Effect of Intraoperative infusion Magnesium Sulfate Infusion on Postoperative Quality of Recovery in Patients Undergoing Total Knee Arthroplasty: A Prospective, Double-Blind, Randomized Controlled Trial.

Background: Magnesium sulfate, an intravenous adjuvant, has recently attracted immense attention in multimodal analgesia. Previous studies confirmed the crucial role of magnesium sulfate in postoperative pain and nociceptive hypersensitivity. However, the effect of magnesium sulfate in multimodal analgesia on the quality of recovery (QoR) for elderly patients has not been thoroughly studied. Therefore, the present experiment aimed to investigate the effect of continuous intravenous magnesium sulfate on the quality of postoperative recovery in elderly patients undergoing total knee arthroplasty (TKA). Patients and Methods: In this study, a total of 148 patients scheduled to undergo unilateral total knee arthroplasty were randomized into a magnesium sulfate group (Group M, n=68) and a control group (Group C, n=66) using a double-blind, randomized controlled trial. Before induction of anesthesia, Group M received intravenous magnesium sulfate (40 mg/kg) for 15 min, followed by a continuous infusion (15 mg/kg) until the end of the procedure. In the same manner, Group C received an infusion of the same amount of isotonic saline using the same method as the Group M. Results: Compared with Group C, Group M had significantly better QoR-15 scores on postoperative day 1(POD1) than Group C (P <0.05). Analysis of the dimensions of QoR-15 scores indicated that Group M exhibited notably reduced levels of pain, and higher levels of emotional state and physical comfort than Group C (P <0.05). Furthermore, Group C had significantly higher numerical rating scale (NRS) scores at POD1 than Group M (P <0.05). Conclusion: For elderly patients undergoing knee arthroplasty, magnesium sulfate can be used as an adjuvant in a multimodal analgesic regimen to reduce early postoperative pain and improve the quality of early postoperative recovery.

Indole Propionic Acid Disturbs the Normal Function of Tryptophanyl-tRNA Synthetase in Mycobacterium tuberculosis.

Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis and the second-most contagious killer after COVID-19. The emergence of drug-resistant TB has caused a great need to identify and develop new anti-TB drugs with novel targets. Indole propionic acid (IPA), a structural analog of tryptophan (Trp), is active against M. tuberculosis in vitro and in vivo. It has been verified that IPA exerts its antimicrobial effect by mimicking Trp as an allosteric inhibitor of TrpE, which is the first enzyme in the Trp synthesis pathway of M. tuberculosis. However, other Trp structural analogs, such as indolmycin, also target tryptophanyl-tRNA synthetase (TrpRS), which has two functions in bacteria: synthesis of tryptophanyl-AMP by catalyzing ATP + Trp and producing Trp-tRNATrp by transferring Trp to tRNATrp. So, we speculate that IPA may also target TrpRS. In this study, we found that IPA can dock into the Trp binding pocket of M. tuberculosis TrpRS (TrpRSMtb), which was further confirmed by isothermal titration calorimetry (ITC) assay. The biochemical analysis proved that TrpRS can catalyze the reaction between IPA and ATP to generate pyrophosphate (PPi) without Trp as a substrate. Overexpression of wild-type trpS in M. tuberculosis increased the MIC of IPA to 32-fold, and knock-down trpS in Mycolicibacterium smegmatis made it more sensitive to IPA. The supplementation of Trp in the medium abrogated the inhibition of M. tuberculosis by IPA. We demonstrated that IPA can interfere with the function of TrpRS by mimicking Trp, thereby impeding protein synthesis and exerting its anti-TB effect.

Rosa laevigata Michx. Polysaccharide Ameliorates Diabetic Nephropathy in Mice through Inhibiting Ferroptosis and PI3K/AKT Pathway-Mediated Apoptosis and Modulating Tryptophan Metabolism.

Diabetic nephropathy (DN) is a metabolic disease wherein chronic hyperglycemia triggers various renal cell dysfunctions, eventually leading to progressive kidney failure. Rosa laevigata Michx. is a traditional Chinese herbal medicine. Many studies have confirmed its antioxidative, anti-inflammatory, and renoprotective effects. However, the effects and mechanisms of Rosa laevigata Michx. polysaccharide (RLP) in DN remain unclear. In this study, a DN mouse model was established to investigate the therapeutic effect of RLP on DN mice. Then, nontargeted metabolomics was used to analyze the potential mechanism of RLP in the treatment of DN. Finally, the effects of RLP on ferroptosis and the PI3K/AKT pathway were investigated. The results demonstrated that RLP effectively alleviated renal injury and reduced inflammation and oxidative stress in the kidney. In addition, nontargeted metabolomic analysis indicated that RLP could modulate riboflavin metabolism and tryptophan metabolism in DN mice. Notably, ferroptosis and PI3K/AKT pathway-mediated apoptosis in the kidney were also ameliorated following RLP treatment. In conclusion, this study confirmed that RLP had a significant therapeutic effect on DN mice. Furthermore, RLP treatment modulated tryptophan metabolism and inhibited ferroptosis and PI3K/AKT pathway-mediated apoptosis in the kidney.

Jingfang granules exert anti-psoriasis effect by targeting MAPK-mediated dendritic cell maturation and PPARγ-mediated keratinocytes cell cycle progression in vitro and in vivo.

BACKGROUND: Jingfang granules (JFG), derived from JingFangBaiDu San (JFBDS), are a traditional herbal formulas used for the treatment of respiratory tract infections. They were initially prescribed to treat skin disease, such as psoriasis in Chinese Taiwan, but are not widely used for psoriasis treatment in mainland China because of the lack of anti-psoriasis mechanism research. PURPOSES: The present study was designed to evaluate the anti-psoriasis effect of JFG and reveal the correlated mechanisms of JFG in vivo and in vitro using network pharmacology, UPLC-Q-TOF-MS technology and molecular biotechnology methods. RESULTS: An imiquimod-induced psoriasis-like murine model was used to verify the anti-psoriasis effect in vivo, with inhibition of lymphocytosis and CD3+CD19+B cell proliferation in the peripheral blood and prevention of the activation of CD4+IL17+T cells and CD11c+ MHC Ⅱ+ dendritic cells (DCs) in the spleen. Network pharmacology analysis demonstrated that the targets of the active components were significantly enriched in pathways involved in cancer, inflammatory bowel disease and rheumatoid arthritis, which were closely related to cell proliferation and immune regulation. The drug-component-target networks and molecular docking analysis demonstrated the active ingredients to be luteolin, naringin and 6'-feruloylnodakenin, which had a good binding affinity to PPARγ, p38a MAPK and TNF-a. Finally, UPLC-Q-TOF-MS analysis to validate the active ingredients in drug-containing serum and in vitro experiments showed that JFG inhibited the maturation and activation of BMDCs via the p38a MAPK signaling pathway and translocation of the agonist PPARγ into the nuclei to reduce the activity of NF-κB/STAT3 inflammatory signaling pathway in keratinocytes. CONCLUSIONS: Our study demonstrated that JFG improved psoriasis by inhibiting the maturation and activation of BMDCs and proliferation and inflammation of keratinocytes, which may facilitate the applications of JFG in anti-psoriasis therapy in clinical settings.

Si-Ni-SAN ameliorates obesity through AKT/AMPK/HSL pathway-mediated lipolysis: Network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Si-Ni-San (SNS) is a famous Chinese herbal formula used in China for thousands of years. It has clinical effects on a variety of lipid metabolism disorders, but the ameliorating effects of SNS on obesity and underlying mechanisms remained poorly elucidated. AIM OF THE STUDY: This study aims to explore the therapeutic effect and mechanism of SNS on obesity from multiple perspectives in vitro and in vivo. MATERIALS AND METHODS: The high-fat diet (HFD)-induced obesity mouse model was established to evaluate the effect of SNS. Then network pharmacologic methods were performed to predict underlying mechanisms, and the core pathways were verified in animal and cell studies. RESULTS: Our results demonstrated that SNS significantly reduced body weight, body fat content, white adipose tissue (WAT) expansion in obese mice, and lipid accumulation in primary mouse embryonic fibroblasts (MEFs) cells. Network pharmacologic analysis identified 66 potential therapeutic targets, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of these genes revealed that the most important signaling pathway includes AMP-activated protein kinase (AMPK) signaling pathway, regulation of lipolysis in adipocytes, lipid and atherosclerosis. Western blot assay confirmed that SNS activated hormone-sensitive triglyceride lipase (HSL) and adipose triglyceride lipase (ATGL) activity and promoted lipolysis through AMPK signaling pathway. CONCLUSION: The results confirmed that SNS improves lipid accumulation through AKT/AMPK/HSL axis mediated lipolysis, which opens a new option for clinical treatment of obesity and associated complications.

Efficacy and safety of Shouhui Tongbian Capsules in the treatment of constipation: A systematic review and meta-analysis.

BACKGROUND: Constipation is a common gastrointestinal disorder, which has seriously affected the quality of people's daily life. Traditional Chinese Medicine (TCM) therapy takes syndrome differentiation and treatment as the theoretical guidance with certain advantages in treating constipation with the holistic approach. However, there are few studies on the treatment of constipation with Shouhui Tongbian Capsules (SHTB). PURPOSE: This study was aimed to evaluate the clinical effect and safety of SHTB in the treatment of constipation and provide evidence-based references for clinical application. STUDY DESIGN: A systematic review and meta-analysis of existing literature on SHTB for treating constipation. METHODS: Chinese databases (China Network Knowledge Infrastructure, Wan Fang Database and Chinese Scientific Journal Database) and English databases (PubMed, EmBase and the Cochrane Library) were thoroughly investigated through screening randomized controlled trials on SHTB for constipation from the establishment of all databases to September 26, 2022. Data extraction and quality evaluation were performed on the literature that met the inclusion criteria and a meta-analysis was performed for selected data using Review Manager 5.4, ROB 2.0 and Stata 17.0. RESULTS: A total of 14 RCTs (randomized controlled trial) including 1310 participants were included in the analysis. The results showed that the test group was superior to the control group in improving the total effective rate and curative effect, clinical symptom score, gastrointestinal peptide index and reducing adverse reactions and recurrence rate. The specific results were as follows: ① The total effective rate increased significantly (RR = 1.24, 95% CI [1.18, 1.30], Z = 8.25, p< 0.00001); ② The clinical symptom indexs, including the difficulty of defecation [SMD = -1.28, 95% CI (-1.44, -1.12), Z = 15.65, p< 0.00001], the frequency of spontaneous defecation [SMD = 1.28, 95% CI (1.01, 1.54), Z = 9.52, p< 0.00001], defecation interval [SMD = -1.47, 95% CI (-1.68, -1.26), Z = 13.79, p < 0.00001], incomplete defecation [SMD = -1.34, 95% CI (-1.57, -1.11), Z = 11.42, p < 0.00001], duration of defecation [SMD = -2.02, 95% CI (-2.39, -1.65), Z = 10.73, p < 0.00001], stool characteristics [SMD = -2.30, 95% CI (-2.60, -1.99), Z = 14.72, p< 0.00001] and TCM main syndrome scores [SMD = -1.25, 95% CI (-1.46, -1.05), Z = 11.79, p< 0.00001] increased observably; ③ The gastrointestinal peptide hormone indexs, including MTL Level [SMD = 0.43, 95% CI (0.24, 0.62), Z = 4.44, p < 0.00001] and SP Level [RR =0.57, 95% CI (0.37, 0.87), Z = 2.61, p = 0.009] were improved obviously; ④ The incidence of adverse reactions (RR = 0.57, 95% CI [0.37, 0.87], Z = 2.61, p = 0.009) and recurrence rate (RR = 0.31, 95% CI [0.18, 0.54], Z = 4.28, P <0.001) reduced significantly. Sensitivity analysis showed that there was no significant change in all outcome indicators, which suggested that the results of meta-analysis were relatively stable. Funnel plot and Egger test results showed that the literature included in the study might have publication bias. CONCLUSION: SHTB can be used to treat functional constipation, especially elderly functional constipation, constipation caused by tumor chemotherapy and disease concomitant constipation. The optimal dosage of SHTB was 0.70 g (2 capsules) each time, 3 times a day, for 28 days. Combined with basic treatment, lactose oral solution, mosaic or castor oil could improve the total effective rate, clinical symptom indicators, gastrointestinal peptide hormone indicators and reduce adverse reaction rate of patients. However, due to the limitations of the included clinical trials, high-quality clinical trials with long follow ups are needed to evaluate the effectiveness and safety of SHTB in treating different types of constipation.

The purinergic receptors 2X3 on spiral ganglion neurons enhance the medial olivocochlear reflex in mice after long-term moderate noise exposure.

Our purpose was to study the expression of purinergic receptors 2X2 (P2X2) and purinergic receptors 2X3 (P2X3) in spiral ganglion neurons (SGNs), the afferent nerves of medial olivocochlear (MOC) reflex, after long-term moderate noise exposure, and its relationship with the enhancement of MOC reflex. Mice were exposed a moderate broadband noise for 4 weeks consecutively. Then mouse hearing functions, including threshold auditory brainstem responses, distortion-product otoacoustic emissions, and MOC reflex, were evaluated and the expression of P2X2 and P2X3 on SGNs were assessed by cochlear immunofluorescence. AF-353 was injected before each noise exposure. Four weeks later, mice were also tested for hearing functions and expression of P2X2 and P2X3 on SGNs. The long-term moderate noise strengthened MOC reflex, and AF-353 reduced it in mice and P2X3 expression on SGNs increased after long-term moderate noise exposure, and AF-353 can downregulate it. The P2X3 on SGNs of mice increased after long-term moderate noise exposure, and the upregulation of it mediated the enhancement of MOC reflex.

Altered dynamic functional connectivity of striatal-cortical circuits in Juvenile Myoclonic Epilepsy.

OBJECTIVE: To investigate whether the dynamic functional connectivity (dFC) of striatal-cortical circuits changes in juvenile myoclonic epilepsy (JME). METHODS: The resting-state EEG-fMRI and the sliding-window approach were adopted to explore the dynamic striatal-cortical circuitry in thirty JME patients compared with 30 well-matched health controls (HCs). Six pairs of striatal seeds were selected as regions of interests. The correlation analysis was performed to reveal the relationship between the altered dFC variability and clinical variables in JME group. RESULTS: JME patients exhibited increased dFC variability mainly involved in fronto-striatal and striatal-thalamic networks; decreased dFC variability between striatum subdivisions and default mode network (DMN) regions compared with HCs (p<0.05, GRF corrected). In addition, the hypervariability between left ventral-rostral putamen and left medial superior frontal gyrus was positively (r= 0.493, p=0.008) correlated with the mean frequency score of myoclonic seizures in JME group. CONCLUSION: JME presented altered dFC variability in striatal-cortical circuits. The pattern of altered circuits showed increased variability in fronto-striatal and striatal-thalamic networks and decreased variability in striatal-DMN. These results provide novel information about the dynamic neural striatal-cortical circuitry of JME.

N-3 polyunsaturated fatty acids prevent the D-galactose-induced cognitive impairment by up-regulating the levels of 5-hydroxymethylcytosine in the mouse brain.

Decreased 5-hydroxymethylcytosine (5hmC) levels caused by mitochondrial dysfunction in the brain are closely associated with the development of neurodegenerative disease. It has been reported that n-3 polyunsaturated fatty acids (PUFAs) prevent cognitive dysfunction by improving mitochondrial function in the brain. However, whether n-3 PUFA prevents cognitive dysfunction by increasing the levels of 5hmC in the brain is undisclosed. Mice were randomly divided into six groups (n = 10), injected with D-galactose (200 mg kg-1 day-1) for the model group and given different oils [0.1 mL per 10 g body weight per day, fish oil (FO), peony seed oil (PSO), corn oil (CO) and olive oil (OO)] for the prevention groups, and injected with the same dose of saline for the normal control group (NC) for 10 weeks, respectively. Peony seed oil and fish oil have shown preventive effects on D-galactose-induced cognitive dysfunction in behavioral tests. The content of docosahexaenoic acid (C22:6n-3, DHA content) in the brain was significantly higher in FO and PSO groups than in the other groups. Brain oxidative stress and neuronal apoptosis were significantly lower in PSO and FO groups than in the other groups. RNA-seq results showed that the different genes between PSO and FO compared with the model group were involved in the DNA demethylation process and the 5-methylcytosine metabolic process. The brain levels of 5hmC and the ten-eleven translocation family of dioxygenases (TETs) were significantly higher in FO and PSO groups compared with the model group, as analyzed by dot-blot and western blot. In conclusion, peony seed oil and fish oil increased the C22:6n-3 content, which activated the TET activity, led to up-regulation of the 5hmc level, resulted in inhibition of neuronal apoptosis, and then improved the cognitive function in D-gal-induced mice.

Chlorogenic acid improves diabetic retinopathy by alleviating blood-retinal-barrier dysfunction via inducing Nrf2 activation.

As one of the major diabetic microvascular complications, diabetic retinopathy (DR) is mainly initiated by the blood-retinal barrier (BRB) dysfunction. Chlorogenic acid (CGA) is a natural polyphenolic compound in Lonicerae Japonicae Flos, which traditionally has the beneficial function for eyes and is commonly included in many anti-diabetic formulas. In this study, the potential protective mechanism of CGA against DR was investigated. Streptozotocin (STZ) was used to induce diabetes in mice. CGA attenuated BRB dysfunction and reversed endothelial-mesenchymal transition (EndoMT) and epithelial-mesenchymal transition (EMT) in retinas in vivo. CGA inhibited microglia activation and reduced tumor necrosis factor (TNF)α release both in vivo and in vitro. CGA promoted nuclear factor erythroid 2-related factor 2 (Nrf2) activation and prevented EndoMT/EMT in TNFα-treated human retinal endothelial cells (HRECs) or retinal pigment epithelial APRE19 cells. CGA alleviated endothelial/epithelial barrier oxidative injury in HRECs or APRE19 cells stimulated with TNFα, but this effect was disappeared in cells co-incubated with Nrf2 inhibitor. Additionally, the CGA-supplied alleviation on BRB damage and EndoMT/EMT was markedly weakened in retinas from STZ-treated Nrf2 knock-out mice. All results suggest that CGA improves DR through attenuating BRB injury by reducing microglia-initiated inflammation and preventing TNFα-induced EndoMT/EMT and oxidative injury via inducing Nrf2 activation.

Idebenone relieves the damage of heat stress on the maturation and developmental competence of porcine oocytes.

The reproductive function of animals is often affected by climatic conditions. High-temperature conditions can cause damage to oocyte maturation and embryonic development in a variety of ways. The purpose of this study was to prove that supplementation idebenone (IDB) to the maturation medium can improve the maturation and development of porcine oocytes after heat stress (HS). Porcine cumulus-oocyte complexes (COCs) were cultured in the maturation medium with different concentrations of IDB (0, 0.1, 1 and 10 µM) for 44 hr at either 38.5°C or under the HS conditions. The cumulus oophorus expansion, nuclear maturation and blastocyst rate after parthenogenetic activation (PA) were measured. We found that HS (in vitro maturation 20-24 hr, 42°C) exposure significantly reduced cumulus expansion index and maturation rate of oocytes and the blastocyst rate of PA embryos, while IDB supplementation significantly improved oocyte maturation and development to the blastocysts stage after PA. Moreover, the addition of IDB decreased the intracellular level of ROS and increased GSH content, hence enhancing the antioxidant capacity of oocytes under HS. Meanwhile, IDB treatment also obviously improved the mitochondrial membrane potential and ATP synthesis of oocytes under HS conditions. Furthermore, IDB treatment increased the expression of GDF9 and BMP15 in IVM oocytes which attribute to improve the quality and outcome of IVM oocytes and the development competence of PA embryos in pigs. In summary, we demonstrated that IDB supplementation into the maturation medium exerted protective effects and improved the ability of maturation and developmental competence of porcine oocytes exposed to HS.

Neuroprotective effect of pseudoginsenoside-F11 on permanent cerebral ischemia in rats by regulating calpain activity and NR2A submit-mediated AKT-CREB signaling pathways.

BACKGROUND: N-methyl-d-aspartate receptors (NMDARs) have been demonstrated to play central roles in stroke pathology and recovery, including dual roles in promoting either neuronal survival or death with their different subtypes and locations. PURPOSE: We have previously demonstrated that pseudoginsenoside-F11 (PF11) can provide long-term neuroprotective effects on transient and permanent ischemic stroke-induced neuronal damage. However, it is still needed to clarify whether NMDAR-2A (NR2A)-mediated pro-survival signaling pathway is involved in the beneficial effect of PF11 on permanent ischemic stroke. MATERIAL AND METHODS: PF11 was administrated in permanent middle cerebral artery occlusion (pMCAO)-operated rats. The effect of PF11 on oxygen-glucose deprivation (OGD)-exposed primary cultured neurons were further evaluated. The regulatory effect of PF11 on NR2A expression and the activation of its downstream AKT-CREB pathway were detected by Western blotting and immunofluorescence in the presence or absence of a specific NR2A antagonist NVP-AAM077 (NVP) both in vivo and in vitro. RESULTS: PF11 dose- and time-dependently decreased calpain1 (CAPN1) activity and its specific breakdown product α-Fodrin expression, while the expression of Ca2+/calmodulin-dependent protein kinase II alpha (CaMKII-α) was significantly upregulated in the cortex and striatum of rats at 24 h after the onset of pMCAO operation. Moreover, PF11 prevented the downregulation of NR2A, p-AKT/AKT, and p-CREB/CREB in both in vivo and in vitro stroke models. Finally, the results indicated treatment with NVP can abolish the effects of PF11 on alleviating the ischemic injury and activating NR2A-mediated AKT-CREB signaling pathway. CONCLUSIONS: Our results demonstrate that PF11 can exert neuroprotective effects on ischemic stroke by inhibiting the activation of CAPN1 and subsequently enhancing the NR2A-medicated activation of AKT-CREB pathway, which provides a mechanistic link between the neuroprotective effect of PF11 against cerebral ischemia and NR2A-associated pro-survival signaling pathway.

Clinical Study on Effect of Solution Focused Approach on the Complications, Pain, Sleep, and Quality of Life in Patients with Hepatocellular Carcinoma Undergoing TACE.

OBJECTIVE: The objective of this study is to explore the effect of solution focused approach (SFA) on the complications, pain, sleep, and quality of life in patients with hepatocellular carcinoma undergoing transcatheter arterial chemoembolization (TACE). METHODS: Total of 106 patients with hepatocellular carcinoma who underwent TACE in our hospital from July 2019 to June 2020 were selected. According to the admission time, they were divided into the control group (n = 53) and the observation group (n = 53). The control group implemented routine nursing intervention, and the observation group implemented SFA on the basis of the control group. The clinical data, complications, pain, sleep status, and quality of life scores were compared between the two groups. RESULTS: The total incidence of complications in the observation group (16.98%) was lower than that in the control group (33.96%) (P < 0.05). There was no significant difference in the score of pain perception between the two groups (P > 0.05). The scores of sleep status in the observation group were lower than those in the control group (P < 0.05). The quality of life scores in the observation group was higher than that in the control group (P < 0.05). CONCLUSION: SFA can effectively reduce the complications, relieve pain, improve sleep status, and improve the quality of life in patients with hepatocellular carcinoma undergoing TACE.

Runjing extract promotes spermatogenesis in rats with ornidazole-induced oligoasthenoteratozoospermia through extracellular signal-regulated kinase signalling, and regulating vimentin expression.

OBJECTIVE: To investigate the efficacy of Runjing (RJ) extract on oligoasthenoteratozoospermia (OAT) induced by ornidazole (ORN) in rats, and to study the underlying mechanism. METHODS: Twenty-four adult male Sprague-Dawley rats were treated with normal saline (control), ORN (OAT model), ORN + 4.725 g·kg－1·d－1 RJ extract (low-dose) and ORN+ 18.9 g·kg－1·d－1 RJ extract (high-dose) for 4 weeks. The rats were then euthanized and sperm and testis samples were collected for analysis. Sperm count, motility and morphology were calculated by sperm suspension from cauda epididymis. Testicular histopathological changes were analyzed by hematoxylin and eosin staining and TdT mediated dUTP nick end labelling. Moreover, the expression of vimentin and extracellular signal-regulated kinase (ERK) were examined through Western blot, and the distribution of vimentin was detected via immunohistochemistry. RESULTS: ORN successfully induces seminiferous epithelium injury, cellular apoptosis, and finally OAT (P < 0.05). However, both low-dose and highdose RJ extract partially rescues the phenotypes (P < 0.05). Moreover, the expressions of vimentin and ERK were significantly altered in ORN testes (all P < 0.001), while RJ extract partially reversed these effects (P < 0.01 or P < 0.001). CONCLUSION: RJ extract can help maintain spermatogenesis through ERK signalling, and regulating vimentin expression.

Study on the alleviation of Fengshi Gutong capsule on rheumatoid arthritis through integrating network pharmacology and experimental exploration.

ETHNOPHARMACOLOGICAL RELEVANCE: Fengshi Gutong (FSGT) capsule, a traditional Chinese medicine formula, has effects including warming meridians and dispersing cold, and relieving pain by dredging collaterals. FSGT is generally used for the treatment of rheumatoid arthritis (RA) in clinic in China. AIM OF THE STUDY: This study aims to investigate the alleviation provided by FSGT capsule on RA in vivo and the engaged mechanism. MATERIALS AND METHODS: The collagen-induced arthritis (CIA) mouse model was used to evaluate the alleviation of FSGT capsule on RA in vivo. Network pharmacology was used to find the potential involved molecular targets. Western-blot, Real-time polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) were conducted. Wound healing assay was performed in human umbilical vein endothelial cells (HUVECs). RESULTS: FSGT capsule (300, 900 mg/kg) alleviated RA in CIA mice with no obvious side effects. The results from network pharmacology showed that the top 6 molecular targets involved in the FSGT-provided alleviation on RA were interleukin 6 (IL-6), tumor necrosis factor α (TNFα), C-C motif chemokine 2 (CCL2), vascular endothelial growth factor (VEGF), intercellular cell adhesion molecule-1 (ICAM-1), interleukin 1ß (IL-1ß), and these results imply the critical participation of inhibiting inflammation or angiogenesis. Next, FSGT capsule decreased the elevated serum contents of rheumatoid factor (RF) and VEGF, and some pro-inflammatory cytokines like TNFα and IL-6. Moreover, FSGT capsule also reduced the elevated protein expression of ICAM1, IL-1ß and phosphorylated protein kinase B (Akt) in synovium from CIA mice. Further in vitro results showed that totally 13 compounds from FSGT reduced the enhanced IL-1ß and inducible nitric oxide synthase (iNOS) mRNA expression in RAW264.7 macrophages stimulated by lipopolysaccharide (LPS). Meanwhile, 7 compounds from FSGT decreased the VEGF-induced HUVEC migration. Among those compounds, benzoylhypaconine (BHA), pseudoephedrine hydrochloride (PSE), glycyrrhetnic acid (GA), isoliquiritigenin (ISL), quercetin (QUER) and kaempferol (KAE) were found to inhibit both inflammation and angiogenesis in vitro. CONCLUSION: FSGT capsule ameliorates RA in CIA mice by reducing inflammation, abrogating angiogenesis and relieving pain. Some compounds in FSGT, including BHA, GA, PSE, ISL, QUER and KAE, reduced both inflammation and angiogenesis in vitro, which suggests that those compounds may contribute to the FSGT capsule-provided alleviation on RA.

Long-term moderate noise exposure enhances the medial olivocochlear reflex.

OBJECTIVE: To investigate the effects of long-term moderate noise on hearing functions, MOCR, and MEMR. METHODS: Mice were exposed to the moderate noise (11.2 - 22.4 kHz, 80 dB SPL, 6 h/day, 4 weeks). Subsequently, the hearing functions, including threshold and input-output roles of ABR (auditory brainstem response) and cubic (2f1-f2) DPOAEs (distortion product otoacoustic emissions) were evaluated. Also, MEMR and MOCR were assessed shortly after or at four weeks following the termination of exposure to the noise. RESULTS: The mice's acoustic suppression reflex was strengthened, hearing functions and MEMR were unaffected four weeks after the moderate noise. For primary tones of 16, 20 and 24 kHz, the strengths of contralateral and ipsilateral suppression in the noise group were about double those recorded in the control group. In order to further determine whether the functional changes of the afferent or efferent nerves increased the strengths of acoustic suppression, the mouse's left ear was inserted the earplug, and then exposed the moderate noise for four weeks. The strengths of contralateral suppression at 16, 20 and 24 kHz were increased for the noise + earplug than for the control group and were indistinguishable between the noise + earplug and the noise group. While no significant changes were found in the strengths of ipsilateral suppression at all frequencies for the noise + earplug group compared with the control group. Under ketamine/xylazine anesthesia, the broadband suppressor noise did not stimulate the MEMR by 20 min post-induction at all frequencies in three groups. CONCLUSION: Our data demonstrated that the long-term moderate noise-exposure strengthened mice's MOCR by changing its afferent nerves, and unaffected cochlear hair cells and type I spiral ganglion neurons.

Feasibility of direct promontory stimulation by bone conduction: A preliminary study of frequency-response characteristics in cats.

BACKGROUND: As an alternative pathway to air conduction, bone conduction is a multipathway process that transmits sound energy to the inner ear through the skull in general. Based on this mechanism, bone conduction devices (BCDs) have been used widely in the rehabilitation of hearing loss. Although great efforts have been devoted to improving BCDs, drawbacks still exist in most categories of BCDs due to the complicated process of bone conduction. We hypothesized that if a bone conduction transducer was placed on the cochlea to stimulate it directly, the attenuation would be minimized, and the frequency dependency would be different from that of the vibratory response induced by traditional BCDs. This study aimed to explore the feasibility of direct promontory stimulation and to investigate its frequency-response characteristics. METHODS: Measurements were conducted in twelve cat ears. To stimulate the promontory directly, the floating mass transducer (FMT) of the Vibrant Soundbridge© (VSB) implant was glued to the promontory coupled with an oval window (OW) coupler. Auditory brainstem response (ABR) and laser Doppler vibrometry (LDV) measurements were used to evaluate the auditory response induced by the FMT. In both measurements, the FMT was driven by direct voltage stimuli. RESULTS: ABR waves could be induced under direct promontory stimulation by the FMT. In the frequency range of 1-12 kHz, the variation in the voltage threshold level were limited to 16 dB SPL with a maximum of 0.2 V at 1 kHz and a minimum of 0.04 V at 10 kHz. In the LDV measurements and the relative motion of the round window membrane (RWM) and the promontory were used to evaluate the cochlear response. The LDV results indicated a weak frequency dependency from 1 to 12 kHz. CONCLUSION: Different from traditional stimulation via transcranial bone conduction, direct promontory stimulation is a new method in which a small bone conduction transducer stimulates the cochlear shell directly. The current experimental data demonstrate that it is feasible to generate sensations through bone conduction by stimulating the cochlea directly. Furthermore, the cochlear response induced by this type of stimulus in cats was weakly frequency dependent at frequencies ranging from 1 to 12 kHz. This study may provide a basis for the design of new transducers that can perform well over a wide range of frequencies.

Pyrazolo[1,5- a]pyridine Inhibitor of the Respiratory Cytochrome bcc Complex for the Treatment of Drug-Resistant Tuberculosis.

Respiration is a promising target for the development of new antimycobacterial agents, with a growing number of compounds in clinical development entering this target space. However, more candidate inhibitors are needed to expand the therapeutic options available for drug-resistant Mycobacterium tuberculosis infection. Here, we characterize a putative respiratory complex III (QcrB) inhibitor, TB47: a pyrazolo[1,5- a]pyridine-3-carboxamide. TB47 is active (MIC between 0.016 and 0.500 µg/mL) against a panel of 56 M. tuberculosis clinical isolates, including 37 multi-drug-resistant and two extensively drug-resistant strains. Pharmacokinetic and toxicity studies showed promising profiles, including negligible CYP450 interactions, cytotoxicity, and hERG channel inhibition. Consistent with other reported QcrB inhibitors, TB47 inhibits oxygen consumption only when the alternative oxidase, cytochrome bd, is deleted. A point mutation in the qcrB cd2-loop (H190Y, M. smegmatis numbering) rescues the inhibitory effects of TB47. Metabolomic profiling of TB47-treated M. tuberculosis H37Rv cultures revealed accumulation of steps in the TCA cycle and pentose phosphate pathway that are linked to reducing equivalents, suggesting that TB47 causes metabolic redox stress. In mouse infection models, a TB47 monotherapy was not bactericidal. However, TB47 was strongly synergistic with pyrazinamide and rifampicin, suggesting a promising role in combination therapies. We propose that TB47 is an effective lead compound for the development of novel tuberculosis chemotherapies.

Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains.

Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB), due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

Health Effects of Dietary Oxidized Tyrosine and Dityrosine Administration in Mice with Nutrimetabolomic Strategies.

This study aims to investigate the health effects of long-term dietary oxidized tyrosine (O-Tyr) and its main product (dityrosine) administration on mice metabolism. Mice received daily intragastric administration of either O-Tyr (320 µg/kg body weight), dityrosine (Dityr, 320 µg/kg body weight), or saline for consecutive 6 weeks. Urine and plasma samples were analyzed by NMR-based metabolomics strategies. Body weight, clinical chemistry, oxidative damage indexes, and histopathological data were obtained as complementary information. O-Tyr and Dityr exposure changed many systemic metabolic processes, including reduced choline bioavailability, led to fat accumulation in liver, induced hepatic injury, and renal dysfunction, resulted in changes in gut microbiota functions, elevated risk factor for cardiovascular disease, altered amino acid metabolism, induced oxidative stress responses, and inhibited energy metabolism. These findings implied that it is absolutely essential to reduce the generation of oxidation protein products in food system through improving modern food processing methods.