Umbilical Cord Mesenchymal Stem Cells Overexpressing Heme Oxygenase-1 Promotes Symptoms Recovery in Cystitis Rats by Alleviating Neuroinflammation.

Interstitial cystitis/bladder pain syndrome (IC/BPS) seriously reduces the patient's quality of life, yet current therapies only provide partial relief. In the spinal dorsal horn (SDH), neuroinflammation plays a pivotal role in the development of IC. Injection of human umbilical cord mesenchymal stem cells (hUMSCs) to reduce inflammation is an effective strategy, and heme oxygenase-1 (HO-1) exhibits anti-nociceptive effect in neuroinflammatory pain. This study aimed to test the therapeutic effects of hUMSCs overexpressing HO-1 on cyclophosphamide-induced cystitis rat model. Cystitis rats were transplanted with altered cells and then assessed for 3 weeks. A series of behavioral measurements would be trial including suprapubic mechanical allodynia, depressive-like behaviors, micturition frequency, and short-term memory function. Additionally, western blot, immunofluorescence staining, and ELISA kit test for anti-inflammation effect. HUMSCs were capable of being transduced to overexpress HO-1. Injection of hUMSCs overexpressing HO-1 was more effective than hUMSCs alone in alleviating behavioral symptoms in rats. Furthermore, hUMSCs overexpressing HO-1 inhibited the activation of glial and TLR4/p65/NLRP3 pathway, decreased the levels of pro-inflammatory cytokines in the SDH region. Surprisingly, it markedly increased anti-inflammatory cytokine IL-10, reduced MDA content, and protected GSH concentrations in local environment. Our results suggest that injecting hUMSCs overexpressing HO-1 intrathecally can significantly promote functional outcomes in cystitis rats by reducing neuroinflammation, at least, partly through downregulating TLR4/p65/NLRP3 signaling pathway in the SDH region. This cell therapy affords a new strategy for IC/BPS treatment.

Intrathecal umbilical cord mesenchymal stem cells injection alleviates neuroinflammation and oxidative stress in the cyclophosphamide-induced interstitial cystitis rats through the Sirt1/Nrf2/HO-1 pathway.

AIMS: Neuroinflammation in the spinal dorsal horn (SDH) region plays an important role in the pathogenesis of interstitial cystitis (IC)/bladder pain syndrome (BPS). Oxidative stress is an important etiological factor for inflammatory diseases. This study aimed to investigate the therapeutic effects of umbilical cord mesenchymal stem cells UMSCs on neuroinflammation and oxidative stress in IC and the underlying mechanisms. MATERIALS AND METHODS: Rats were intraperitoneally injected with cyclophosphamide (50 mg/kg bodyweight) to establish the IC animal model. Additionally, rats were intrathecally injected with a Sirt1-specific agonist (SRT1720; 8 µg/rat) or inhibitor (EX527; 8 µg/rat). Furthermore, rats were intrathecally injected with human UMSCs (hUMSCS; 8 × 105 cells/rat). Rat behavior was examined using the mechanical allodynia test, novel object recognition test, sucrose preference test, and urodynamics analysis. Neuroinflammation and oxidative stress the SDH region were examined using western blotting, immunofluorescence, enzyme-linked immunosorbent assay, and commercial kits. KEY FINDINGS: The Sirt1/Nrf2/HO-1 pathway was downregulated in IC rats. Sirt1 activation and inhibition differentially affected the behavior of IC rats. hUMSCs effectively mitigated the upregulation of oxidative stress, proinflammatory cytokines, and glial activation in the SDH region. Additionally, hUMSCs suppressed mechanical allodynia, dysregulated urodynamics, memory deficits, and depressive-like behavior in IC rats. hUMSCs exerted therapeutic effects through the Sirt1/Nrf2/HO-1 pathway. SIGNIFICANCE: intrathecal hUMSCs injection alleviated behavioral deficits of IC rats by mitigating neuroinflammation and oxidative stress through the Sirt1/Nrf2/HO-1 pathway and can be potentially an effective therapeutic strategy for IC.

Effect of auricular acupuncture on neuroplasticity of stroke patients with motor dysfunction: A fNIRS study.

Cerebral Stroke is an acute cerebrovascular disease, a disease of brain tissue damage caused by the sudden rupture or blockage of blood vessels in the brain that prevents blood flow to the brain. Acupuncture has become a popular treatment for stroke, with auricular acupuncture providing a new idea for stroke treatment. However, the neuromodulatory mechanism of auricular acupuncture in the brain is still unclear. The aim of this study was to investigate the effect of auricular acupuncture in the treatment of upper limb dysfunction and the activation of specific brain regions in stroke patients. Forty patients with stroke hemiplegia who met the nerf criteria were included in the experiment and randomly assigned into two groups (20 patients in each group): the auricular acupuncture group and the control group. Fugl-Meyer score (FMA) assessment of upper limb motor function, motor evoked potential (MEP) measurement, and functional near-infrared brain function imaging (fNIRS) data acquisition in the primary motor M1 area of the brain at rest were performed before and after treatment, respectively. It was found that: 1) after auricular acupuncture treatment, the patients in the auricular acupuncture group showed significantly greater peak MEP and significantly higher oxyhemoglobin content in the M1 region of the brain compared with the control group, with a significant activation effect (MEP: P-value = 0.032, t = -2.22; HbO2; f = 4.225, p = 0.046); 2) in the clinical efficacy assessment, the FMA score in the auricular acupuncture group after treatment (p = 0.0122, t = 2.769). The results suggest that auricular acupuncture has an ameliorative effect on upper limb motor deficits after stroke and that activation of the M1 region of the brain may be a key node in auricular acupuncture for treating upper limb dysfunction in stroke patients, a finding that emphasizes the potential for clinical application of auricular acupuncture therapy for stroke patients with potential mechanisms influencing the outcome.

Activation of the bile acid receptors TGR5 and FXR in the spinal dorsal horn alleviates neuropathic pain.

AIMS: Beyond digestion, bile acids have been recognized as signaling molecules with broad paracrine and endocrine functions by activating plasma membrane receptor (Takeda G protein-coupled receptor 5, TGR5) and the nuclear farnesoid X receptor (FXR). The present study investigated the role of bile acids in alleviating neuropathic pain by activating TGR5 and FXR. METHOD: Neuropathic pain was induced by spared nerve injury (SNI) of the sciatic nerve. TGR5 or FXR agonist was injected intrathecally. Pain hypersensitivity was measured with Von Frey test. The amount of bile acids was detected using a bile acid assay kit. Western blotting and immunohistochemistry were used to assess molecular changes. RESULTS: We found that bile acids were downregulated, whereas the expression of cytochrome P450 cholesterol 7ahydroxylase (CYP7A1), a rate-limiting enzyme for bile acid synthesis, was upregulated exclusively in microglia in the spinal dorsal horn after SNI. Furthermore, the expression of the bile acid receptors TGR5 and FXR was increased in glial cells and GABAergic neurons in the spinal dorsal horn on day 7 after SNI. Intrathecal injection of either TGR5 or FXR agonist on day 7 after SNI alleviated the established mechanical allodynia in mice, and the effects were blocked by TGR5 or FXR antagonist. Bile acid receptor agonists inhibited the activation of glial cells and ERK pathway in the spinal dorsal horn. All of the above effects of TGR5 or FXR agonists on mechanical allodynia, on the activation of glial cells, and on ERK pathway were abolished by intrathecal injection of the GABAA receptor antagonist bicuculline. CONCLUSION: These results suggest that activation of TGR5 or FXR counteracts mechanical allodynia. The effect was mediated by potentiating function of GABAA receptors, which then inhibited the activation of glial cells and neuronal sensitization in the spinal dorsal horn.

Effects of auricular acupuncture stimulation on healthy adults' upper limb motor-evoked potentials: A randomized, crossover, double-blind study.

Objective: The aim of this study was to determine whether auricular acupuncture has neuromodulatory effects on the motor cortex of healthy adults. Methods: Fourteen healthy subjects received a real auricular acupuncture stimulation (SF1) session and a sham acupuncture stimulation session. The interval between the two types of stimulation was more than 24 h. A finger dexterity test (taping score and taping speed by using ipad) was assessed, and motor-evoked potentials (MEP) were assessed before and after each stimulation. Results: Before the treatment, there were no significant differences in MEP amplitude, tapping score, or tapping speed (P > 0.05) between the real and sham stimulation conditions. After the treatment, the MEP amplitude, tapping score, and tapping speed in the real stimulation condition increased significantly compared to the pre-stimulation measurements and were significantly higher than those in the sham stimulation condition (P < 0.01). In the sham stimulation condition, the MEP amplitude, tapping score, and tapping speed decreased significantly compared to the pre-stimulation measurements (P < 0.05). Conclusion: Acupuncture of auricular points can modulate the excitability of the motor cortex area of controlling the upper limbs. Clinical trial registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR2100051608].

Extracellular vesicles derived from mesenchymal stem cells alleviate neuroinflammation and mechanical allodynia in interstitial cystitis rats by inhibiting NLRP3 inflammasome activation.

BACKGROUND: Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation. METHODS: Female IC rat model was established by intraperitoneal injection of cyclophosphamide (50 mg/kg, every 3 days for 3 doses). Inhibition of NLRP3 inflammasome was performed by intraperitoneal injection of MCC950 (10 mg/kg). MSC-EVs were isolated from the culture supernatants of human umbilical cord derived MSCs using ultracentrifugation, and then injected intrathecally into IC rats (20 µg in 10 µl PBS, every other day for 3 doses). Suprapubic mechanical allodynia was assessed using up-down method with von Frey filaments, and micturition frequency was examined by urodynamics. The expression of NLRP3 inflammasome components (NLRP3 and Caspase-1), glial cell markers (IBA-1 and GFAP), proinflammatory cytokines (TNF-α, IL-1ß, IL-6 and IL-18) and TLR4/NF-κB signal pathway (TLR4, p65 NK-κB and phospho-p65 NK-κB) in L6-S1 SDH was measured by Western blot analysis. The cellular localization of NLRP3 in SDH was detected using immunofluorescence co-staining. RESULTS: NLRP3 inflammasome was activated in neurons in SDH of IC rats. NLRP3 inflammasome activation contributed to activation of glial cells and process of spinal neuroinflammation in IC rats, and was related to suprapubic mechanical allodynia and frequent micturition. Intrathecal injection of MSC-EVs alleviated suprapubic mechanical allodynia and frequent micturition in IC rats, restrained activation of glial cells and attenuated neuroinflammation in SDH. In addition, MSC-EV treatment significantly inhibited activation of both NLRP3 inflammasomes and TLR4/NF-κB signal pathway. CONCLUSIONS: NLRP3 inflammasome activation is involved in the neuroinflammation of IC. Intrathecal injection of MSC-EVs alleviates neuroinflammation and mechanical allodynia in IC by inhibiting the activation of NLRP3 inflammasome, and TLR4/NF-κB signal pathway may be the potential regulatory target.

Activation of translocator protein alleviates mechanical allodynia and bladder dysfunction in cyclophosphamide-induced cystitis through repression of BDNF-mediated neuroinflammation.

BACKGROUND: Bladder pain syndrome/interstitial cystitis (BPS/IC) is a refractory disease accompanied by bladder-related pain and hyperactivity. Studies have shown that the translocator protein (TSPO) modulates neuroinflammation and central sensitisation associated with pain. Moreover, we previously demonstrated that brain-derived neurotrophic factor (BDNF) regulates neuroinflammation and mechanical allodynia in cyclophosphamide (CYP)-induced cystitis through activation of glial cells. Here, we aimed to explore whether activation of TSPO attenuates mechanical allodynia and bladder dysfunction by regulating BDNF induced neuroinflammation in a CYP-induced cystitis model. METHODS: Injection of CYP was performed to form a rat model of BPS/IC. The expression of TSPO was regulated by intrathecal injection of the TSPO agonist Ro5-4864. The von Frey filament test was applied to evaluate suprapubic allodynia. Bladder function was assessed using filling cystometry. Western blotting was used to detect the expression of TSPO, BDNF, GFAP, Iba-1, p-p38, p-JNK, TNF-α, and IL-1ß, and double immunofluorescence was performed to localise TSPO in the L6-S1 spinal dorsal horn (SDH). RESULTS: TSPO was activated in the SDH after CYP injection and was primarily colocalised with astrocytes. Ro5-4864 reversed mechanical allodynia and bladder dysfunction induced by CYP. Moreover, the upregulation of BDNF and activation of astrocytes and microglia was suppressed by Ro5-4864, resulting in downregulation of p-p38, p-JNK, TNF-α, and IL-1ß. CONCLUSIONS: Ro5-4864 alleviated mechanical allodynia and bladder dysfunction in the CYP model, possibly by inhibiting the elevation of BDNF and consequent activation of astrocytes and microglia induced neuroinflammation. TSPO may be a potential target for the treatment of BPS/IC. SIGNIFICANCE: This study examined the mechanism underlying the ability of the translocator protein to modulate bladder pain syndrome/interstitial cystitis.

Qihuzha granule attenuated LPS-induced acute spleen injury in mice via Src/MAPK/Stat3 signal pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Qihuzha granule (QHZG), is one of traditional Chinese patent medicines composed of eleven edible medicinal plant, which has been used in the clinic for the treatment of indigestion and anorexia in children caused by deficiency of the spleen and stomach. Yet it is noteworthy that QHZG has therapeutic effect on recurrent respiratory tract infection (RRTI) in children. However, its potential molecular mechanisms remained unclear. AIM OF THE STUDY: The aim of this study was to investigate the therapeutic effect and potential mechanism of QHZG on lipopolysaccharide (LPS) induced acute spleen injury. MATERIALS AND METHODS: The acute spleen injury model was induced by intraperitoneal injection of LPS (10 mg/kg) and safe doses of QHZG was administered by gavage once a day for 23 days before LPS treatment. Serum inflammatory cytokines including interleukin-2 (IL-2), IL-1ß, IFN-γ, and tumor necrosis factor-α (TNF-α) were tested by ELISA. Related protein levels were detected by Western blotting. Hematoxylin-eosin (HE) staining was employed to observe the histological alterations. The distribution of macrophages and neutrophils in the mouse spleen was examined by immunofluorescence analysis. RESULTS: QHZG pretreatment significantly abolished the increased secretion of cytokines such as interleukin-2 (IL-2), IL-1ß, IFN-γ, and tumor necrosis factor-α (TNF-α), which were attributable to LPS treatment. Immunofluorescence staining and Histological analysis of spleen tissue revealed the protective effect of QHZG against LPS-induced acute spleen injury in mice. Further study indicated that pretreatment with QHZG significantly inhibited LPS-induced phosphorylation of Src. Accordingly, the increased phosphorylation of Src downstream components (JNK, ERK, P38 and STAT3) induced by LPS was remarkably diminished by QHZG, suggesting the involvement of Src/MAPK/STAT3 pathway in the inhibitory effects of QHZG on spleen injury in mice. CONCLUSION: Our study demonstrated that QHZG protected mice from LPS-induced acute spleen injury via inhibition of Src/MAPK/Stat3 signal pathway. These results suggested that QHZG might serve as a new drug for the treatment of LPS-stimulated spleen injury.

Normalization of magnesium deficiency attenuated mechanical allodynia, depressive-like behaviors, and memory deficits associated with cyclophosphamide-induced cystitis by inhibiting TNF-α/NF-κB signaling in female rats.

BACKGROUND: Bladder-related pain symptoms in patients with bladder pain syndrome/interstitial cystitis (BPS/IC) are often accompanied by depression and memory deficits. Magnesium deficiency contributes to neuroinflammation and is associated with pain, depression, and memory deficits. Neuroinflammation is involved in the mechanical allodynia of cyclophosphamide (CYP)-induced cystitis. Magnesium-L-Threonate (L-TAMS) supplementation can attenuate neuroinflammation. This study aimed to determine whether and how L-TAMS influences mechanical allodynia and accompanying depressive symptoms and memory deficits in CYP-induced cystitis. METHODS: Injection of CYP (50 mg/kg, intraperitoneally, every 3 days for 3 doses) was used to establish a rat model of BPS/IC. L-TAMS was administered in drinking water (604 mg·kg-1·day-1). Mechanical allodynia in the lower abdomen was assessed with von Frey filaments using the up-down method. Forced swim test (FST) and sucrose preference test (SPT) were used to measure depressive-like behaviors. Novel object recognition test (NORT) was used to detect short-term memory function. Concentrations of Mg2+ in serum and cerebrospinal fluid (CSF) were measured by calmagite chronometry. Western blot and immunofluorescence staining measured the expression of tumor necrosis factor-α/nuclear factor-κB (TNF-α/NF-κB), interleukin-1ß (IL-1ß), and N-methyl-D-aspartate receptor type 2B subunit (NR2B) of the N-methyl-D-aspartate receptor in the L6-S1 spinal dorsal horn (SDH) and hippocampus. RESULTS: Free Mg2+ was reduced in the serum and CSF of the CYP-induced cystitis rats on days 8, 12, and 20 after the first CYP injection. Magnesium deficiency in the serum and CSF correlated with the mechanical withdrawal threshold, depressive-like behaviors, and short-term memory deficits (STMD). Oral application of L-TAMS prevented magnesium deficiency and attenuated mechanical allodynia (n = 14) and normalized depressive-like behaviors (n = 10) and STMD (n = 10). The upregulation of TNF-α/NF-κB signaling and IL-1ß in the L6-S1 SDH or hippocampus was reversed by L-TAMS. The change in NR2B expression in the SDH and hippocampus in the cystitis model was normalized by L-TAMS. CONCLUSIONS: Normalization of magnesium deficiency by L-TAMS attenuated mechanical allodynia, depressive-like behaviors, and STMD in the CYP-induced cystitis model via inhibition of TNF-α/NF-κВ signaling and normalization of NR2B expression. Our study provides evidence that L-TAMS may have therapeutic value for treating pain and comorbid depression or memory deficits in BPS/IC patients.

BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis.

BACKGROUND: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. METHODS: Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis. RESULTS: BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1ß in the SDH of our CYP-induced cystitis model. CONCLUSIONS: In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1ß, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.

Neuregulin-1-ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide-induced cystitis.

AIMS: Central sensitization playsimportant roles in cyclophosphamide (CYP)-induced cystitis. In addition, as a visceral pain, CYP-induced chronic pain shares common pathophysiological mechanisms with neuropathic pain. Previous studies demonstrated that neuregulin-1 (Nrg1)-ErbB signaling contributes to neuropathic pain, but whether and how this signaling influences mechanical allodynia in CYP-induced cystitis is unclear. This study aimed to determine whether and how Nrg1-ErbB signaling modulates mechanical allodynia in a CYP-induced cystitis rat model. METHODS: Systemic injection with CYP was used to establish a rat model of bladder pain syndrome/interstitial cystitis (BPS/IC). An irreversible ErbB family receptor inhibitor, PD168393, and exogenous Nrg1 were intrathecally injected to modulate Nrg1-ErbB signaling. Mechanical allodynia in the lower abdomen was assessed with von-Frey filaments using the up-down method. Western blot analysis and immunofluorescence staining were used to measure the expression of Nrg1-ErbB signaling, Iba-1, p-p38, and IL-1ß in the L6-S1 spinal dorsal horn (SDH). RESULTS: We observed upregulation of Nrg1-ErbB signaling as well as overexpression of the microglia activation markers Iba-1 and p-p38 and the proinflammatory factor, interleukin-1ß (IL-1ß), in the SDH of the cystitis group. Further, treatment with PD168393 attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of IL-1ß. The inhibitor PD168393 reversed the algesic effect of exogenous Nrg1 on the cystitis model. CONCLUSIONS: Nrg1-ErbB signaling may promote microglia activation, contributing to mechanical allodynia of CYP-induced cystitis. Our study showed that modulation of Nrg1-ErbB signaling may have therapeutic value for treating pain symptoms in BPS/IC.

Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis.

BACKGROUND: Previous studies have demonstrated that glial cells play an important role in the generation and maintenance of neuropathic pain. Activated glial cells produce numerous mediators such as proinflammatory cytokines that facilitate neuronal activity and synaptic plasticity. Similarly, bladder pain syndrome/interstitial cystitis shares many characteristics of neuropathic pain. However, related report on the involvement of spinal glia in bladder pain syndrome/interstitial cystitis-associated pathological pain and the underlying mechanisms are still lacking. The present study investigated spinal glial activation and underlying molecular mechanisms in a rat model of bladder pain syndrome/interstitial cystitis. RESULTS: A rat model of bladder pain syndrome/interstitial cystitis was established via systemic injection with cyclophosphamide. Mechanical allodynia was tested with von Frey monofilaments and up-down method. Moreover, Western blots and double immunofluorescence were used to detect the expression and location of glial fibrillary acidic protein, OX42/Iba1, P-P38, NeuN, interleukin (IL)-1ß, phosphorylation of N-methyl-D-aspartate receptor 1 (P-NR1), and IL-1 receptor I (IL-1RI) in the L6-S1 spinal cord. We found that glial fibrillary acidic protein rather than OX42/Iba1 or P-P38 was significantly increased in the spinal cord of cyclophosphamide-induced cystitis. L-alpha-aminoadipate but not minocycline markedly attenuated the allodynia. Furthermore, we found that spinal IL-1ß was dramatically increased in cyclophosphamide-induced cystitis, and activated astrocytes were the only source of IL-1ß release, which contributed to allodynia in cystitis rats. Besides, spinal P-NR1 was statistically increased in cyclophosphamide-induced cystitis and only localized in IL-1RI positive neurons in spinal dorsal horn. Additionally, NR antagonist significantly attenuated the cystitis-induced pain. Interestingly, the time course of the P-NR1 expression paralleled to that of IL-1ß or glial fibrillary acidic protein. CONCLUSIONS: Our results demonstrated that astrocytic activation but not microglial activation contributed to the allodynia in cyclophosphamide-induced cystitis and IL-1ß released from astrocytes might bind to its endogenous receptor on the neurons inducing the phosphorylation of NR1 subunit, leading to sensory neuronal hyperexcitability and pathological pain.

Adding a sexual dysfunction domain to UPOINT system improves association with symptoms in women with interstitial cystitis and bladder pain syndrome.

OBJECTIVE: To examine whether adding a sexual dysfunction domain to urinary, psychosocial, organ specific, infection, neurologic or systemic, and tenderness (UPOINT) system improves the association with interstitial cystitis and bladder pain syndrome (IC-BPS) symptom severity due to a high prevalence of sexual dysfunction in women. METHODS: A total of 90 Chinese women with IC-BPS were prospectively collected and classified in each domain of the UPOINT system. Symptom severity was measured using the Interstitial Cystitis Symptom Index (ICSI). The sexual function was evaluated using the Female Sexual Function Index (FSFI). Clinically relevant associations were calculated. RESULTS: The percentage of patients positive for each domain were 90 of 90 (100%), 33 of 90 (37%), 88 of 90 (98%), 21 of 90 (23%), 36 of 90 (40%), 38 of 90 (42%), 62 of 90 (69%) for the urinary, psychosocial, organ specific, infection, neurologic or systemic, tenderness, and sexual dysfunction, respectively. There were significant associations between the number of domains and ICSI (Spearman r = 0.386; P <.05) and FSFI (Spearman r = 0.614; P <.001) scores. After adding a sexual dysfunction domain to create a modified UPOINTS system, the association between the number of domains and symptom severity was improved (correlation coefficient r changed from 0.386 to 0.572; P <.001). The presence of sexual dysfunction had a significant impact on the ICSI scores (P = .032), pain scores (P = .042), and quality of life index scores (P = .035). Significantly reduced FSFI scores were found in patients who had positive psychosocial, organ specific, and tenderness domains (all P values <.05). CONCLUSION: Our study demonstrated sexual dysfunction was an important component of IC-BPS phenotype, and adding a sexual dysfunction domain to the UPOINT system improved the association with IC-BPS symptom severity.

[Effect of electroacupuncture on expression of signal transducer and activator of transcription 3 in focal ischemic cerebral tissue in cerebral ischemia rats].

OBJECTIVE: To observe the effect of electroacupuncture (EA) intervention on expression of signal transducer and activator of transcription 3 (STAT 3) in the focal ischemic cerebral tissue, so as to study its mechanism underlying improving ischemic stroke. METHODS: A total of 150 SD rats were randomized into sham operation (control) group, cerebral ischemia (CI) model (model) group and EA group which were further randomly divided into 2 hour (2 h), 1 day (1 d), 3 d, 1 week (1 W) and 3 W subgroups (n = 6/subgroup for immunohistochemistry, n = 4/subgroup for Western blot). CI model was established by occlusion of the middle cerebral artery with electro-coagulation method. EA (3 Hz/20 Hz, 2-3 V) was applied to "Baihui" (GV 20) and "Dazhui "(GV 14) for 30 min. The expression of cerebral STAT 3 was detected by immunofluorescence histochemistry and laser-confocal microscopy, and Western blot, separately. RESULTS: Compared with the control group, cerebral STAT 3 immunofluorescence intensity values at the time-points of 2 h, 1 d, 3 d and 1 W, STAT 3 protein expression levels at the time-points of 2 h, 1 d and 3 d in the model group were increased significantly (P < 0.001, P < 0.05). After acupuncture intervention, cerebral STAT 3 immunofluorescence intensity values at the time-points of 1 d, 3 d, 1 W and 3 W, STAT 3 protein expression levels at the time-points of 1 d, 3 d and 3 W in the EA group were down-regulated considerably (P < 0.001, P < 0.01, P < 0.05). No significant differences were found between the control and model groups in STAT 3 immunofluorescence intensity at 3 W, and in STAT 3 protein expression levels at 1 W and 3 W, and between the EA and model groups in STAT 3 immunofluorescence intensity at 2 h, and in STAT 3 protein expression at 2 h, 3 d and 1 W (P > 0.05). CONCLUSION: EA therapy can down-regulate the expression level of STAT 3 protein in the regional ischemic cerebral tissue in cerebral ischemia rats, which may contribute to its efficacy in the treatment of acute and chronic ischemic stroke.

Electroacupuncture effect on neurological behavior and tyrosine kinase-JAK 2 in rats with focal cerebral ischemia.

OBJECTIVE: Electroacupuncture effect on neurological behavior and the expression of tyrosine kinase Janus kinase 2 (JAK 2) of ischemic cortex in rats with the focal cerebral ischemia were investigated in this study. METHODS: The model of focal cerebral ischemia was established by the heat-coagulation induced the occlusion of the middle cerebral artery. The electro-acupuncture was applied on Baihui (GV 20) and Dazhui (GV 14), and AG490 was applied by intracerebroventricular infusion. The expressions of JAK2 mRNA and phospharylated JAK2 (p-JAK2) in the ischemic cortex were observed by in situ hybridization and western blotting. RESULTS: The expressions of JAK2 mRNA and p-JAK2 were rarely found in sham surgery group. In model group, the expression of JAK2 mRNA and JAK2 phosphorylation had increased. After 1 day of cerebral ischemia, the expression had reached its peak. After cerebral ischemia, the expressions of JAK2 mRNA and p-JAK2 were consistent with the neurological deficit score. Electroacupuncture treatment and AG490 intervention were able to improve the neurological deficit score after cerebral ischemia, and down-regulate the expressions of JAK2 mRNA and JAK2 phosphorylation. CONCLUSION: After cerebral ischemia, the excessive expressions of JAK2 and the JAK2 phosphorylation would be one of mechanisms by which the brain injury got worse. The therapy of electro-acupuncture could reduce the expression of JAK2, and inhibit JAK2 phosphorylated activation, so as to block the abnormal activation of signal transduction pathway which was induced by JAK2.