Emerging role and mechanism of HACE1 in the pathogenesis of neurodegenerative diseases: A promising target.

HACE1 is a member of the HECT domain-containing E3 ligases with 909 amino acid residues, containing N-terminal ankyrin-repeats (ANK) and C-terminal HECT domain. Previously, it was shown that HACE1 is inactive in human tumors and plays a crucial role in the initiation, progression, and invasion of malignant tumors. Recent studies indicated that HACE1 might be closely involved in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. HACE1 interacts with its substrates, including Ras-related C3 botulinum toxin substrate 1 (Rac1), nuclear factor erythroid 2-related factor 2 (Nrf2), tumor necrosis factor receptor (TNFR), and optineurin (OPTN), through which participates in several pathophysiological processes, such as oxidative stress, autophagy and inflammation. Therefore, in this review, we elaborately describe the essential substrates of HACE1 and illuminate the pathophysiological processes by which HACE1 is involved in neurodegenerative diseases. We provide a new molecular target for neurodegenerative diseases.

Yinma Jiedu Granule attenuates LPS-induced acute lung injury in rats via suppressing inflammation level.

ETHNOPHARMACOLOGICAL RELEVANCE: Yinma Jiedu Granule (YMJD) is a traditional Chinese patent medicine (CPM), which has been proved to have anti-inflammatory effects and therapeutical effects on obstructive pulmonary disease. AIM OF STUDY: The purpose of the current investigation is to find out if YMJD can alleviate acute lung injury (ALI) induced by lipopolysaccharide (LPS) in rats and its underlying mechanisms. MATERIALS AND METHODS: Rats were treated with either vehicle or YMJD for 14 consecutive days, and 2 h after the last administration, the rat model of ALI was induced by the intratracheal instillation of LPS. High performance liquid chromatography (HPLC) was applied for the fingerprint analysis of YMJD. The efficacy and molecular mechanisms were investigated. RESULTS: The results showed that treatment with YMJD improved the general state of rats, reduced weight loss and serum lactate (LA) levels, attenuated pulmonary edema and pathological damage of the lung tissue. Moreover, we found that YMJD effectively decreased the infiltration of white blood cells (WBC), lymphocytes (LYM), mononuclear cells (MON) and neutrophils (NEUT) in bronchoalveolar lavage fluid (BALF), reduced the concentration of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) and inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the lung tissue. Additionally, we found that YMJD could significantly increase the activity of superoxide dismutase (SOD) and reduce the malondialdehyde (MDA) level in the lung tissue. By employing RNA-sequencing, we have identified that JAK2/STAT1 is an important pathway that is involved in the lung protection of YMJD, and further Western blot assay verified that YMJD could effectively inhibit the activation of the JAK2/STAT1 pathway. CONCLUSIONS: YMJD could attenuate LPS-induced ALI through suppressing inflammation and oxidative stress in the lung tissue of rats, associating with the inhibition of JAK2/STAT1 activation. These findings provide evidence for the clinical use of YMJD for treatment of inflammatory pulmonary diseases like ALI.

Application of metabolomics in urolithiasis: the discovery and usage of succinate.

Urinary stone is conceptualized as a chronic metabolic disorder punctuated by symptomatic stone events. It has been shown that the occurrence of calcium oxalate monohydrate (COM) during stone formation is regulated by crystal growth modifiers. Although crystallization inhibitors have been recognized as a therapeutic modality for decades, limited progress has been made in the discovery of effective modifiers to intervene with stone disease. In this study, we have used metabolomics technologies, a powerful approach to identify biomarkers by screening the urine components of the dynamic progression in a bladder stone model. By in-depth mining and analysis of metabolomics data, we have screened five differential metabolites. Through density functional theory studies and bulk crystallization, we found that three of them (salicyluric, gentisic acid and succinate) could effectively inhibit nucleation in vitro. We thereby assessed the impact of the inhibitors with an EG-induced rat model for kidney stones. Notably, succinate, a key player in the tricarboxylic acid cycle, could decrease kidney calcium deposition and injury in the model. Transcriptomic analysis further showed that the protective effect of succinate was mainly through anti-inflammation, inhibition of cell adhesion and osteogenic differentiation. These findings indicated that succinate may provide a new therapeutic option for urinary stones.

Inhibition of CXCR2 enhances CNS remyelination via modulating PDE10A/cAMP signaling pathway.

CXC chemokine receptor 2 (CXCR2) plays an important role in demyelinating diseases, but the detailed mechanisms were not yet clarified. In the present study, we mainly investigated the critical function and the potential molecular mechanisms of CXCR2 on oligodendrocyte precursor cell (OPC) differentiation and remyelination. The present study demonstrated that inhibiting CXCR2 significantly enhanced OPC differentiation and remyelination in primary cultured OPCs and ethidium bromide (EB)-intoxicated rats by facilitating the formation of myelin proteins, including PDGFRα, MBP, MAG, MOG, and Caspr. Further investigation identified phosphodiesterase 10A (PDE10A) as a main downstream protein of CXCR2, interacting with the receptor to regulate OPC differentiation, in that inhibition of CXCR2 reduced PDE10A expression while suppression of PDE10A did not affect CXCR2. Furthermore, inhibition of PDE10A promoted OPC differentiation, whereas overexpression of PDE10A down-regulated OPC differentiation. Our data also revealed that inhibition of CXCR2/PDE10A activated the cAMP/ERK1/2 signaling pathway, and up-regulated the expression of key transcription factors, including SOX10, OLIG2, MYRF, and ZFP24, that ultimately promoted remyelination and myelin protein biosynthesis. In conclusion, our findings suggested that inhibition of CXCR2 promoted OPC differentiation and enhanced remyelination by regulating PDE10A/cAMP/ERK1/2 signaling pathway. The present data also highlighted that CXCR2 may serve as a potential target for the treatment of demyelination diseases.

[Research progress of different types of stem cells in treatment of ischemic stroke].

OBJECTIVE: To review the recent research progress of different types of stem cells in the treatment of ischemic stroke. METHODS: By searching the PubMed database, a systematic review had been carried out for the results of applying different types of stem cells in the treatment of ischemic stroke between 2000 and 2020. RESULTS: Stem cells can be transplanted via intracranial, intravascular, cerebrospinal fluid, and intranasal route in the treatment of ischemic stroke. Paracrine and cell replacement are the two major mechanisms of the therapy. The researches have mainly focused on utilization of neural stem cells, embryonic stem cells, and mesenchymal stem cells. Each has its own advantages and disadvantages in terms of capability of migration, survival rate, and safety. Certain stem cell therapies have completed phase one clinical trial. CONCLUSION: Stem cells transplantation is feasible and has a great potential for the treatment of ischemic stroke, albeit that certain obstacles, including the selection of stem cells, transplantation strategy, migration ability, survival rate, still wait to be solved.

Procyanidins-crosslinked small intestine submucosa: A bladder patch promotes smooth muscle regeneration and bladder function restoration in a rabbit model.

Currently the standard surgical treatment for bladder defects is augmentation cystoplasty with autologous tissues, which has many side effects. Biomaterials such as small intestine submucosa (SIS) can provide an alternative scaffold for the repair as bladder patches. Previous studies have shown that SIS could enhance the capacity and compliance of the bladder, but its application is hindered by issues like limited smooth muscle regeneration and stone formation since the fast degradation and poor mechanical properties of the SIS. Procyanidins (PC), a natural bio-crosslinking agent, has shown anti-calcification, anti-inflammatory and anti-oxidation properties. More importantly, PC and SIS can crosslink through hydrogen bonds, which may endow the material with enhanced mechanical property and stabilized functionalities. In this study, various concentrations of PC-crosslinked SIS (PC-SIS) were prepared to repair the full-thickness bladder defects, with an aim to reduce complications and enhance bladder functions. In vitro assays showed that the crosslinking has conferred the biomaterial with superior mechanical property and anti-calcification property, ability to promote smooth muscle cell adhesion and upregulate functional genes expression. Using a rabbit model with bladder defects, we demonstrated that the PC-SIS scaffold can rapidly promote in situ tissue regrowth and regeneration, in particular smooth muscle remodeling and improvement of urinary functions. The PC-SIS scaffold has therefore provided a promising material for the reconstruction of a functional bladder.

[Advance in functional bladder engineering].

Bladder has many important functions as a urine storage and voiding organ. Bladder injury caused by various pathological factors may need bladder reconstruction. Currently the standard procedure for bladder reconstruction is gastrointestinal replacement. However, due to the significant difference in their structure and function, intestinal segment replacement may lead to complications such as hematuria, dysuria, calculi and tumor. With the recent advance in tissue engineering and regenerative medicine, new techniques have emerged for the repair of bladder defects. This paper reviews the recent progress in three aspects of urinary bladder tissue engineering, i.e., seeding cells, scaffolds and growth factors.

[Effect of auricular-point pressure combined with personalized music therapy on perioperative stress response in primipara].

OBJECTIVE: To explore the effect of auricula-point pressure combined with personalized music therapy on perioperative stress response in primipara. METHODS: A total of 1000 primiparas who were elective for cesarean section were randomly divided into an observation group and a control group, 500 cases in each one. 1 h before surgery and 3 h, 6 h, 12 h and 24 h after surgery, individualized music relaxation intervention was given for 1 h in the two groups. On the basis of the treatment, auricular-point pressure was added at Pizhixia (AT4), Shenmen (TF4), Xin (CO15), Zigong (uterus), Luanchao (ovary), Neishengzhiqi (TF2) in the observation group. Each point was pressed for 1 min each time, repeated once every 15 min, the force is from light to heavy, and it is better to have a feeling of distension, sourness and radiation in the auricle. The scores of anxiety self-rating scale, visual analog scale (VAS), heart rate, systolic blood pressure, thyroid stimulating hormone, cortisol and blood glucose levels were observed in the two groups. RESULTS: A total of 973 primiparas completed the clinical study in the end, including 488 patients in the observation group and 485 patients in the control group. Compared to enrollment, the scores of anxiety self-rating scale before entering the operating room in the two groups were significantly improved (P<0.05), and the observation group was superior to the control group (P<0.05). Entering the operating room and tracheal extubation, the heart rate and systolic blood pressure of the primiparas in the observation group were more stable than those in the control group, and the differences were statistically significant (P<0.05). Entering the operating room, 1 h into the surgery and 3 h after surgery, the thyroid stimulating hormone, cortisol and blood glucose levels of the primiparas in the observation group were significantly better than those in the control group (P<0.05). The VAS scores in the observation group at 6 h, 12 h and 24 h after surgery were lower than those in the control group (P<0.05). CONCLUSION: Auricular-point pressure combined with personalized music therapy can reduce the perioperative stress response in primipara and promote the improvement of psychological, physiological and emotional.

[Effect of auricular acupuncture on postpartum rehabilitation of primipara with cesarean].

OBJECTIVE: To explore the postoperative effect of auricular acupuncture on primipara with cesarean in order to promote postpartum rehabilitation. METHODS: A total of 120 primiparas with cesarean were randomly divided into an observation group and a control group, 60 cases in each group. The routine treatment and care after surgery were given in the two groups. On the basis treatment, auricular acupuncture was applied at penqiang (TF5), shenmen (TF4), jiaogan (AH6a), pizhixia (AT4), neishengzhiqi(TF2), pi(CO13), wei(CO4) in the observation group, even-needling technique at all points. The needles were retained for 30 min, 3 times a day, the acupuncture was alternately every other day for 5 days continuously. The postpartum pain, anus exhaust time, incidence of postpartum hemorrhage, urinary retention and constipation, and postpartum average hospitalization day were recorded and compared between the two groups. RESULTS: Twenty-seven cases of postpartum uterine contraction pain (45.0%), 25 cases of wound pain (41.7%), 19 cases of breast distending pain (31.7%) and 11 cases of muscle soreness (18.3%) in the observation group, which was significantly lower than 38 cases (63.3%), 36 cases (60.0%), 30 cases (50.0%) and 21 cases (35.0%) respectively in the control group (P<0.05). The anus exhaust time in the observation group was earlier than that in the control group (P<0.05), and the average hospitalization time was shorter than that in the control group (P<0.05). The incidence of postpartum hemorrhage, urinary retention and constipation in the observation group was lower than that in the control group (P<0.05). CONCLUSION: Auricular acupuncture can effectively relieve postpartum pain in primipara with cesarean, promote postpartum exhaust and shorten hospitalization days, and reduce the incidence of postpartum complications such as postpartum hemorrhage, urinary retention and constipation, it is conducive to postpartum rehabilitation.

[Effect of auricular point pressing combined with electroacupuncture on postoperative pain and inflammatory cytokines in children with hernia].

OBJECTIVE: To explore the clinical efficacy and action mechanism of auricular point pressing combined with electroacupuncture (EA) on postoperative pain in children with hernia. METHODS: A total of 93 children with inguinal hernia were randomly divided into an auricular point group, an EA group and a combination group, 31 cases in each group. All the three groups were treated with routine postoperative treatment and nursing, and analgesic and sedative drugs were used when necessary. After awaking, the children in the auricular point group were treated with auricular point pressing at Shenmen (TF4), Jiaogan (AH6a) and Pizhixia (AT4); the seeds of cowherb were placed at the auricular points and the same nurse used index finger and thumbs to press the points for 2 min, and repeated after 30 min. The pressing time was 8-11 AM and 14-17 PM for 3 days. The children in the EA group were treated with EA at Sanyinjiao (SP 6) and Zusanli (ST 36); the needles were perpendicularly inserted with mild reinforcing-reducing method; EA instrument was connected with needles and the current intensity was under the maximal tolerance of children; the needles were retained for 20 min, three times a day for continuous 3 days. The children in the combination group were treated with auricular point pressing and EA for 3 days. The Wong-Baker facial expression evaluation method was used to observe the pain scores 1-3 h, 4-24 h, 25-48 h and 49-72 h after operation; the contents of TNF-α, IL-6 and IL-8 were compared 1 day, 2 days and 3 days after operation; the number of cases using sedative drugs and average hospitalization days were compared among the three groups. RESULTS: ①Among the children aged 8-15 years old, the pain scores 4-24 h and 25-48 h after operation in the combination group were lower than those in the auricular point group and the EA group (all P<0.05); among the children aged 4-7 years old, differences of the pain scores in each time after operation were not significant statistically among the three groups (all P>0.05). ②The contents of TNF-α, IL-6 and IL-8 in serum 1 day, 2 days and 3 days after operation in the combination group were lower than those in the auricular point group and the EA group (all P<0.05). ③The number of cases using analgesic and sedative drugs after operation in the combination group was fewer than that in the auricular point group and the EA group (all P<0.05). ④The average hospitalization days in the combination group were shorter than those in the auricular point group and the EA group (all P<0.05). CONCLUSION: Compared with auricular point pressing or EA alone, the combination of auricular point pressing and EA could not only effectively relieve the postoperative pain, but also reduce the expression of inflammatory cytokines in children with hernia, improving the clinical efficacy.

[Effects of the combined therapy of the auricular-point pressure at the free position and the unprotected perineal delivery technique during the second stage of labor in the primiparas].

OBJECTIVE: To observe the effects of the combined therapy of the auricular-point pressure at the free position and the unprotected perineal delivery technique during the 2nd stage of labor in the primiparas so as to improve the clinical delivery quality. METHODS: A total of 146 primiparas who accepted the natural delivery willingly were collected. According to the visit sequence, they were divided into an observation group (72 cases) and a control group (74 cases). The free position and the unprotected perineal delivery were adopted in combination during the labor in both of the two groups. Additionally, in the observation group, the auricular-point pressure with semen vaccariae was intervened when entering the active phase. The points were pengqiang (TF5), zigong (uterus), neishengzhiqi (TF2), pizhixia (AT4), shenmen (TF4), jiaogan (AH6a), pi (CO13) and wei (CO4). Each point was pressed for 1 to 2 min each time, repeated once every 10 to 20 min until the end of the 2nd stage of labor. The episiotomy rate, perineal laceration degree, perineal pain degree, the duration of the 2nd labor stage, postpartum hemorrhage, postpartum urine retention and neonatal asphyxia rate were recorded and compared in the primiparas between the two groups. RESULTS: The perineal laceration of the degree Ⅲ and Ⅳ did not occur in the two groups. Compared with the control group, the effect on the perineal laceration was better in the observation group (P<0.05). The episiotomy rate was 5.6% (4/72) in the observation group, lower than that in the control group (P<0.05). The total perineal laceration rate was 68.1% (48/72) in the observation group, similar to the control group (P>0.05). In the observation group, the neonatal asphyxia rate was 1.4% (1/72), the postpartum hemorrhage 6.9% (5/72) and the incidence of urine retention 5.6% (4/72), all lower than 10.8% (8/74), 18.9% (14/74) and 17.6% (13/74) in the control group respectively (all P<0.05). In the observation group, on the 1st, 2nd and 3rd days after labor, the perineal pain degree and the duration of the 2nd stage of labor were superior to the control group (all P<0.001). CONCLUSION: The combined therapy of the auricular-point pressure intervention at the free position and the unprotected perineal delivery technique effectively reduces the episiotomy rate and perineal laceration degree, relieves the perineal pain, reduces the neonatal asphyxia rate and improves the delivery quality during the 2nd stage of labor in the primiparas.

[Studies on chemical constituents of the extract of Lonicera japonica].

OBJECTIVE: To isolate and elucidate the structure of the constituents of the extract of Lonicera japonica. METHODS: The compounds were isolated and repeatedly purified on TLC, silica gel column chromatography, and gel column chromatography. The structures were elucidated by physico-chemical properties, MS and NMR. RESULTS: Seven compounds were obtained and elucidated as luteolin (I), luteoloside (II), quercetin (III), quercetin-3-0-beta-D-glucoside (IV), quercetin-7-0-beta-D-glucoside (V), rutin (VI), chlorogenic acid (VII). CONCLUSION: Compound V is isolated from this genus for the first time.