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Article ; Online: Phosphorylated Upstream Frameshift 1-dependent Nonsense-mediated μ-Opioid Receptor mRNA Decay in the Spinal Cord Contributes to the Development of Neuropathic Allodynia-like Behavior in Rats.

Hsieh, Ming-Chun / Lai, Cheng-Yuan / Yeh, Chou-Ming / Yang, Po-Sheng / Cheng, Jen-Kun / Wang, Hsueh-Hsiao / Lin, Kuan-Hung / Nie, Siao-Tong / Lin, Tzer-Bin / Peng, Hsien-Yu

Anesthesiology

2023 Volume 138, Issue 6, Page(s) 634–655

MeSH term(s)	Male ; Female ; Rats ; Animals ; Hyperalgesia/metabolism ; Rats, Sprague-Dawley ; Nonsense Mediated mRNA Decay ; Spinal Cord/metabolism ; Spinal Nerves ; Neuralgia/metabolism ; Spinal Cord Dorsal Horn ; Receptors, Opioid ; Ligation/adverse effects
Chemical Substances	Receptors, Opioid
Language	English
Publishing date	2023-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	269-0
ISSN	1528-1175 ; 0003-3022
ISSN (online)	1528-1175
ISSN	0003-3022
DOI	10.1097/ALN.0000000000004550
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Article ; Online: Data on lung and intestinal microbiome after air pollution exposure in ageing rats.

Laiman, Vincent / Lo, Yu-Chun / Chen, Hsin-Chang / Yuan, Tzu-Hsuen / Hsiao, Ta-Chih / Chen, Jen-Kun / Chang, Ching-Wen / Lin, Ting-Chun / Li, Ssu-Ju / Chen, You-Yin / Heriyanto, Didik Setyo / Chung, Kian Fan / Chuang, Kai-Jen / Ho, Kin-Fai / Chang, Jer-Hwa / Chuang, Hsiao-Chi

Data in brief

2023 Volume 47, Page(s) 109004

Abstract: Air pollution has been linked to respiratory diseases, and urban air pollution can be attributed to a number of emission sources. The emitted particles and gases are the primary components of air pollution that enter the lungs during respiration. ... ...

Abstract	Air pollution has been linked to respiratory diseases, and urban air pollution can be attributed to a number of emission sources. The emitted particles and gases are the primary components of air pollution that enter the lungs during respiration. Particulate matter with an aerodynamic diameter of ≤ 2.5 µm (PM
Language	English
Publishing date	2023-02-23
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2786545-9
ISSN	2352-3409 ; 2352-3409
ISSN (online)	2352-3409
ISSN	2352-3409
DOI	10.1016/j.dib.2023.109004
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Article: The nephrotoxic potential of polystyrene microplastics at realistic environmental concentrations

Chen, Yi-Chun / Chen, Ku-Fan / Lin, Kun-Yi Andrew / Chen, Jen-Kun / Jiang, Xin-Yu / Lin, Chia-Hua

Journal of hazardous materials. 2022 Apr. 05, v. 427

2022

Abstract: As microplastics (MPs) dispersed into the environment, people might be exposed to MPs. Most pollutants either pass through or concentrate in the kidney. Therefore, nephrotoxicity tests are needed to verify the toxic potential of MPs. Here we used human ... ...

Abstract	As microplastics (MPs) dispersed into the environment, people might be exposed to MPs. Most pollutants either pass through or concentrate in the kidney. Therefore, nephrotoxicity tests are needed to verify the toxic potential of MPs. Here we used human embryonic kidney 293 (HEK293) cells to determine the association between nephrotoxicity and round-shape polystyrene MPs (PSMPs) (3.54 ± 0.39 μm) under realistic environmental exposure concentrations. Results revealed that PSMPs can adhere to the cell membrane and get entirely engulfed by HEK293 cells. PSMPs can induce cytotoxicity by oxidative stress via inhibition of the antioxidant haem oxygenase-1. Depolarisation of the mitochondrial membrane potential and formation of autophagosomes confirmed that apoptosis and autophagy can be simultaneously induced by PSMPs. The inflammatory factor was only activated (33 cytokines) by noncytotoxic concentration of PSMPs (3 ng/mL); however, the cytotoxic concentration (300 ng/mL) of PSMPs induced autophagy, which might further reduce NLRP3 expression, thus contributing to dampening inflammation (35 cytokines) in HEK293 cells. PSMPs (300 ng/mL) can impair kidney barrier integrity and increase the probability of developing acute kidney injury through the depletion of the zonula occludens-2 proteins and α1-antitrypsin. Altogether, our results demonstrated that environmental exposure to PSMPs may lead to an increased risk of renal disease.
Keywords	acute kidney injury ; antioxidants ; apoptosis ; autophagosomes ; autophagy ; cytokines ; cytotoxicity ; environmental exposure ; humans ; inflammation ; kidneys ; membrane potential ; microplastics ; mitochondrial membrane ; nephrotoxicity ; oxidative stress ; polystyrenes ; risk
Language	English
Dates of publication	2022-0405
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1491302-1
ISSN	1873-3336 ; 0304-3894
ISSN (online)	1873-3336
ISSN	0304-3894
DOI	10.1016/j.jhazmat.2021.127871
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Article ; Online: Integrating the microneedles with carboplatin to facilitate the therapeutic effect of radiotherapy for skin cancers.

Chen, Min-Hua / Lee, Chun-Hung / Liang, Hsiang-Kuang / Huang, Su-Chin / Li, Jui-Ping / Lin, Cheng-An J / Chen, Jen-Kun

Biomaterials advances

2022 Volume 141, Page(s) 213113

Abstract: In most skin cancer patients, excisional surgery is required to remove tumorous tissue. However, the risk of locoregional recurrence after surgery alone is relatively high, particularly for a locally advanced stage of melanoma. Therefore, additional ... ...

Abstract	In most skin cancer patients, excisional surgery is required to remove tumorous tissue. However, the risk of locoregional recurrence after surgery alone is relatively high, particularly for a locally advanced stage of melanoma. Therefore, additional adjuvant treatments, such as radiotherapy, can be used after surgery to inhibit recurrent melanoma after surgical removal. To enhance local radiotherapy, we present the combined X-ray radiation and radiosensitizers (carboplatin) through microneedles (MNs) to treat melanoma. The MNs could be beneficial to precisely delivering carboplatin into the sub-epidermal layer of the melanoma region and alleviate patients' fear and discomfort during the drug administration compared to the traditional local injection. The carboplatin was loaded into the tips of dissolving gelatin MNs (carboplatin-MNs) through the molding method. The results show gelatin MNs have sufficient mechanical strength and can successfully administer carboplatin into the skin. Both in vitro and in vivo studies suggest that carboplatin can enhance radiotherapy in melanoma treatment. With a combination of radiotherapy and carboplatin, the inhibition effect of carboplatin delivered into the B16F10 murine melanoma model through MNs administration (1.2 mg/kg) is equivalent to that through an intravenous route (5 mg/kg). The results demonstrate a promise of combined carboplatin and X-ray radiation treatment in treating melanoma by MNs administration.
MeSH term(s)	Administration, Cutaneous ; Animals ; Carboplatin/therapeutic use ; Gelatin ; Humans ; Melanoma/drug therapy ; Mice ; Needles ; Skin Neoplasms/drug therapy
Chemical Substances	Gelatin (9000-70-8) ; Carboplatin (BG3F62OND5)
Language	English
Publishing date	2022-09-06
Publishing country	Netherlands
Document type	Journal Article
ISSN	2772-9508
ISSN (online)	2772-9508
DOI	10.1016/j.bioadv.2022.213113
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Article ; Online: Melatonin Relieves Paclitaxel-Induced Neuropathic Pain by Regulating pNEK2-Dependent Epigenetic Pathways in DRG Neurons.

Hsieh, Ming-Chun / Lai, Cheng-Yuan / Lin, Li-Ting / Chou, Dylan / Yeh, Chou-Ming / Cheng, Jen-Kun / Wang, Hsueh-Hsiao / Lin, Kuan-Hung / Lin, Tzer-Bin / Peng, Hsien-Yu

ACS chemical neuroscience

2023 Volume 14, Issue 23, Page(s) 4227–4239

Abstract: The neurohormone melatonin (MLT) demonstrates promising potential in ameliorating neuropathic pain induced by paclitaxel (PTX) chemotherapy. However, little is known about its protective effect on dorsal root ganglion (DRG) neurons in neuropathic pain ... ...

Abstract	The neurohormone melatonin (MLT) demonstrates promising potential in ameliorating neuropathic pain induced by paclitaxel (PTX) chemotherapy. However, little is known about its protective effect on dorsal root ganglion (DRG) neurons in neuropathic pain resulting from the chemotherapeutic drug PTX. Here, PTX-treated rats revealed that intrathecal administration of MLT dose-dependently elevated hind paw withdrawal thresholds and latency, indicating that MLT significantly reversed PTX-induced neuropathic pain. Mechanistically, the analgesic effects of MLT were found to be mediated via melatonin receptor 2 (MT2), as pretreatment with an MT2 receptor antagonist inhibited these effects. Moreover, intrathecal MLT injection reversed the pNEK2-dependent epigenetic program induced by PTX. All of the effects caused by MLT were blocked by pretreatment with an MT2 receptor-selective antagonist, 4P-PDOT. Remarkably, multiple MLT administered during PTX treatment (PTX+MLTs) exhibited not only rapid but also lasting reversal of allodynia/hyperalgesia compared to single-bolus MLT administered after PTX treatment (PTX+MLT). In addition, PTX+MLTs exhibited greater efficacy in reversing PTX-induced alterations in pRSK2, pNEK2, JMJD3, H3K27me3, and TRPV1 expression and interaction in DRG neurons than PTX+MLT. These results indicated that MLT administered during PTX treatment reduced the incidence and/or severity of neuropathy and had a better inhibitory effect on the pNEK2-dependent epigenetic program compared to MLT administered after PTX treatment. In conclusion, MLT/MT2 is a promising therapy for the treatment of pNEK2-dependent painful neuropathy resulting from PTX treatment. MLT administered during PTX chemotherapy may be more effective in the prevention or reduction of PTX-induced neuropathy and maintaining quality.
MeSH term(s)	Rats ; Animals ; Melatonin/pharmacology ; Melatonin/metabolism ; Receptor, Melatonin, MT2/metabolism ; Receptor, Melatonin, MT2/therapeutic use ; Ganglia, Spinal/metabolism ; Neuralgia/chemically induced ; Neuralgia/drug therapy ; Neuralgia/metabolism ; Hyperalgesia/chemically induced ; Hyperalgesia/drug therapy ; Hyperalgesia/metabolism ; Neurons/metabolism ; Epigenesis, Genetic
Chemical Substances	Melatonin (JL5DK93RCL) ; Receptor, Melatonin, MT2
Language	English
Publishing date	2023-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1948-7193
ISSN (online)	1948-7193
DOI	10.1021/acschemneuro.3c00616
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Article ; Online: The nephrotoxic potential of polystyrene microplastics at realistic environmental concentrations.

Chen, Yi-Chun / Chen, Ku-Fan / Lin, Kun-Yi Andrew / Chen, Jen-Kun / Jiang, Xin-Yu / Lin, Chia-Hua

Journal of hazardous materials

2021 Volume 427, Page(s) 127871

Abstract	As microplastics (MPs) dispersed into the environment, people might be exposed to MPs. Most pollutants either pass through or concentrate in the kidney. Therefore, nephrotoxicity tests are needed to verify the toxic potential of MPs. Here we used human embryonic kidney 293 (HEK293) cells to determine the association between nephrotoxicity and round-shape polystyrene MPs (PSMPs) (3.54 ± 0.39 μm) under realistic environmental exposure concentrations. Results revealed that PSMPs can adhere to the cell membrane and get entirely engulfed by HEK293 cells. PSMPs can induce cytotoxicity by oxidative stress via inhibition of the antioxidant haem oxygenase-1. Depolarisation of the mitochondrial membrane potential and formation of autophagosomes confirmed that apoptosis and autophagy can be simultaneously induced by PSMPs. The inflammatory factor was only activated (33 cytokines) by noncytotoxic concentration of PSMPs (3 ng/mL); however, the cytotoxic concentration (300 ng/mL) of PSMPs induced autophagy, which might further reduce NLRP3 expression, thus contributing to dampening inflammation (35 cytokines) in HEK293 cells. PSMPs (300 ng/mL) can impair kidney barrier integrity and increase the probability of developing acute kidney injury through the depletion of the zonula occludens-2 proteins and α1-antitrypsin. Altogether, our results demonstrated that environmental exposure to PSMPs may lead to an increased risk of renal disease.
MeSH term(s)	HEK293 Cells ; Humans ; Microplastics ; Oxidative Stress ; Plastics ; Polystyrenes/toxicity ; Water Pollutants, Chemical/analysis ; Water Pollutants, Chemical/toxicity
Chemical Substances	Microplastics ; Plastics ; Polystyrenes ; Water Pollutants, Chemical
Language	English
Publishing date	2021-11-25
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1491302-1
ISSN	1873-3336 ; 0304-3894
ISSN (online)	1873-3336
ISSN	0304-3894
DOI	10.1016/j.jhazmat.2021.127871
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Article ; Online: Phosphate NIMA-Related Kinase 2-Dependent Epigenetic Pathways in Dorsal Root Ganglion Neurons Mediates Paclitaxel-Induced Neuropathic Pain.

Hsieh, Ming-Chun / Lai, Cheng-Yuan / Cho, Wen-Long / Lin, Li-Ting / Yeh, Chou-Ming / Yang, Po-Sheng / Cheng, Jen-Kun / Wang, Hsueh-Hsiao / Lin, Kuan-Hung / Nie, Siao-Tong / Lin, Tzer-Bin / Peng, Hsien-Yu

Anesthesia and analgesia

2023 Volume 137, Issue 6, Page(s) 1289–1301

Abstract: Background: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of ... ...

Abstract	Background: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established. Methods: Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests. Results: PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain. Conclusions: pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches.
MeSH term(s)	Humans ; Rats ; Male ; Animals ; Paclitaxel/adverse effects ; Paclitaxel/metabolism ; Hyperalgesia/chemically induced ; Hyperalgesia/genetics ; Rats, Sprague-Dawley ; Ganglia, Spinal ; Phosphates/adverse effects ; Phosphates/metabolism ; Histones/metabolism ; Quality of Life ; TRPV Cation Channels ; Neuralgia/chemically induced ; Neuralgia/genetics ; Neuralgia/metabolism ; Antineoplastic Agents/adverse effects ; Neurons/metabolism ; Epigenesis, Genetic ; NIMA-Related Kinases/genetics ; NIMA-Related Kinases/metabolism
Chemical Substances	Paclitaxel (P88XT4IS4D) ; Phosphates ; Histones ; TRPV Cation Channels ; Antineoplastic Agents ; NEK2 protein, human (EC 2.7.11.1) ; NIMA-Related Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-02-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000006397
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Article ; Online: TLR9 and STING agonists cooperatively boost the immune response to SARS-CoV-2 RBD vaccine through an increased germinal center B cell response and reshaped T helper responses.

Yang, Jing-Xing / Tseng, Jen-Chih / Tien, Chih-Feng / Lee, Chia-Yin / Liu, Yi-Ling / Lin, Jhe-Jhih / Tsai, Pei-Ju / Liao, Hung-Chun / Liu, Shih-Jen / Su, Yu-Wen / Hsu, Li-Chung / Chen, Jen-Kun / Huang, Ming-Hsi / Yu, Guann-Yi / Chuang, Tsung-Hsien

International journal of biological sciences

2023 Volume 19, Issue 9, Page(s) 2897–2913

Abstract: Vaccines are a powerful medical intervention for preventing epidemic diseases. Efficient inactivated or protein vaccines typically rely on an effective adjuvant to elicit an immune response and boost vaccine activity. In this study, we investigated the ... ...

Abstract	Vaccines are a powerful medical intervention for preventing epidemic diseases. Efficient inactivated or protein vaccines typically rely on an effective adjuvant to elicit an immune response and boost vaccine activity. In this study, we investigated the adjuvant activities of combinations of Toll-like receptor 9 (TLR9) and stimulator of interferon genes (STING) agonists in a SARS-CoV-2 receptor binding domain protein vaccine. Adjuvants formulated with a TLR9 agonist, CpG-2722, with various cyclic dinucleotides (CDNs) that are STING agonists increased germinal center B cell response and elicited humoral immune responses in immunized mice. An adjuvant containing CpG-2722 and 2'3'-c-di-AM(PS)2 effectively boosted the immune response to both intramuscularly and intranasally administrated vaccines. Vaccines adjuvanted with CpG-2722 or 2'3'-c-di-AM(PS)2 alone were capable of inducing an immune response, but a cooperative adjuvant effect was observed when both were combined. CpG-2722 induced antigen-dependent T helper (Th)1 and Th17 responses, while 2'3'-c-di-AM(PS)2 induced a Th2 response. The combination of CpG-2722 and 2'3'-c-di-AM(PS)2 generated a distinct antigen-dependent Th response profile characterized by higher Th1 and Th17, but lower Th2 responses. In dendritic cells, CpG-2722 and 2'3'-c-di-AM(PS)2 showed a cooperative effect on inducing expression of molecules critical for T cell activation. CpG-2722 and 2'3'-c-di-AM(PS)2 have distinct cytokine inducing profiles in different cell populations. The combination of these two agonists enhanced the expression of cytokines for Th1 and Th17 responses and suppressed the expression of cytokines for Th2 response in these cells. Thus, the antigen-dependent Th responses observed in the animals immunized with different vaccines were shaped by the antigen-independent cytokine-inducing profiles of their adjuvant. The expanded targeting cell populations, the increased germinal center B cell response, and reshaped T helper responses are the molecular bases for the cooperative adjuvant effect of the combination of TLR9 and STING agonists.
MeSH term(s)	Animals ; Mice ; COVID-19 Vaccines ; Toll-Like Receptor 9/agonists ; SARS-CoV-2 ; Oligodeoxyribonucleotides/pharmacology ; COVID-19 ; Adjuvants, Immunologic/pharmacology ; Adjuvants, Immunologic/chemistry ; Cytokines ; Vaccines ; Immunity ; Germinal Center
Chemical Substances	COVID-19 Vaccines ; Toll-Like Receptor 9 ; Oligodeoxyribonucleotides ; Adjuvants, Immunologic ; Cytokines ; Vaccines
Language	English
Publishing date	2023-05-29
Publishing country	Australia
Document type	Journal Article
ZDB-ID	2179208-2
ISSN	1449-2288 ; 1449-2288
ISSN (online)	1449-2288
ISSN	1449-2288
DOI	10.7150/ijbs.81210
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Article ; Online: Effects of aloe vera on burn injuries: A systematic review and meta-analysis of randomized controlled trials.

Huang, Yu-Ning / Chen, Kun-Chuan / Wang, Jen-Hung / Lin, Yun-Kuan

Journal of burn care & research : official publication of the American Burn Association

2024

Abstract: Burn injuries cause severe pain, infection risks, psychological distress, financial burdens, and mortality, necessitating effective care. Aloe vera, a traditional burn remedy, shows wound healing potential, but its analgesic effects and efficacy with ... ...

Abstract	Burn injuries cause severe pain, infection risks, psychological distress, financial burdens, and mortality, necessitating effective care. Aloe vera, a traditional burn remedy, shows wound healing potential, but its analgesic effects and efficacy with varying burn severity are uncertain. This study aims to investigate aloe vera's impact on wound healing, pain management, and infection prevention in burn patients. A systematic search on PubMed, Embase, and CENTRAL was performed on 9th October 2023 for randomized controlled trials (RCTs). The risk of bias was examined using the Cochrane risk-of-bias tool (version 2), and the meta-analysis was carried out using a random-effects model. The primary outcome was wound healing time, with secondary outcomes examining pain severity and wound infection. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the quality of evidence for each outcome. Nine RCTs were included in the current study, of which six provided data on the primary outcome. Aloe vera significantly reduced mean wound healing time compared to other topicals [mean difference (MD) -3.76 days; 95% confidence interval (CI) -5.69 to -1.84]. Additionally, the meta-analysis of the secondary outcomes found no significant differences in pain reduction (MD -0.76 points; 95% CI -1.53 to 0.01) and wound infection risk (risk ratio 1.10; 95% CI 0.34 to 3.59) between aloe vera and control groups. In conclusion, aloe vera expedites wound healing in second-degree burn patients without increased infection risk compared to other antimicrobial agents. The analgesic effects on burn injuries remain uncertain.
Language	English
Publishing date	2024-04-12
Publishing country	England
Document type	Journal Article
ZDB-ID	2224246-6
ISSN	1559-0488 ; 1559-047X
ISSN (online)	1559-0488
ISSN	1559-047X
DOI	10.1093/jbcr/irae061
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Article ; Online: Protein Arginine Methyltransferase 5 Contributes to Paclitaxel-Induced Neuropathic Pain by Activating Transient Receptor Potential Vanilloid 1 Epigenetic Modification in Dorsal Root Ganglion.

Yeh, Chou-Ming / Lai, Cheng-Yuan / Peng, Hsien-Yu / Lin, Tzer-Bin / Chou, Dylan / Wang, Hsueh-Hsiao / Yang, Po-Sheng / Cheng, Jen-Kun / Peng, Yun-Chih / Hsieh, Ming-Chun

Anesthesia and analgesia

2023 Volume 138, Issue 5, Page(s) 1107–1119

Abstract: Background: Paclitaxel (PTX), which is a first-line chemotherapy drug used to treat various types of cancers, exhibits peripheral neuropathy as a common side effect that is difficult to treat. Protein arginine methyltransferase 5 (PRMT 5) is a key ... ...

Abstract	Background: Paclitaxel (PTX), which is a first-line chemotherapy drug used to treat various types of cancers, exhibits peripheral neuropathy as a common side effect that is difficult to treat. Protein arginine methyltransferase 5 (PRMT 5) is a key regulator of the chemotherapy response, as chemotherapy drugs induce PRMT5 expression. However, little is known about the PRMT5-mediated epigenetic mechanisms involved in PTX-induced neuropathic allodynia. Methods: Sprague-Dawley rats were intraperitoneally given PTX to induce neuropathic pain. Biochemical analyses were conducted to measure the protein expression levels in the dorsal root ganglion (DRG) of the animals. The von Frey test and hot plate test were used to evaluate nociceptive behaviors. Results: PTX increased the PRMT5 (mean difference [MD]: 0.68, 95% confidence interval [CI], 0.88-0.48; P < .001 for vehicle)-mediated deposition of histone H3R2 dimethyl symmetric (H3R2me2s) at the transient receptor potential vanilloid 1 ( Trpv1 ) promoter in the DRG. PRMT5-induced H3R2me2s recruited WD repeat domain 5 (WDR5) to increase trimethylation of lysine 4 on histone H3 (H3K4me3) at Trpv1 promoters, thus resulting in TRPV1 transcriptional activation (MD: 0.65, 95% CI, 0.82-0.49; P < .001 for vehicle) in DRG in PTX-induced neuropathic pain. Moreover, PTX increased the activity of NADPH oxidase 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 for vehicle), PRMT5-induced H3R2me2s, and WDR5-mediated H3K4me3 in the DRG in PTX-induced neuropathic pain. Pharmacological antagonism and the selective knockdown of PRMT5 in DRG neurons completely blocked PRMT5-mediated H3R2me2s, WDR5-mediated H3K4me3, or TRPV1 expression and neuropathic pain development after PTX injection. Remarkably, NOX4 inhibition not only attenuated allodynia behavior and reversed the above-mentioned signaling but also reversed NOX4 upregulation via PTX. Conclusions: Thus, the NOX4/PRMT5-associated epigenetic mechanism in DRG has a dominant function in the transcriptional activation of TRPV1 in PTX-induced neuropathic pain.
MeSH term(s)	Rats ; Animals ; Paclitaxel/toxicity ; Paclitaxel/metabolism ; Protein-Arginine N-Methyltransferases/genetics ; Protein-Arginine N-Methyltransferases/metabolism ; Protein-Arginine N-Methyltransferases/pharmacology ; Rats, Sprague-Dawley ; Hyperalgesia/chemically induced ; Hyperalgesia/genetics ; Hyperalgesia/metabolism ; Ganglia, Spinal ; TRPV Cation Channels/genetics ; Antineoplastic Agents/adverse effects ; Neuralgia/chemically induced ; Neuralgia/genetics ; Neuralgia/metabolism ; Epigenesis, Genetic
Chemical Substances	Paclitaxel (P88XT4IS4D) ; Protein-Arginine N-Methyltransferases (EC 2.1.1.319) ; TRPV Cation Channels ; Antineoplastic Agents
Language	English
Publishing date	2023-06-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	80032-6
ISSN	1526-7598 ; 0003-2999
ISSN (online)	1526-7598
ISSN	0003-2999
DOI	10.1213/ANE.0000000000006595
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