibiting bladder cancer cells growth. Among them, SRT1720 was identified to inhibit bladder cancer cell proliferation in vitro and in vivo. SRT1720 treatment also suppressed bladder cancer cells migration, invasion and induced apoptosis. Mechanism studies shown that SRT1720 promoted autophagosomes accumulation by inducing early-stage autophagy but disturbed the late-stage of autophagy by blocking fusion of autophagosomes and lysosomes. SRT1720 appears to induce autophagy related proteins expression and alter autophagy-related proteins acetylation to impede the autophagy flux. LAMP2, an important lysosomal associated membrane protein, may mediate SRT1720-inhibited autophagy flux as SRT1720 treatment significantly deacetylated LAMP2 which may influence its activity. Taken together, our results demonstrated that SRT1720 mediated apoptosis and autophagy flux inhibition may be a novel therapeutic strategy for bladder cancer treatment.

SiRNF8 Delivered by DNA Framework Nucleic Acid Effectively Sensitizes Chemotherapy in Colon Cancer.

Background: The evident side effects and decreased drug sensitivity significantly restrict the use of chemotherapy. However, nanoparticles based on biomaterials are anticipated to address this challenge. Methods: Through bioinformatics analysis and colon cancer samples, we initially investigated the expression level of RNF8 in colon cancer. Next, we constructed nanocarrier for delivering siRNF8 based on DNA tetrahedron (si-Tet), and Doxorubicin (DOX) was further intercalated into the DNA structure (si-DOX-Tet) for combination therapy. Further, the effects and mechanism of RNF8 inhibition on the sensitivity of colon cancer cells to DOX chemotherapy have also been studied. Results: RNF8 expression was increased in colon cancer. Agarose gel electrophoresis, transmission electron microscopy, and size distribution and potential analysis confirmed the successful preparation of the two nanoparticles, with particle sizes of 10.29 and 37.29 nm, respectively. Fluorescence imaging reveals that the carriers can be internalized into colon cancer cells and escape from lysosomes after 12 hours of treatment, effectively delivering siRNF8 and DOX. Importantly, Western blot analysis verified treatment with 50nM si-Tet silenced RNF8 expression by approximately 50% in colon cancer cells, and combined treatment significantly inhibited cell proliferation. Furthermore, the CCK-8 assay demonstrated that si-Tet treatment enhanced the sensitivity of colon cancer cells to the three chemotherapeutic drugs. Significant more DNA damage was detected after treatment with both si-Tet or si-DOX-Tet. Further flow cytometry analysis revealed that si-DOX-Tet treatment led to significantly more apoptosis, approximately 1.6-fold higher than treatment with DOX alone. Mechanistically, inhibiting RNF8 led to decreased ABCG2 expression and DOX efflux, but increased DNA damage, thereby enhancing the chemotherapeutic effect of DOX. Conclusion: We have successfully constructed si-DOX-Tet. By inhibiting the expression of RNF8, it enhances the chemotherapy sensitivity of DOX. Therefore, this tetrahedral FNA nanocarrier offers a new approach for the combined treatment of colon cancer.

HIF-1α: A potential therapeutic opportunity in renal fibrosis.

Renal fibrosis is a common outcome of various renal injuries, leading to structural destruction and functional decline of the kidney, and is also a critical prognostic indicator and determinant in renal diseases therapy. Hypoxia is induced in different stress and injuries in kidney, and the hypoxia inducible factors (HIFs) are activated in the context of hypoxia in response and regulation the hypoxia in time. Under stress and hypoxia conditions, HIF-1α increases rapidly and regulates intracellular energy metabolism, cell proliferation, apoptosis, and inflammation. Through reprogramming cellular metabolism, HIF-1α can directly or indirectly induce abnormal accumulation of metabolites, changes in cellular epigenetic modifications, and activation of fibrotic signals. HIF-1α protein expression and activity are regulated by various posttranslational modifications. The drugs targeting HIF-1α can regulate the downstream cascade signals by inhibiting HIF-1α activity or promoting its degradation. As the renal fibrosis is affected by renal diseases, different diseases may trigger different mechanisms which will affect the therapy effect. Therefore, comprehensive analysis of the role and contribution of HIF-1α in occurrence and progression of renal fibrosis, and determination the appropriate intervention time of HIF-1α in the process of renal fibrosis are important ideas to explore effective treatment strategies. This study reviews the regulation of HIF-1α and its mediated complex cascade reactions in renal fibrosis, and lists some drugs targeting HIF-1α that used in preclinical studies, to provide new insight for the study of the renal fibrosis mechanism.

Machine Learning Algorithms for Intelligent Decision Recognition and Quantification of Cr(III) in Chromium Speciation.

Cr(III) is a common oxidation state of chromium, and its presence in the environment can occur naturally or as a result of human activities, such as industrial processes, mining, and waste disposal. This article explores the application of machine learning algorithms for the intelligent decision recognition and quantification of Cr(III) in chromium speciation. Three different machine learning models, namely, the Decision Tree (DT) model, the PCA-SVM (Principal Component Analysis-Support Vector Machine) model, and the LDA (Linear Discriminant Analysis) model, were employed and evaluated for accurate and efficient classification of chromium concentrations based on their fluorescence responses. Furthermore, stepwise multiple linear regression analysis was utilized to achieve a more precise quantification of trivalent chromium concentrations through fluorescence visualization. The results demonstrate the potential of machine learning algorithms in accurately detecting and quantifying Cr(III) in chromium speciation with implications for environmental and industrial applications in chromium detection and quantification. The findings from this research pave the way for further exploration and implementation of these models in real-world scenarios, offering valuable insights into various environmental and industrial contexts.

Identification and targeting of cancer-associated fibroblast signature genes for prognosis and therapy in Cutaneous melanoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) play pivotal roles in tumor invasion and metastasis. However, studies on CAF biomarkers in Cutaneous Melanoma (CM) are still scarce. This study aimed to explore the potential CAF biomarkers in CM, propose the potential therapeutic targets, and provide new insights for targeted therapy of CAFs in CM. METHODS: We utilized weighted gene co-expression network analysis to identify CAF signature genes in CM, and conducted comprehensive bioinformatics analysis on the CAF risk score established by these genes. Moreover, single-cell sequencing analysis, spatial transcriptome analysis, and cell experiments were utilized for verifying the expression and distribution pattern of signature genes. Furthermore, molecular docking was employed to screen potential target drugs. RESULTS: FBLN1 and COL5A1, two crucial CAF signature genes, were screened to establish the CAF risk score. Subsequently, a comprehensive bioinformatic analysis of the CAF risk score revealed that high-risk score group was significantly enriched in pathways associated with tumor progression. Besides, CAF risk score was significantly negatively correlated with clinical prognosis, immunotherapy response, and tumor mutational burden in CM patients. In addition, FBLN1 and COL5A1 were further identified as CAF-specific biomarkers in CM by multi-omics analysis and experimental validation. Eventually, based on these two targets, Mifepristone and Dexamethasone were screened as potential anti-CAFs drugs. CONCLUSION: The findings indicated that FBLN1 and COL5A1 were the CAF signature genes in CM, which were associated with the progression, treatment, and prognosis of CM. The comprehensive exploration of CAF signature genes is expected to provide new insight for clinical CM therapy.

Protein crotonylation: An emerging regulator in DNA damage response.

DNA damage caused by internal or external factors lead to increased genomic instability and various diseases. The DNA damage response (DDR) is a crucial mechanism that maintaining genomic stability through detecting and repairing DNA damage timely. Post-translational modifications (PTMs) play significant roles in regulation of DDR. Among the present PTMs, crotonylation has emerged as a novel identified modification that is involved in a wide range of biological processes including gene expression, spermatogenesis, cell cycle, and the development of diverse diseases. In the past decade, numerous crotonylation sites have been identified in histone and non-histone proteins, leading to a more comprehensive and deep understanding of the function and mechanisms in protein crotonylation. This review provides a comprehensive overview of the regulatory mechanisms of protein crotonylation and the effect of crotonylation in DDR. Furthermore, the effect of protein crotonylation in tumor development and progression is presented, to inspire and explore the novel strategies for tumor therapy.

Histone post-translational modification and the DNA damage response.

DNA is highly vulnerable to spontaneous and environmental timely damage in living cells. DNA damage may cause genetic instability and increase cancer risk if the damages are not repaired timely and efficiently. Human cells possess several DNA damage response (DDR) mechanisms to protect the integrity of their genome. Clarification of the mechanisms underlying the DNA damage response following lethal damage will facilitate the identification of therapeutic targets for cancers. Histone post-translational modifications (PTMs) have been indicated to play different roles in the repair of DNA damage. In this context, histone PTMs regulate recruitment of downstream effectors, and facilitate appropriate repair response. This review outlines the current understanding of different histone PTMs in response to DNA damage repair, besides, enumerates the role of new type PTMs such as histone succinylation and crotonylation in regulating DNA damage repair processes.

RNF8 enhances the sensitivity of PD-L1 inhibitor against melanoma through ubiquitination of galectin-3 in stroma.

The failure of melanoma immunotherapy can be mediated by immunosuppression in the tumor microenvironment (TME), and insufficient activation of effector T cells against the tumor. Here, we show that inhibition of galectin-3 (gal-3) enhances the infiltration of T cells in TME and improves the sensitivity of anti-PD-L1 therapy. We identify that RNF8 downregulated the expression of gal-3 by K48-polyubiquitination and promoted gal-3 degradation via the ubiquitin-proteasome system. RNF8 deficiency in the host but sufficiency in implanted melanoma results in immune exclusion and tumor progression due to the upregulation of gal-3. Upregulation of gal-3 decreased the immune cell infiltration by restricting IL-12 and IFN-γ. Inhibition of gal-3 reverses immunosuppression and induces immune cell infiltration in the tumor microenvironment. Moreover, gal-3 inhibitor treatment can increase the sensitivity of PD-L1 inhibitors via increasing immune cell infiltration and enhancing immune response in tumors. This study reveals a previously unrecognized immunoregulation function of RNF8 and provides a promising strategy for the therapy of "cold" tumors. Tremendous effects of melanoma treatment can be achieved by facilitating immune cell infiltration combined with anti-PD-L1 treatment.

Macrophage-Related Testicular Inflammation in Individuals with Idiopathic Non-Obstructive Azoospermia: A Single-Cell Analysis.

Male infertility is a global issue that seriously affects reproductive health. This study aimed to understand the underlying causes of idiopathic non-obstructive azoospermia (iNOA), which is a type of male infertility with unknown origins that accounts for 10-15% of cases. By using single-cell analysis techniques, we aimed to uncover the mechanisms of iNOA and gain insight into the cellular and molecular changes in the testicular environment. In this study, we performed bioinformatics analysis using scRNA-seq and microarray data obtained from the GEO database. The analysis included techniques such as pseudotime analysis, cell-cell communication, and hdWGCNA. Our study showed a significant difference between the iNOA and the normal groups, indicating a disorder in the spermatogenic microenvironment in iNOA. We observed a reduction in the proportion of Sertoli cells and blocked germ cell differentiation. Additionally, we found evidence of testicular inflammation related to macrophages and identified ODF2 and CABYR as potential biomarkers for iNOA.

Carbon ion irradiation induces DNA damage in melanoma and optimizes the tumor microenvironment based on the cGAS-STING pathway.

PURPOSES: Increased number of studies reveal the crucial role of the Cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway in anti-tumor immunity. In this study, we aim to explore the effect of cGAS/STING on tumor immune microenvironment of melanoma after carbon ion radiotherapy (CIRT) and the underlying mechanism. METHODS: C57BL/6 mouse tumor models were used to evaluate the efficacy of different treatments (X-ray, carbon ion, PD-L1 inhibitor and combination therapies) on tumor growth and process. Mass cytometry was performed to assess tumor-infiltrating lymphocytes (TILs). DNA damage response (DDR) and cGAS/STING pathway were investigated by immunofluorescence-co-localization assays, γ-H2AX, P53-binding protein 1 (53BP1), Breast Cancer 1 (BRCA1), and cGAS measurements. RESULTS: Carbon ion irradiation caused more DNA damages and cGAS-STING pathway activation compared with X-ray irradiation, and the former slowed the melanoma growth in syngeneic model. Although X-ray irradiation is not sensitive for melanoma treatment, carbon ion irradiation showed a significant anti-tumor effect for melanoma treatment. TILs analysis revealed that CIRT boosted the infiltration of natural killer (NK), CD4+, and CD8+ T cells, meanwhile increased the number of immune checkpoint (programmed death-1, PD-1, lymphocyte activation gene 3, LAG-3 and T-cell immunoglobulin and mucin domain-containing protein 3, TIM-3). Moreover, CIRT increased PD-L1 exposure on cell surface compared with X-ray group. Furthermore, CIRT combined with PD-L1 inhibitor therapy increased the number of T cells and NK cells in melanoma, and slowed the growth of melanoma compared with other therapies. CONCLUSIONS: Our findings showed that CIRT displayed biological effects by increasing DNA damages of tumor cells and improving immunity in melanoma, which indicated that CIRT might be a potential synergetic treatment for radiotherapy and radioimmunotherapy in melanoma patients. Our works put forward a new insight to provide an effective strategy for melanoma therapy. These findings may help in the design of strategies on melanoma in clinical studies.

DNA replication: Mechanisms and therapeutic interventions for diseases.

Accurate and integral cellular DNA replication is modulated by multiple replication-associated proteins, which is fundamental to preserve genome stability. Furthermore, replication proteins cooperate with multiple DNA damage factors to deal with replication stress through mechanisms beyond their role in replication. Cancer cells with chronic replication stress exhibit aberrant DNA replication and DNA damage response, providing an exploitable therapeutic target in tumors. Numerous evidence has indicated that posttranslational modifications (PTMs) of replication proteins present distinct functions in DNA replication and respond to replication stress. In addition, abundant replication proteins are involved in tumorigenesis and development, which act as diagnostic and prognostic biomarkers in some tumors, implying these proteins act as therapeutic targets in clinical. Replication-target cancer therapy emerges as the times require. In this context, we outline the current investigation of the DNA replication mechanism, and simultaneously enumerate the aberrant expression of replication proteins as hallmark for various diseases, revealing their therapeutic potential for target therapy. Meanwhile, we also discuss current observations that the novel PTM of replication proteins in response to replication stress, which seems to be a promising strategy to eliminate diseases.

HIF-1α mediates renal fibrosis by regulating metabolic remodeling of renal tubule epithelial cells.

Hypoxia-inducible factor 1-α (HIF-1α) mediates the occurrence and development of renal diseases and fibrosis. In the process, dysregulated cellular metabolism was suggested to be involved in several pathological processes. Here, we found that HIF-1α expression was increased in the early stage of renal fibrosis, and significant metabolic remodeling was triggered. Epigenetic events that drive diseases were characterized previously. Our study showed that ten-eleven translocation-2 (TET2) was upregulated in both renal fibrosis models and metabolite-treated samples. Furthermore, we found that the promoter of α-SMA was hypomethylated at CpG sites, which promoted the expression of α-SMA and the occurrence of renal fibrosis. HIF-1α inhibition alleviated renal fibrosis development by improving metabolic remodeling and TET2 activation. Our studies provide novel insight into HIF-1α-mediated metabolic remodeling in the pathogenesis of renal fibrosis and propose a concept that targets this pathway to treat fibrotic disorders.

Dual-Site Fluorescent Sensor as a Multiple Logic System for Studying the Dichotomous Function of Sulfur Dioxide under Oxidative Stress Induced by Peroxynitrite.

Intracellular reactive oxygen species and reactive sulfur play a vital role in regulating redox homeostasis and maintaining cell functions. Sulfur dioxide (SO2) has emerged as an important gas signal molecule recently, which is not only a potential reducing agent but also a potential inductor of oxidative stress in organisms. Due to high reactivity, peroxynitrite (ONOO-) could act on many biomolecules, such as proteins, lipids, and nucleic acids, and cause irreversible damage, eventually leading to cell apoptosis or necrosis. In order to further illuminate the dichotomous role of SO2 under oxidative stress induced by ONOO-, we designed the first dual-site fluorescent sensor (NIR-GYf) for separate or continuous detection of SO2 and ONOO-. NIR-GYf was successfully used for cell imaging of endogenous SO2 and ONOO-. In addition, western blotting analysis was used to verify the oxidation and antioxidation of SO2 and its dichotomous biological influence. Finally, NIR-GYf was integrated with multiple Boolean logic operations to construct an advanced analysis device, thereby realizing the direct analysis of SO2 and ONOO- levels.

Accumulation of polystyrene microplastics induces liver fibrosis by activating cGAS/STING pathway.

The environmental pollution from microplastics has caused concern from the whole society due to its harm to organisms. However, the effect of microplastics on liver damage and fibrosis remains unclear in the case of long-term accumulation. The present study demonstrated that the 0.1 µm microplastic could enter hepatocytes from circulation and result liver damage even at a low concentration. Microplastic exposure could induce DNA damage in both nucleus and mitochondria, by which the dsDNA fragment was translocated into cytoplasm and triggered the DNA sensing adaptor STING. The activation of cGAS/STING pathway initiated the downstream cascade reaction, the NFκB translocated into nucleus and upregulated pro-inflammatory cytokines expression, and thus facilitating liver fibrosis eventually. Furthermore, inhibition of STING could alleviate the liver fibrosis via blocking the NFκB translocation and fibronectin expression. This study provided a valuable insight to elucidate the potential risk and mechanism of hepatic toxicity and fibrosis induced by microplastics.

Biochanin A Sensitizes Glioblastoma to Temozolomide by Inhibiting Autophagy.

Resistance to temozolomide (TMZ) chemotherapy is the main reason for treatment failure in patients with glioblastoma (GBM). In the present study, we investigated biochanin A (BCA) a potent sensitizer of TMZ in GBM. We observed that BCA significantly enhanced cell sensitivity to TMZ in vitro and in vivo. Mechanistically, the specific chemosensitizing effect of BCA is mediated by autophagy inhibition. Moreover, by performing a molecular docking analysis, we demonstrated that BCA interacts with AMPK residues and impairs autophagy by regulating the AMPK/ULK1 pathway. These results suggest that BCA is a potential therapeutic agent that sensitizes GBM to TMZ and provide new insight into its therapeutic potential in chemoresistant GBM.

The Role of RAD6B and PEDF in Retinal Degeneration.

RAD6B is an E2 ubiquitin-conjugating enzyme, playing an important role in DNA damage repair, gene expression, senescence, apoptosis and protein degradation. However, the specific mechanism between ubiquitin and retinal degeneration requires more investigation. Pigment epithelium-derived factor (PEDF) has a potent neurotrophic effect on the retina, protecting retinal neurons and photoreceptors from cell death caused by pathological damage. In this study, we found that loss of RAD6B leads to retinal degeneration in mice, especially in old age. Affymetrix microarray analysis showed that the PEDF signal was changed in RAD6B deficient groups. The expression of γ-H2AX, ß-Gal, P53, Caspase-3, P21 and P16 was increased significantly in retinas of RAD6B knockout (KO) mice. Our studies suggest that RAD6B and PEDF play an important role in the health of retina, whereas the absence of RAD6B accelerates the degeneration.

Design, synthesis, and biological evaluation of carbamate derivatives of N-salicyloyl tryptamine as multifunctional agents for the treatment of Alzheimer's disease.

In this study, we designed, synthesized, and evaluated a series of carbamate derivatives of N-salicyloyl tryptamine as multifunctional therapeutic agents for the treatment of Alzheimer's disease (AD). After screening the acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) inhibitory activities, target compound 1g stood out as a mixed type reversible dual inhibitor of AChE and BChE. In addition, molecular docking studies were conducted to explore the actions on AChE and BChE. The results showed that 1g could decrease the level of pro-inflammatory cytokines NO, iNOS, IL-6, TNF-α, and ROS, increase the level of anti-inflammatory cytokines IL-4, and inhibit the aggregation of Aß1-42. Moreover, the administration of 1g suppressed the activity of AChE in the brain. In a word, the compound 1g is effective for improving learning and memory behavior, blood-brain barrier permeation, pharmacokinetics, ChE inhibition, and anti-neuroinflammation. It may be considered as a promising multi-functional therapeutic agent for further investigation for the treatment of AD.

N-salicyloyl tryptamine derivatives as potential therapeutic agents for Alzheimer's disease with neuroprotective effects.

Alzheimer's disease (AD) has become a serious threat to the developed nations with burgeoning patients and annual costs on health care system in modern society. Neuroinflammation, as one of the specific biochemical factors in the progress of neurodegeneration diseases, performs a crucial role in the pathogenesis and development of AD. Therefore, it is of great significance to develop effective anti-neuroinflammatory strategies for the treatment of AD. N-salicyloyl tryptamine derivatives were previously reported and demonstrated that possessed great potential anti-neuroinflammatory effects and favorable blood-brain barrier (BBB) permeation. Herein, a series of novel N-salicyloyl tryptamine derivatives were synthesized and their anti-AD potential was evaluated both in vitro and in vivo. Among them, L7 performed well anti-neuroinflammatory effects and excellent neuroprotective effects, as well as little toxicity. To lucubrate its potential for the treatment of AD, behavior tests including morris water maze (MWM), eight-arm radial maze, open field test and novel object recognition (NOR) test were carried out and the results showed that L7 could remarkably improve Aß-induced cognitive impairment. Moreover, the mechanism of action of L7 on improving Aß-induced AD was preliminarily investigated, and the results uncovered that the neuroprotective effects of L7 was might exerte via intervening Aß-induced pyroptosis through NLRP3-caspase-1-GSDMD axis and ameliorating neuronal apoptosis by mitochondrial apoptosis pathway. Besides, the distribution of Aß plaques in brain tissues were detected by immunohistochemical (IHC) assay and the results indicated that L7 could significantly attenuate the deposition of Aß plaques in the brain.

Overexpression of thioredoxin reductase 1 can reduce DNA damage, mitochondrial autophagy and endoplasmic reticulum stress in Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Several factors, including neuroinflammation, neuronal excitotoxicity, genetic mutations and incorrect protein folding are involved in PD pathophysiology. However, the precise mechanism that contributes to the decreased number of dopaminergic neurons is unknown. A growing body of research suggests that oxidative stress is a major factor in PD. Therefore, antioxidant therapy is an important approach for treating PD. The thioredoxin system is an important antioxidant system, and thioredoxin reductase 1 (TR1) is a major member of the thioredoxin system. The present study demonstrates that oxidative stress is increased and that the expression of TR1 is decreased in the SNc of A53T mice; TR1 has emerged as an important antioxidant agent in dopaminergic neurons. Therefore, we over-expressed TR1 in the MPP+-induced cellular model and in the A53T transgenic mouse model of PD. We confirmed that the overexpression of TR1 in neuronal cells decreased DNA damage and malondialdehyde (MDA) and ROS generation, increased T-SOD and GSH production, and decreased the ER stress, and autophagy in the PD model. In summary, our findings demonstrate that the overexpression of TR1 could be effective as a novel neuroprotective strategy for PD. This research suggests a novel direction in the treatment of PD.