Endophilin A2 controls touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking.

BACKGROUND: Tactile and mechanical pain are crucial to our interaction with the environment, yet the underpinning molecular mechanism is still elusive. Endophilin A2 (EndoA2) is an evolutionarily conserved protein that is documented in the endocytosis pathway. However, the role of EndoA2 in the regulation of mechanical sensitivity and its underlying mechanisms are currently unclear. METHODS: Male and female C57BL/6 mice (8-12 weeks) and male cynomolgus monkeys (7-10 years old) were used in our experiments. Nerve injury-, inflammatory-, and chemotherapy-induced pathological pain models were established for this study. Behavioral tests of touch, mechanical pain, heat pain, and cold pain were performed in mice and nonhuman primates. Western blotting, immunostaining, co-immunoprecipitation, proximity ligation and patch-clamp recordings were performed to gain insight into the mechanisms. RESULTS: The results showed that EndoA2 was primarily distributed in neurofilament-200-positive (NF200+) medium-to-large diameter dorsal root ganglion (DRG) neurons of mice and humans. Loss of EndoA2 in mouse NF200+ DRG neurons selectively impaired the tactile and mechanical allodynia. Furthermore, EndoA2 interacted with the mechanically sensitive ion channel Piezo2 and promoted the membrane trafficking of Piezo2 in DRG neurons. Moreover, as an adaptor protein, EndoA2 also bound to kinesin family member 5B (KIF5B), which was involved in the EndoA2-mediated membrane trafficking process of Piezo2. Loss of EndoA2 in mouse DRG neurons damaged Piezo2-mediated rapidly adapting mechanically activated currents, and re-expression of EndoA2 rescued the MA currents. In addition, interference with EndoA2 also suppressed touch sensitivity and mechanical hypersensitivity in nonhuman primates. CONCLUSIONS: Our data reveal that the KIF5B/EndoA2/Piezo2 complex is essential for Piezo2 trafficking and for sustaining transmission of touch and mechanical hypersensitivity signals. EndoA2 regulates touch and mechanical allodynia via kinesin-mediated Piezo2 trafficking in sensory neurons. Our findings identify a potential new target for the treatment of mechanical pain.

Hen Egg Lysozyme Alleviates Static Mechanical Pain Via NRF1-Parkin-TACAN Signaling Axis in Sensory Neurons.

Mechanical allodynia impinges on the life quality of patients. Hen Egg Lysozyme (HEL) is a substance extracted from eggs that is commonly used to inhibit bacterial activity. The role of HEL in regulating and treating pain is unclear. Here, we find that HEL selectively attenuates static mechanical allodynia of mice induced by complete Freund's adjuvant (CFA), spinal nerve ligation (SNL) and chemotherapeutic agent. RNA-seq screening reveals that CFA significantly reduces the expression of Parkin in dorsal root ganglion (DRG) neurons of mice, while pre-administration of HEL increases the expression of Parkin and remits the static mechanical allodynia induced by Parkin-siRNA. Moreover, HEL increases the interaction between nuclear respiratory factor 1 (NRF1) and histone acetyltransferase P300 and then enhances the NRF1 mediated histone acetylation in prkn promoter region in DRGs of mice. Further, Parkin interacts with mechanotransducing ion channel TACAN (Tmem120a) and knockdown of Parkin significantly increases the membrane trafficking of TACAN in sensory neurons of mice. While pre-administration of HEL inhibits the increased membrane trafficking of TACAN in sensory neurons of mice induced by Parkin-siRNA. In addition, pre-given of HEL also significantly attenuates the static mechanical allodynia induced by overexpression of TACAN in mice, and the effect of HEL can be blocked by Parkin-siRNA. This indicates that HEL increases the expression of Parkin through epigenetic mechanisms and then decreases TACAN membrane trafficking in sensory neurons to relieve static mechanical hypersensitivity. Therefore, we reveal a novel function of HEL, which is a potential substance for the treatment of static mechanical pain.

ATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking.

Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.

Difference of pain vulnerability in adult and juvenile rodents: the role of SIRT1-mediated ClC-3 trafficking in sensory neurons.

ABSTRACT: Adults are more likely to suffer from chronic pain than minors, and its underlying mechanism remains unclear. SIRT1 an important age-related protein with function of lifespan extension; whether SIRT1 plays a role in the different pain vulnerability of adult and juvenile remains unclear. Here, we found that the expression level of SIRT1 in dorsal root ganglia (DRG) was related to the pain vulnerability. After nerve injury, the expression of SIRT1 in DRG was decreased in adult rodents whereas increased in juvenile rodents. Differential manipulation of SIRT1 abolished the different pain vulnerability between adult and juvenile rodents. Furthermore, SIRT1 interacted with ClC-3 channel and mediated ClC-3 membrane trafficking and Cl- current in DRG neurons. Differential manipulation of ClC-3 also abolished the difference in pain vulnerability between adult and juvenile rodents. The different anti-inflammatory ability determined the different change trends of SIRT1 and ClC-3 trafficking contributed to the different pain vulnerability in adult and juvenile rodents. In addition, the serum SIRT1 level was negatively correlated with the pain score in patients with chronic pain. These findings revealed the mechanism of the difference in pain vulnerability between adult and juvenile rodents and provided evidence for age-specific treatment of chronic pain.

Foxo1 selectively regulates static mechanical pain by interacting with Nav1.7.

ABSTRACT: Mechanical allodynia is a debilitating condition for millions of patients with chronic pain. Mechanical allodynia can manifest in distinct forms, including brush-evoked dynamic and filament-evoked static allodynia. In the nervous system, the forkhead protein Foxo1 plays a critical role in neuronal structures and functions. However, the role of Foxo1 in the somatosensory signal remains unclear. Here, we found that Foxo1 selectively regulated static mechanical pain. Foxo1 knockdown decreased sensitivity to static mechanical stimuli in normal rats and attenuated static mechanical allodynia in rat models for neuropathic, inflammatory, and chemotherapy pain. Conversely, Foxo1 overexpression selectively enhanced sensitivity to static mechanical stimuli and provoked static mechanical allodynia. Furthermore, Foxo1 interacted with voltage-gated sodium Nav1.7 channels and increased the Nav1.7 current density by accelerating activation rather than by changing the expression of Nav1.7 in dorsal root ganglia neurons. In addition, the serum level of Foxo1 was found to be increased in chronic pain patients and to be positively correlated with the severity of chronic pain. Altogether, our findings suggest that serum Foxo1 level could be used as a biological marker for prediction and diagnosis of chronic pain. Moreover, selective blockade of Foxo1/Nav1.7 interaction may offer a new therapeutic approach in patients with mechanical pain.

Radiofrequency ablation versus hepatic resection for breast cancer liver metastasis: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the comparative therapeutic efficacy of radiofrequency ablation (RFA) and hepatic resection (HR) for breast cancer liver metastases (BCLMs). METHODS: Studies that had examined the outcomes for both RFA and HR for BCLM were identified by searching the electronic databases PubMed, EMBASE, and the Cochrane Library. Pooled analyzes of the overall survival (OS), disease-free survival (DFS), and short-term outcomes of BCLM were performed. RESULTS: Patients with BCLM gained many more survival benefits from HR than from RFA with regard to the 3-year OS rate (combined odds ratio (OR) 0.41, 95% confidence interval (CI) 0.29-0.59, P<0.001), 5-year OS rate (combined OR 0.38, 95% CI 0.32-0.46, P<0.001), 3-year DFS (combined OR 0.36, 95% CI 0.27-0.49, P<0.001), and 5-year DFS (combined OR 0.51, 95% CI 0.40-0.66, P<0.001). RFA had fewer postoperative complications (combined OR 0.30, 95% CI 0.20-0.44, P<0.001) and shorter hospital stays (combined OR -9.01, 95% CI -13.49-4.54, P<0.001) than HR. CONCLUSIONS: HR takes precedence over RFA in the treatment of patients with BCLM, considering the better survival rate. RFA gives rise to fewer complications and can be carried out with a shorter hospital stay, compared to HR. RFA should be reserved for patients who are not optimum candidates for resection.

Metric characterizations for well-posedness of split hemivariational inequalities.

In this paper, we generalize the concept of well-posedness to a class of split hemivariational inequalities. By imposing very mild assumptions on involved operators, we establish some metric characterizations of the well-posedness for the split hemivariational inequality. The obtained results generalize some related theorems on well-posedness for hemivariational inequalities and variational inequalities in the literature.

[Evaluation of islet beta cell function in subjects with normal glucose tolerance, impaired glucose regulation, and type 2 diabetes mellitus].

OBJECTIVE: To investigate the function of islet beta cells in subjects with normal glucose tolerance (NGT), impaired glucose regulation (IGR), and type 2 diabetes mellitus (T2DM). Different indexes of insulin secretion, including DeltaI30/DeltaG30, AIR or HOMAbeta, were compared. METHODS: 178 subjects without overt diabetes were classified into three groups according to the results of 75 g oral glucose tolerance test (OGTT): NGT group (n = 68), IGR group (n = 75), and T2DM group (n = 35). Intravenous glucose tolerance test (IVGTT) was carried out 1 approximately 3 days later in all participants, with measurement of plasma insulin. The ratio of insulin-to-glucose levels increment during the first 30 min of OGTT (DeltaI30/DeltaG30) and the acute insulin response (AIR) in IVGTT were used as indexes of early insulin secretion. Homeostasis model assessment of insulin secretion (HOMAbeta) was another indicator of insulin secretion. The fasting plasma proinsulin level (FPI) was measured and the ratio fasting proinsulin to fasting insulin (PI/I) was calculated. HOMA insulin resistance index (HOMA IR) was used to assess the insulin resistance. RESULTS: The DeltaI30/DeltaG30 and AIR of the IGR group, adjusted by age, sex, and BMI, were both significantly lower than those of the NGT group. But the HOMAbeta of the IGR group was only slightly lower than that of the NGT group. Compared with the NGT subjects, the T2DM patients had a very severe islet beta cell dysfunction (84% decrease in AIR, 70% decrease in DeltaI30/DeltaG30 and 62% decrease in HOMA beta). When the DeltaI30/DeltaG30 was adjusted by HOMR IR, the extent of impairment in early insulin response was similar to that of AIR (87% versus 84% lower than that of the NGT group). The FPI and ratio of proinsulin to insulin were higher in the T2DM subjects compared with the NGT subjects (24.4 pmol/L +/- 18.0 pmol/L vs 10.9 pmol/L +/- 6.7 pmol/L; and 14.7% +/- 10.5% vs. 10.0% +/- 6.5%, both P < 0.05). There was a significantly positive correlation between DeltaI30/DeltaG30 and AIR (r = 0.75, P < 0.001). CONCLUSION: In the stage of IGR, an evident deficit in phasic insulin secretion after glucose load and a decreasing HOMAbeta are exhibited. In addition to this, qualitative decrease of insulin secretion appears in the DM stage. AIR is a reliable index of isletbeta cell function. DeltaI30/DeltaG30 is an alternative one in the subjects with NGT and IGR. But it should be adjusted by IR in diabetic patients.

[Clinical observation on 136 cases of chilblains treated by acupuncture combined with massage].

OBJECTIVE: To compare therapeutic effects of acupuncture plus massage and medicine on chilblains. METHODS: Two hundred and sixty-four cases of chilblains were randomly divided into an acupuncture group of 136 cases and a medicine group of 128 cases. The acupuncture group were treated by acupuncture at 9 acupoints such as Yamen (GV 15), Laogong (PC 8), Sanyinjiao (SP 6), etc. plus massage, and the medicine group by dong chuang Plaster. RESULTS: In the acupuncture group, 111 cases were cured and 136 cases were effective, the effective rate being 100.0%; and in the medicine group, 55 cases were cured and 98 cases were effective, the effective rate being 76.6%, with a very significant difference between the two groups in the therapeutic effect (P < 0.01). CONCLUSION: Acupuncture plus massage is superior to dong chuang plaster in therapeutic effect on chilblains.

[Influencing factors for the curative effects of short-term continuous subcutaneous insulin infusion on newly diagnosed type 2 diabetes].

OBJECTIVE: To investigate the effects of short-term continuous subcutaneous insulin infusion (CSII) on newly diagnosed type 2 diabetes and to identify the influencing factors for the curative effects of CSII. METHODS: 138 newly diagnosed type 2 diabetic patients with fasting plasma glucose > 11.1 mmol/L were treated with CSII for 2 weeks. Intravenous glucose tolerance test (IVGTT) was performed before and after CSII. The target of glycemic control were fasting blood glucose < 6.1 mmol/L and postprandial blood glucose (PBG) < 8.0 mmol/L. The age, body mass index (BMI), fasting and postprandial plasma glucose, hemoglobin A(1C) (GHbA(1C)), Homa beta, Homa IR, area under the curve of insulin (AUC) during IVGTT were compared between the good glycemic control group and the inadequate glycemic control group. RESULTS: After 2 weeks' CSII treatment, good glycemic control was achieved in 126 patients (group A) but not in the remaining 12 patients (group B). There were no differences in age, BMI, postprandial plasma glucose, GHbA(1C), and Homa IR between the two groups before and after CSII treatment. But the fasting plasma glucose was higher and Homa B was lower in group B than in group A before CSII treatment. The DeltaAUC (AUC after CSII subtracted from that before CSII) representing the recovery of beta-cell function was much greater in group A than in group B. The insulin dose of group B was significantly higher than that of the good glycemic control group. CONCLUSION: More severe hyperglycemia and relative beta-cell function deficiency may be the main reasons responsible for not achieving good glycemic control in newly diagnosed type 2 diabetic patients with short-term intensive CSII treatment.