From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders.

The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.

Krüppel-like factors in tumors: Key regulators and therapeutic avenues.

Krüppel-like factors (KLFs) are a group of DNA-binding transcriptional regulators with multiple essential functions in various cellular processes, including proliferation, migration, inflammation, and angiogenesis. The aberrant expression of KLFs is often found in tumor tissues and is essential for tumor development. At the molecular level, KLFs regulate multiple signaling pathways and mediate crosstalk among them. Some KLFs may also be molecular switches for specific biological signals, driving their transition from tumor suppressors to promoters. At the histological level, the abnormal expression of KLFs is closely associated with tumor cell stemness, proliferation, apoptosis, and alterations in the tumor microenvironment. Notably, the role of each KLF in tumors varies according to tumor type and different stages of tumor development rather than being invariant. In this review, we focus on the advances in the molecular biology of KLFs, particularly the regulations of several classical signaling pathways by these factors, and the critical role of KLFs in tumor development. We also highlight their strong potential as molecular targets in tumor therapy and suggest potential directions for clinical translational research.

Protective Mechanism of Electroacupuncture on Peripheral Neurotoxicity Induced by Oxaliplatin in Rats.

OBJECTIVE: To study the effect of electroacupuncture (EA) on oxaliplatin-induced peripheral neuropathy (OIPN) in rats. METHODS: Male Sprague-Dawley rats were equally divided into 3 groups using a random number table: the control group, the OIPN group, and the EA (OIPN + EA) group, with 10 rats in each. The time courses of mechanical, cold sensitivity, and microcirculation blood flow intensity were determined. The morphology of the dorsal root ganglion (DRG) was observed by electron microscopic examination. The protein levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the transient receptor potential (TRP) protein family in DRGs were assayed by Western blot. RESULTS: EA treatment significantly reduced mechanical allodynia and cold allodynia in OIPN rats (P<0.01). Notably, oxaliplatin treatment resulted in impaired microcirculatory blood flow and pathomorphological defects in DRGs (P<0.01). EA treatment increased the microcirculation blood flow and attenuated the pathological changes induced by oxaliplatin (P<0.01). In addition, the expression levels of Nrf2 and HO-1 were down-regulated, and the TRP protein family was over-expressed in the DRGs of OIPN rats (P<0.01). EA increased the expression levels of Nrf2 and HO-1 and decreased the level of TRP protein family in DRG (P<0.05 or P<0.01). CONCLUSION: EA may be a potential alternative therapy for OIPN, and its mechanism may be mainly mediated by restoring the Nrf2/HO-1 signaling pathway.

Spatial topological analysis of sympathetic neurovascular characteristic of acupoints in Ren meridian using advanced tissue-clearing and near infrared II imaging.

Acupuncture has been used for treating various medical conditions in traditional Chinese medicine. Both manual and electro-acupuncture stimulate specific acupoints to obtain local and systemic biological effects, but the underlying mechanisms remain unclear. Here, we used three-dimensional tissue-clearing technology to study acupoints on the Ren meridian of mice to reveal the distribution, density, branching, and relationships between blood vessels and nerves. Using topological Mapper methods, we found that sympathetic neurovascular networks were denser in the CV 4 acupoint compared with surrounding non-acupoints. Furthermore, high resolution in vivo real-time vascular imaging using the near infrared-II probe LZ-1105 demonstrated increased blood flow in the CV 4 acupoint compared with neighboring non-acupoints after manual or electro-acupuncture. Consistent with earlier findings, our research indicated that acupuncture could enhance local blood flow, and our high-resolution 3D images show for the first time the important role of sympathetic neurovascular networks in the CV 4 acupoint.

Effects of 10.6-µm laser moxibustion and electroacupuncture at ST36 in a 5-Fu-induced diarrhea rat model.

OBJECTIVE: The aim of this study was to investigate the effect of 10.6-µm laser moxibustion and electroacupuncture in 5-fluorouracil (5-Fu)-induced diarrhea model rats. METHODS: Forty-eight Sprague Dawley rats were randomly divided into 4 groups: a normal group, model group, 10.6-µm laser moxibustion (LM) group, and electroacupuncture (EA) group. Diarrhea was induced by 5-Fu (50 mg/kg) injection in 36 rats; the LM and EA groups received treatment at acupoint ST36 (Zusanli) on hind limbs once a day for 6 days. RESULTS: 5-Fu injection caused body weight decline and diarrhea. From the 5th to 7th day, the LM group showed higher body weights than the model group (P < 0.05). On the 6th day, diarrhea score of the LM group was better than that of the EA group (P < 0.05). Both scores of the LM group and EA group were better than that of model group (P < 0.05). The LM group and EA group both had better intestine pathological scores and lower endotoxin (ET) and diamine oxide (DAO) activity than the model group (P < 0.01). The LM group got better pathological scores than the EA group (P < 0.01). Ultramicroscopic structures of the model group showed severe damage while the LM group and EA group remained good in their small intestines. The model group had obviously decreased occludin protein in intestine tissues than the control group (P < 0.01), while occludin expressions in the LM group and EA group were both obviously increased compared with the model group (P < 0.01). CONCLUSION: LM and EA treatment on ST36 could alleviate damage to intestinal barrier function and alleviate diarrhea caused by 5-Fu.

[Research advances in the limbic system involved in acupuncture treatment of chronic pain].

Pain, especially chronic pain, can cause multiple changes including sensory-discriminative, emotional-affective, and cognitive-behavior changes and thus greatly affects patients' physical and mental health and quality of life. Therefore, multi-dimensional regulation of paralgesia, cognitive impairment, and negative emotion in patients with chronic pain has become a hot spot in recent studies. The brain regions in the limbic system are involved in the formation and expression of "pain sensation-emotion-cognition". Existing evidence suggests that acupuncture has a multi-dimensional comprehensive regulatory effect on chronic pain, and the brain regions in the limbic system also mediate the analgesic effect of acupuncture. However, further studies are still needed to explore the role and mechanism of action of these brain regions in the multi-dimensional regulation of chronic pain by acupuncture. This article reviews the research advances in the neural mechanism of the limbic system in chronic pain and the role of the limbic system in mediating acupuncture analgesia and mainly elaborates on the mechanism of action of the brain regions in the limbic system in the multi-dimensional regulation of chronic pain.

Cardioprotective effect of electroacupuncture in cardiopulmonary bypass through apelin/APJ signaling.

Aim Acupuncture, particularly electroacupuncture (EA), can improve the clinical outcomes of cardiopulmonary bypass (CPB) patients; however, the mechanisms remain unclear. This study aimed to examine the effects of EA pre-treatment on myocardial injury after CPB and investigate its potential mechanisms. MAIN METHODS: Male Sprague-Dawley rats were subjected to CPB and divided into Control (sham-operated), CPB, and EA (CPB + EA) groups. In the EA group, rats were treated with EA at the "PC6" acupoint for 30 min before being subjected to CPB. At 0.5, 1, and 2 h after CPB, the expression levels of plasma cardiac troponin I (cTnI) and lactate dehydrogenase (LDH), and myeloperoxidase (MPO) activity, TNFα, IL-1ß, reduced glutathione (GSH), oxidized glutathione (GSSH), and the ratio of GSH/GSSH in the myocardial tissue were measured. Apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining. The expression of cleaved caspase-3 was detected by immunofluorescence. The expression of apelin, APJ, AKT, p-Akt, ERK1/2, and p-ERK1/2 was determined using western blotting. KEY FINDINGS: Decreased myocardial injury marker levels, myocardial apoptosis, oxidative stress, and the inflammatory response were found in the EA group compared with the CPB group. The expression levels of apelin, APJ, and p-Akt/AKT were increased in the EA group, and the p-ERK1/2/ERK1/2 level was decreased. SIGNIFICANCE: This study showed that EA pre-treatment can protect the heart from damage following CPB, which might be mainly mediated by restoring the apelin/APJ signaling pathway.

Effect of electroacupuncture on mice model of permenopausal depressive disorder.

OBJECTIVE: Study the effect of electroacupuncture on permenopausal depressive disorder (PDD) model through the peri-menopausal depression model mice. METHODS: KM female mice were selected. Except for the blank group (BG), the other groups of mice were removed by castration method. The mice of PDD was prepared by combining chronic unpredictable stimulation. Mice in the model group (MG) were not treated and fed normally. The western medicine group (WG) was given the corresponding drug for treatment. The electroacupuncture group (EAG) was given the electroacupuncture for treatment, and consecutive for 28 days. The levels of T, E2, FSH and LH in serum of mice were measured, and the brain tissue of 5-HT, DA and NE level were measured. Through the HE staining observed the morphological changes of mice hypothalamus. RESULTS: Compared with MG, EAG could increase the number of spontaneous activities of PDD model mice, the level of T, E2 in serum and the level of 5-HT, DA, NE in brain tissue was improved, and the level of FSH, LH in serum was reduced, and the hypothalamic lesions was improved. CONCLUSION: Electroacupuncture could improve the activity and memory of PDD mice, adjust the disorder of sex hormone, and increased the levels of monoamine transmitters (5-HT, NE, DA), and it could effectively improve the behavior and related biochemical indexes of PDD, and thus play an important therapeutic role.

The Effects of Electroacupuncture on the Apelin/APJ System in the Spinal Cord of Rats With Inflammatory Pain.

BACKGROUND: Electroacupuncture (EA) is widely applied for pain management, but the analgesic effects of EA have not been fully elucidated. In this study, we investigated the effect of EA on inflammatory pain caused by intraplantar injection of complete Freund's adjuvant (CFA) and apelin/APJ expression in the spinal cord of rats. METHODS: The study was conducted in 3 parts. In part 1, Sprague-Dawley rats were divided into 4 groups (n = 10): sham, CFA, EA (CFA + 2 Hz EA at acupoints), and NA-EA (CFA + acupuncture without electrical stimulation). The time courses of mechanical and thermal sensitivity were determined. The protein and messenger RNA (mRNA) levels of apelin and APJ in the spinal cord were assayed by Western blotting and real-time polymerase chain reaction, respectively. In part 2, the rats were divided into 5 groups (n = 7-8): sham, CFA, EA, F13A (CFA + intrathecal injection of F13A), and EA-F13A (CFA + EA + intrathecal injection of F13A). In part 3, the rats were divided into 5 groups (n = 8): sham, CFA, EA, apelin-13 (CFA + intrathecal injection of apelin-13), and EA + apelin-13 (CFA + EA + intrathecal injection of apelin-13). RESULTS: EA treatment exhibited significant antinociceptive effects (mechanical sensitivity: mean difference [99% confidence interval {CI}]: 5.86 [4.96-6.77]; thermal sensitivity: mean difference [99% CI]: 2.45 [0.91-4.00]; EA versus CFA) and mitigated the CFA-induced reduction of apelin and APJ protein and mRNA expression in the spinal cord. Furthermore, intrathecal injection of the apelin/APJ system antagonist F13A blocked the analgesic effect of EA (mechanical sensitivity: mean difference [99% CI]: 8.99 [5.81-12.17]; thermal sensitivity: mean difference [99% CI]: 4.22 [1.33-7.12]; EA versus EA-F13A). When EA was combined with apelin-13 through intrathecal administration, it was more potent in reducing mechanical allodynia (mean difference [99% CI]: 5.98 [2.38-9.57], EA + apelin-13 versus apelin-13; mean difference [99% CI]: 4.29 [0.72-7.87], EA + apelin-13 versus EA) and thermal hyperalgesia (mean difference [99% CI]: 5.23 [2.19-8.28], EA + apelin-13 versus apelin-13; mean difference [99% CI]: 6.43 [3.38-9.48], EA + apelin-13 versus EA). CONCLUSIONS: EA stimulation could alleviate inflammatory pain, at least in part, by restoring apelin and APJ mRNA and protein expression levels, which are downregulated in the CFA pain model.

Electroacupuncture with different current intensities to treat knee osteoarthritis: a single-blinded controlled study.

BACKGROUND: To assess the efficacy of Electroacupuncture (EA) stimulation with high-intensity compared with low-intensity on knee osteoarthritis (KOA). METHODS: Participants with KOA were randomized to either high-intensity EA group or low-intensity EA group. EA was applied unilaterally on the affected leg with the local points GB34, ST34, EX-LE4, EX-LE5, ST36, and SP9. The visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were measured before and after participation. Plasma TNFα, IL-1ß, IL-6, and apelin levels were also assessed by enzyme immunoassay (ELA) before and after treatment. RESULTS: Of 80 participants who consented to study participation, 77 completed the program. The patients showed a significant improvement in their pain, stiffness, and physical function on the VAS and WOMAC, accompanying with a significantly reduction in plasma levels of apelin and TNFα. Furthermore, high-intensity group exhibited statistically significant improvements in stiffness and physical function symptoms compared with low-intensity group. Plasma level of IL-6 was significantly decreased only after high-intensity EA treatment. Furthermore, apelin level was significantly inhibited in high-intensity EA group than in low-intensity EA group. CONCLUSIONS: Both high- and low-intensity EA treatments alleviate the clinical symptoms of KOA patients. High-intensity EA is more effective than low-intensity EA. Changes in plasma levels of TNFα, apelin and IL-6 may be involved in the therapeutic effect of EA on KOA.

Molecular mechanisms underlying the effects of acupuncture on neuropathic pain.

Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.

[Effect of aconite cake-separated moxibustion at Guanyuan (CV 4) and Mingmen (GV 4) on thyroid function in patients of Hashimoto's thyroiditis].

OBJECTIVE: To explore the effects on thyroid function in patients of Hashimoto's thyroiditis treated with aconite cake-separated moxibustion and option the better therapeutic program. METHODS: Eighty-five cases were randomly divided into a moxibustion group (42 cases) and a western medication group (43 cases). The moxibustion group was treated by aconite cake-separated moxibustion therapy with acupoints of two groups [(1) Danzhong (CV 17), Zhongwan (CV 12), Guanyuan (CV 4); (2) Dazhui (GV 14), Shenshu (BL 23), Mingmen (GV 4)] alternatively and oral administration of 25 microg Euthyrox everyday. The western medication group was oral administration of 25 microg Euthyrox everyday. Indices of thyroid function before and after treatment and clinical effect were compared between two groups. RESULTS: The clinical total effective rate and effective rate of thyroid function were 25.0% (10/40), 87.5% (35/40) in moxibustion group respectively, 7.53% (3/40) and 57.5% (23/40) in western medication group, with significant differences between two groups (both P < 0.05). Content of serum free thyroxine index (FT4) increased significantly in the moxibustion group after treatment (P < 0.01); content of serum supersensitive thyrotropin (S-TSH) in the moxibustion group was lower than that of western medication group, and contents of serum FT4 and free triiodothyronine (FT3) were higher than those of western medication group, but with no significant differences (all P > 0.05). CONCLUSION: Aconite cake-separated moxibustion at Guanyuan (CV 4) and Mingmen (GV 4) combined with oral administration of Euthyrox can improve clinical symptoms and thyroid function in patients of Hashimoto's thyroiditis, which is better than simple oral administration of Euthyrox.