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![FIG URE 1 Schematic presentation for the immune and inflammatory responses in Parkinson pathology. Abbreviations: APC 5 antigenpresenting cells; CNS 5 central nervous system; GDNF 5 growth-derived neurotrophic factor; IL 5 interleukin; NFjB 5 nuclear factor kappa light chain enhancer of activated B cells; ROS 5 reactive oxygen species; TGF 5 transforming growth factor; TNF 5 tumor necrosis factor [Color figure can be viewed at wileyonlinelibrary.com]](profile/Sarika-Singh-2/publication/320243512/figure/fig1/AS:1021014389559297@1620440208510/FIG-URE-1-Schematic-presentation-for-the-immune-and-inflammatory-responses-in-Parkinson.png)
FIG URE 1 Schematic presentation for the immune and inflammatory responses in Parkinson pathology. Abbreviations: APC 5 antigenpresenting cells; CNS 5 central nervous system; GDNF 5 growth-derived neurotrophic factor; IL 5 interleukin; NFjB 5 nuclear factor kappa light chain enhancer of activated B cells; ROS 5 reactive oxygen species; TGF 5 transforming growth factor; TNF 5 tumor necrosis factor [Color figure can be viewed at wileyonlinelibrary.com]
Source publication
Studies in the last decade have suggested the association of both neuroinflammatory processes and immune responses in Parkinson disease (PD) pathology. PD pathology is related to depleted dopamine levels, α-synuclein aggregation, and death of nigrostriatal dopaminergic neurons. Reports have suggested central and peripheral inflammation in the prodr...
Citations
... Other lncRNA studies have focused on the role lncRNAs play in significant inflammation in PD cases, often regulated by microglial cells, and how this can lead to the progression of neuron injury [66,67]. Patients with PD tend to have a consistent inflammatory response, which could worsen neuron injury [68]. LncRNA MALAT1 was upregulated in MPTPtreated mice, along with increased expression of pro-inflammatory cytokines through epigenetic regulation. ...
Citation: Anilkumar, A.K.; Vij, P.; Lopez, S.; Leslie, S.M.; Doxtater, K.; Khan, M.M.; Yallapu, M.M.; Chauhan, S.C.; Maestre, G.E.; Tripathi, M.K. Abstract: Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are gradually becoming a burden to society. The adverse effects and mortality/morbidity rates associated with these NDDs are a cause of many healthcare concerns. The pathologic alterations of NDDs are related to mitochondrial dysfunction, oxidative stress, and inflammation, which further stimulate the progression of NDDs. Recently, long non-coding RNAs (lncRNAs) have attracted ample attention as critical mediators in the pathology of NDDs. However, there is a significant gap in understanding the biological function, molecular mechanisms, and potential importance of lncRNAs in NDDs. This review documents the current research on lncRNAs and their implications in NDDs. We further summarize the potential implication of lncRNAs to serve as novel therapeutic targets and biomarkers for patients with NDDs.
... its pathological manifestations include dopaminergic neuron deficit, gliosis in the substantia nigra, and intercellular accumulation of α-synuclein produced by lewy bodies [14,15]. similar to aD, inflammatory intermediates play a crucial role in PD pathology, and they can serve as early diagnostic and monitoring biomarkers. it has been confirmed that the activation of neuroinflammatory cascades in the brain of PD patients, triggered by microglial activation, is associated with a significant increase in the plasma levels of various inflammatory metabolites and cytokines such as prostaglandin e2 (PGe2), iFN-γ, il-1α, il-6, il-10, and tNF-α [16][17][18][19]. ...
Background:
Neurodegenerative disorders such as Alzheimer's and Parkinson's disease inflict economic and health burdens on societies. Alzheimer's disease (AD), the most prevalent form of dementia, is accompanied by progressive degradation of memory, decision-making, and judgment. Parkinson's disease (PD) is characterized by resting tremor, rigidity, bradykinesia, and loss of balance. Extensive research has pinpointed inflammation as a cause of the onset and progression of both diseases. However, it has not been confirmed which one is more formidable in terms of inflammation.
Methods:
To assess the extent of inflammation that is implicated in AD and PD and answer the question of which one is more inflammatory, serum levels of inflammatory biomarkers, including cytokines, chemokines, and prostaglandin E2 (PEG2), were measured in AD and PD patients as well as a healthy group.
Results:
Our results showed a significant increase in IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-12p70, IP-10, MCP-1, PEG2, and TNF-α in AD and PD patients compared with the control. Interestingly, IFN-γ did not manifest any significant difference in AD or PD patients compared with the control.
Conclusion:
As a hallmark of our results, it could be inferred that inflammation, as the underlying etiological cause, plays a more crucial role in PD compared with AD. Based on our results, it is proposed that anti-inflammatory remedies would be putatively more effective in PD rather than AD.
... If the acute inflammatory reaction is not successful in halting the stimulus, it will transform into a chronic inflammatory cascade. Disorders such as obesity (Villarroya et al. 2018), atherosclerosis (Kasikara et al. 2018), rheumatoid arthritis (RA) (Chimenti et al. 2015), gout (So and Martinon 2017), Alzheimer's disease (AD) (Heneka et al. 2015), depression (Koopman and Aidy 2017), Parkinson's disease (PD) (Joshi and Singh 2018), and cancer (Coussens and Werb 2002) are all linked to chronic inflammation and its physiological and pathological processes (Fig. 1). ...
Chronic inflammation is a common underlying factor in many major diseases, including heart disease, diabetes, cancer, and autoimmune disorders, and is responsible for up to 60% of all deaths worldwide. Metformin, statins, and corticosteroids, and NSAIDs (non-steroidal anti-inflammatory drugs) are often given as anti-inflammatory pharmaceuticals, however, often have even more debilitating side effects than the illness itself. The natural product-based therapy of inflammation-related diseases has no adverse effects and good beneficial results compared to substitute conventional anti-inflammatory medications. In this review article, we provide a concise overview of present pharmacological treatments, the pathophysiology of inflammation, and the signaling pathways that underlie it. In addition, we focus on the most promising natural products identified as potential anti-inflammatory therapeutic agents. Moreover, preclinical studies and clinical trials evaluating the efficacy of natural products as anti-inflammatory therapeutic agents and their pragmatic applications with promising outcomes are reviewed. In addition, the safety, side effects and technical barriers of natural products are discussed. Furthermore, we also summarized the latest technological advances in the discovery and scientific development of natural products-based medicine.
... Interleukins and tumor necrosis factors (TNFs) are crucial immune activation signaling molecules that affect both the brain and the periphery [16]. In vivo findings of positron emission tomography and postmortem in PD patients revealed elevated inflammatory reactions, such as microglial activation [17,18], and higher levels of immunological markers in the brain [18][19][20]. ...
Background
The goal of this research was to explore the role of Neutrophil to lymphocyte ratio (NLR) in Parkinson’s disease (PD).
Methods
From inception to 4 June 2023, PubMed, Web of Science, and ProQuest were searched for papers comparing NLR in PD to healthy individuals. Standardized mean difference (SMD) with a confidence interval (CI) of 95% were calculated.
Results
A random-effect model revealed that PD patients had elevated NLR values compared to healthy individuals (SMD = 0.81, 95% CI = 0.47 to 1.14, P < 0.001). The results of subgroup analysis were as follows: (1) study design: We observed that patients with PD had higher levels of NLR than healthy controls in either retrospective (SMD = 1.12, 95% CI = 0.58 to 1.66, P < 0.001) or prospective (SMD = 0.43, 95% CI = 0.18 to 0.68, P = 0.001) studies. (2) Ethnicity: We noticed that individuals with PD had higher levels of NLR than healthy controls, whether they were East Asian (SMD = 0.93, 95% CI = 0.22 to 1.63, P = 0.010) or Caucasian (SMD = 0.75, 95% CI = 0.40 to 1.10, P < 0.001).The pooled sensitivity of NLR in the prediction of PD was 0.67 (95% CI = 0.61–0.73), and the pooled specificity was 0.66 (95% CI, 0.61–0.70).
Conclusions
Increased levels of NLR is highly related with the presence of PD. Further research is needed to determine the potential clinical benefits of this simple and low-cost biomarker in the PD diagnosis.
... Proinflammatory cytokines, reactive oxygen/nitrogen species, and prostaglandins are released by activated microglia, which cause neurotoxicity. The release of proinflammatory cytokines by microglia is also a powerful activator of NF-κB and inducible nitric oxide synthase (iNOS), both of which lead to neuronal death [34]. Various reports have documented the neuroinflammation alleviating effect of biochanin-A by using different neuronal cell line models i.e., lipopolysaccharides (LPS) treated BV2, amyloid beta elicited neurotoxic PC-12 cells, etc. [35][36][37][38]. ...
Biochanin-A is a naturally occurring plant phytoestrogen, which mimics specific the agonistic activity of estrogens. Biochanin-A is known to possess numerous activities, including neuroprotective, anti-diabetic, hepatoprotective, anti-inflammatory, antioxidant, and antimicrobial activities, along with the anticancer activity. Neuroinflammation is thought to play a pivotal pathological role in neurodegenerative disease. Sustained neuroinflammatory processes lead to progressive neuronal damage in Parkinson’s and Alzheimer’s disease. Activation of PI3K/Akt cascade and inhibition of MAPK signaling cascade have been observed to be responsible for conferring protection against neuroinflammation in neurodegenerative diseases. An increased oxidative stress promotes neuronal apoptosis via potentiating the TLR-4/NF-κB and inhibiting PI3K/Akt signaling mediated increase in pro-apoptotic and decreases in antiapoptotic proteins. Various authors have explored biochanin-A’s neuroprotective effect by using various cell lines and animal models. Biochanin-A has been reported to mediate its neuroprotective via reducing the level of oxidants, inflammatory mediators, MAPK, TLR-4, NF-κB, NADPH oxidase, AchE, COX-2 and iNOS. Whereas, it has been observed to increase the level of anti-oxidants, along with phosphorylation of PI3K and Akt proteins. The current review has been designed to provide insights into the neuroprotective effect of biochanin-A and possible signaling pathways leading to protection against neuroinflammation and apoptosis in the central nervous system. This review will be helpful in guiding future researchers to further explore biochanin A at a mechanistic level to obtain useful lead molecules.
... This may occur in many different diseases including diabetes, rheumatoid arthritis, chronic hyperammonemia or liver cirrhosis [9]. Peripheral inflammation also plays a key role in cognitive impairment in neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's or Alzheimer`s diseases [10][11][12][13]. In all these pathological situations, sustained peripheral inflammation triggers neuroinflammation, which alters neurotransmission, leading to mild cognitive impairment. ...
... Protein content of A IκBα (n = 10-19) and B phosphorylated IκBα (n = 8-18). C Protein content (n = 8-22) and D membrane expression of TNFR1 (n = [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. Protein content of E phosphorylated IκBα (n = 12-16), F IL-1β (n = 11-13) and G TNFα (n = 12-15) in experiments using R7050 to block TNFR1 signaling. ...
... These agrees with the study by Zhang et al. showing that TNFα associated to the membrane of EVs isolated from synovial fibroblasts of patients with rheumatoid arthritis Fig. 10 Ex vivo treatment with EVs from hyperammonemic rats downregulates TGFβ receptor TGFβR2 and Smad7 in hippocampal slices from control rats. Protein content of A Smad7 (n = 8-16), B TGFβ (n = 8-15) and C TGFβR2 (n = [10][11][12][13][14][15][16][17][18][19][20][21][22]. D Membrane expression (n = 8-10) of TGFβR2. ...
Patients with liver cirrhosis show hyperammonemia and peripheral inflammation and may show hepatic encephalopathy with cognitive impairment, reproduced by rats with chronic hyperammonemia. Peripheral inflammation induces neuroinflammation in hippocampus of hyperammonemic rats, altering neurotransmission and leading to cognitive impairment. Extracellular vesicles (EVs) may transmit pathological effects from the periphery to the brain. We hypothesized that EVs from peripheral blood would contribute to cognitive alterations in hyperammonemic rats. The aims were to assess whether EVs from plasma of hyperammonemic rats (HA-EVs) induce cognitive impairment and to identify the underlying mechanisms. Injection of HA-EVs impaired learning and memory, induced microglia and astrocytes activation and increased TNFα and IL-1β. Ex vivo incubation of hippocampal slices from control rats with HA-EVs reproduced these alterations. HA-EVs increased membrane expression of TNFR1, reduced membrane expression of TGFβR2 and Smad7 and IκBα levels and increased IκBα phosphorylation. This led to increased activation of NF-κB and IL-1β production, altering membrane expression of NR2B, GluA1 and GluA2 subunits, which would be responsible for cognitive impairment. All these effects of HA-EVs were prevented by blocking TNFα, indicating that they were mediated by enhanced activation of TNFR1 by TNFα. We show that these mechanisms are very different from those leading to motor incoordination, which is due to altered GABAergic neurotransmission in cerebellum. This demonstrates that peripheral EVs play a key role in the transmission of peripheral alterations to the brain in hyperammonemia and hepatic encephalopathy, inducing neuroinflammation and altering neurotransmission in hippocampus, which in turn is responsible for the cognitive deficits.
... Resting tremor, stiffness, bradykinesia, and other clinical symptoms of PD are brought on by the increasing weakening of dopaminergic neurons in the substantia nigra (2). Currently, a great amount of clinical and genetic evidences has revealed that inflammation and immune system malfunction are related to the development of PD (3,4). ...
... According to some theories, both central and peripheral inflammation begin to manifest in the prodromal stage of PD and remain as the condition worsens (4). The origin of inflammation arises from the central nervous system (CNS), where resting microglia are activated by a-syn, triggering an inflammatory cascade response that leads to the death of dopaminergic neurons (3,5). ...
... However, it is important to note that the activation of peripheral inflammatory is nonspecific and can be evaluated using some generalized markers like neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) (13). The discordant central inflammatory response is enhanced concurrently with peripheral immune system activation, which may be a factor exacerbating the neurodegeneration (4). ...
Background
The dysfunction of immune system and inflammation contribute to the Parkinson’s disease (PD) pathogenesis. Cytokines, oxidative stress, neurotoxin and metabolism associated enzymes participate in neuroinflammation in PD and the genes involved in them have been reported to be associated with the risk of PD. In our study, we performed a quantitative and causal analysis of the relationship between inflammatory genes and PD risk.
Methods
Standard process was performed for quantitative analysis. Allele model (AM) was used as primary outcome analysis and dominant model (DM) and recessive model (RM) were applied to do the secondary analysis. Then, for those genes significantly associated with the risk of PD, we used the published GWAS summary statistics for Mendelian Randomization (MR) to test the causal analysis between them.
Results
We included 36 variants in 18 genes for final pooled analysis. As a result, IL-6 rs1800795, TNF-α rs1799964, PON1 rs854560, CYP2D6 rs3892097, HLA-DRB rs660895, BST1 rs11931532, CCDC62 rs12817488 polymorphisms were associated with the risk of PD statistically with the ORs ranged from 0.66 to 3.19 while variants in IL-1α, IL-1β, IL-10, MnSOD, NFE2L2, CYP2E1, NOS1, NAT2, ABCB1, HFE and MTHFR were not related to the risk of PD. Besides, we observed that increasing ADP-ribosyl cyclase (coded by BST1) had causal effect on higher PD risk (OR[95%CI] =1.16[1.10-1.22]) while PON1(coded by PON1) shown probably protective effect on PD risk (OR[95%CI] =0.81[0.66-0.99]).
Conclusion
Several polymorphisms from inflammatory genes of IL-6, TNF-α, PON1, CYP2D6, HLA-DRB, BST1, CCDC62 were statistically associated with the susceptibility of PD, and with evidence of causal relationships for ADP-ribosyl cyclase and PON1 on PD risk, which may help understand the mechanisms and pathways underlying PD pathogenesis.
... Proinflammatory cytokines contribute to neurodegeneration in both AD and PD (for reviews, see Heneka et al. 2015;Calsolaro and Edison 2016;Joshi and Singh 2018;Rocha et al. 2018). We have shown that proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and interleukin-6 (IL-6) induce the accumulation of GPC1-derived HS-anMan and APP-derived β-CTF and also aggregation of SYN in dividing neuroblastoma cells, neural stem cells, and neural progenitor cells (NPCs), while the nondividing cortical neurons are unaffected (Cheng et al. 2020(Cheng et al. , 2022. ...
... see e.g. Heneka et al. 2015;Calsolaro and Edison 2016;Joshi and Singh 2018;Rocha et al. 2018; see also Cheng et al. 2020 and refs. therein). ...
... Proinflammatory cytokines promote neurodegeneration in both AD and PD (for reviews, see Heneka et al. 2015;Calsolaro and Edison 2016;Joshi and Singh 2018;Rocha et al. 2018). A mixed AD-PD pathology may thus be initiated by the increased expression of β-secretase, which results in increased processing of APP into β-NTF and β-CTF. ...
In Parkinson's disease there is accumulation of α-synuclein (SYN) aggregates in neurons, which is promoted by neuroinflammation. In neural cells, cytokine-induced SYN aggregation is modulated by heparan sulfate (HS) derived from glypican-1 (GPC1) by amyloid precursor protein (APP) and NO-dependent cleavage. We have explored possible interplay between APP, GPC1 and SYN in undifferentiated and differentiated neural progenitor cells (NPC) by modulating APP and GPC1 processing. Effects were monitored by immunofluorescence microscopy and slot immunoblotting using antibodies recognizing APP degradation products, HS released from GPC1, and SYN aggregates (SYNfil). Suppression of HS release from GPC1 by inhibition of β-secretase or by NO-deprivation resulted in no or slight increase in SYNfil aggregation. Stimulation of HS release by ascorbate did not further increase SYNfil staining. Interleukin-6 (IL-6) induced increased APP and GPC1 processing and SYNfil formation, which was reduced when β-secretase was inhibited, and when HS release was impeded by NO-deprivation. Ascorbate restored APP and GPC1 processing but did not affect SYNfil formation. Ascorbate-dependent differentiation of NPC resulted in expression of tyrosine hydroxylase (TH) which co-localized with SYNfil. Suppression of APP processing by inhibition of β-secretase greatly disturbed the differentiation process. IL-6 induced co-clustering of APP-degradation products, TH, HS and SYNfil, which could be reversed by stimulation of HS release from GPC1 by excess ascorbate. We suggest that continuous release of HS from GPC1 moderates SYN aggregation and supports differentiation of NPC to dopaminergic neurons.
... Multiple pathophysiological mechanisms have been observed to play a role in PD, such as inflammation, dysregulation of metabolism, oxidative stress, insulin resistance and disruption of gut microbiome composition. Inflammation has been found to be a key mechanism in PD patients and animal models alike 86 . Rotenone blocks the electron transport chain complex I which in turn causes mitochondrial dysfunction via increased levels of Fig. 9 Linear discriminant analysis effect size (LEfSe) for organisms most like to explain differences in gut microbiome between treatment groups. ...
Glucose metabolism is dysregulated in Parkinson’s disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.
... have a family history of disease in 15%, with 5e10% having monogenic Mendelian inheritance [1]. Neuropathology of PD is characterized by the apoptosis of neurons in the substantia nigra pars compacta (SNpc) and other areas via several pathways caused by ⍺-synuclein aggregation in the form of Lewy body cytoplasmic inclusions, contributing to the symptoms of Parkinson's Disease [2]. PD is asymptomatic in the early neuronal death of the SNpc, mainly due to compensation of the striatum [3]. ...
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease, characterized by apoptosis of dopaminergic neurons in substansia nigra pars compacta (SNpc) caused by ⍺-synuclein aggregation. The use of secretomes released by medicinal signaling cells (MSCs) is one the promising preventive approaches that target several mechanisms in the neuropathology of PD. Its components target the lack of neurotrophin factors, proteasome dysfunction, oxidative stress, mitochondrial dysfunction, and at last neuroinflammation via several pathways. The complex and obscure pathology of PD induce the difficulty of the search of potential preventive approach for this disease. We described the potential of secretome of MSC as the novel preventive approach for PD, especially by targeting the said major pathogenesis of PD.
