Online tools to predict individualised survival for primary oesophageal cancer patients with and without pathological complete response after neoadjuvant therapy followed by oesophagectomy: development and external validation of two independent nomograms.

OBJECTIVE: This study aimed to develop and validate robust predictive models for patients with oesophageal cancer who achieved a pathological complete response (pCR) and those who did not (non-pCR) after neoadjuvant therapy and oesophagectomy. DESIGN: Clinicopathological data of 6517 primary oesophageal cancer patients who underwent neoadjuvant therapy and oesophagectomy were obtained from the National Cancer Database for the training cohort. An independent cohort of 444 Chinese patients served as the validation set. Two distinct multivariable Cox models of overall survival (OS) were constructed for pCR and non-pCR patients, respectively, and were presented using web-based dynamic nomograms (graphical representation of predicted OS based on the clinical characteristics that a patient could input into the website). The calibration plot, concordance index and decision curve analysis were employed to assess calibration, discrimination and clinical usefulness of the predictive models. RESULTS: In total, 13 and 15 variables were used to predict OS for pCR and non-pCR patients undergoing neoadjuvant therapy followed by oesophagectomy, respectively. Key predictors included demographic characteristics, pretreatment clinical stage, surgical approach, pathological information and postoperative treatments. The predictive models for pCR and non-pCR patients demonstrated good calibration and clinical utility, with acceptable discrimination that surpassed that of the current tumour, node, metastases staging system. CONCLUSIONS: The web-based dynamic nomograms for pCR (https://predict-survival.shinyapps.io/pCR-eso/) and non-pCR patients (https://predict-survival.shinyapps.io/non-pCR-eso/) developed in this study can facilitate the calculation of OS probability for individual patients undergoing neoadjuvant therapy and radical oesophagectomy, aiding clinicians and patients in making personalised treatment decisions.

Ginsenoside Rd, a natural production for attenuating fibrogenesis and inflammation in hepatic fibrosis by regulating the ERRα-mediated P2X7r pathway.

Ginseng, when used as a food and nutritional supplement, has the ability to regulate human immunity. Here, the potential anti-hepatic fibrosis effect of ginsenoside Rd (Rd), one of the protopanaxadiol types of ginsenoside, was investigated. We established a hepatic fibrosis model using intraperitoneal injection of thioacetamide (TAA) for five weeks in mice. In addition, an in vitro model was established by using TGF-ß to activate hepatic stellate cells (HSCs), treated with Rd and an estrogen-related receptor α (ERRα) inhibitor (XCT-790). The ERRα knockdown (shRNA-ERRα) of the primary mouse hepatocytes was used to establish hepatocyte injury by TGF-ß, and they were then incubated in Rd. The Rd significantly alleviated the histopathological changes, and reduced the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. The Rd could upregulate the ERRα and downregulate the fibrosis markers in the livers of mice. In TAA-induced mice, the Rd inhibited the purinergic ligand-gated ion channel 7 receptor (P2X7r)-mediated NLRP3 inflammasome activation, consequently reversing the liver inflammatory response. The Rd significantly increased the expression of ERRα and suppressed the extracellular matrix (ECM) in the HSCs or primary hepatocytes. The Rd significantly decreased the P2X7r-mediated NLRP3 inflammasome activation, consequently reversing the inflammatory response, including the production of IL-1ß, IL-23 in the activated HSCs and primary hepatocytes. The Rd could ameliorate the damage of the hepatocytes and further inhibit the entry of IL-1ß and IL-18 into the extracellular matrix. The Rd reduced the inflammatory reaction by regulating the ERRα-P2X7r signaling pathway while suppressing the fibrogenesis, which suggests that the Rd can serve as a novel dietary supplement approach to combat hepatic fibrosis.

Blocking SP/NK1R signaling improves spinal cord hemisection by inhibiting the release of pro-inflammatory cytokines in rabbits.

OBJECTIVE: Incomplete spinal cord injury (SCI) is the most common spinal cord injury in clinic, however its mechanism is still not fully understood. DESIGN: We constructed the rabbit spinal cord hemisection (SCH) model and used RT-PCR, western blotting, immunohistochemistry, and immunofluorescence experiments to explore the potential mechanism of SCI. SETTING: The sham operation (SH) group, the observation (OB, which is the SCH) group, the OB+ substance p (SP) inhibitor group, the OB + NK1R inhibitor group, the OB + NK1R agonist group and the OB + SP inhibitor + NK1R agonist group. PARTICIPANTS: New Zealand white rabbits. INTERVENTIONS: Use NK1R inhibitors, NK1R agonists, SP inhibitors to treat the SCH model. OUTCOME MEASURES: IL-1ß, IKKγ, IL-6 and NF-κB. RESULTS: The results showed that nissl bodies, inflammatory cells and SP increased notably in the spinal cord cells of the rabbit SCH model. Through in vivo experiments with SP or NK1R inhibitors or NK1R agonists, we found that inhibiting SP/NK1R signaling can help improve SCH by inhibiting the release of pro-inflammatory cytokines IL-1ß, IKKγ, IL-6 and NF-κB. REGISTERED TRIALS: Animal experiments were approved by Ruijin Hospital, Shanghai Jiaotong University School of Medicine.

TNF-α-mediated podocyte injury via the apoptotic death receptor pathway in a mouse model of IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and it is characterized by mesangial IgA deposits. Proteinuria is a common clinical feature of IgAN, which has a critical connection to podocyte injury and has been used as a clinical prognostic factor for IgAN. Evidence has shown that TNF-α released from mesangial cells may lead to podocyte apoptosis. METHODS: Forty male BALB/c mouse were randomly divided into the control group and IgAN group. A mice model of IgAN was developed by oral administration of bovine serum albumin (BSA) combined with Staphylococcus Enterotoxin B (SEB) tail vein injection. Urinary protein concentrations, renal function, renal morphological, IgA deposition, apoptosis situation, and the mRNA and protein expression of nephrin, podocin, TNF-α, TNFR1, caspase-8 and caspase-3, were detected after 12 weeks. RESULTS: BSA and SEB can successfully establish an IgAN mouse model, and the main pathological changes are the IgA immune complex deposition in the mesangial area. The gene and protein expression levels of nephrin and podocin were found to be downregulated, and death receptor pathway-related indicators were upregulated, and they were involved in TNF-α-activated podocyte injury and apoptosis in IgAN mice. CONCLUSION: TNF-α may play an important role in the pathogenesis of podocyte apoptosis in IgAN, and its effects may be mediated through the apoptotic death receptor pathway.

Enhanced conservation of vital pulp and apical tissues by the application of crown rotation surgery for inversely impacted central incisors: A follow-up analysis of two patients over 4 years.

AIM: To describe a novel surgical method (crown rotation surgery) to manage inversely impacted central incisors with immature roots. METHODOLOGY: Two young patients each presented with an inversely impacted maxillary central incisor. To protect the apical tissues, the two impacted incisors were rotated downwards to a relatively normal position without extraction from their bony sockets. RESULTS: After crown rotation surgery, spontaneous eruption, continuous root development, and periodontal healing of the rotated incisors were observed. The pulp retained vitality and blood flow was normal. Moreover, there were no obvious signs of pulp canal obliteration (PCO), as indicated by Cone Beam Computed Tomography (CBCT) imaging. CONCLUSIONS: By optimising protection of the vital pulp and apical tissues, crown rotation surgery represents a minimally invasive, conservative, and practical surgical technique for treating inversely impacted incisors with developing roots. In contrast to existing surgical methods, crown rotation surgery may avoid certain complications, including PCO and abnormal or arrested root development. KEY LEARNING POINTS: By optimizing protection of the vital pulp and apical tissues, crown rotation surgery represents a minimally invasive, conservative and practical surgical technique for treating inversely impacted incisors with developing roots. In contrast to existing surgical methods, crown rotation surgery may avoid certain complications, including PCO and abnormal or arrested root development.

Correlation between the fatty infiltration of paraspinal muscles and disc degeneration and the underlying mechanism.

BACKGROUND: Low back pain (LBP) is associated with lumbar disc degeneration (LDD) and fatty infiltration of paraspinal muscles. However, there are some controversies about the relationship between LDD and fatty infiltration of paraspinal muscles, and the causation of them is also not clear. Thus, we investigated whether the degree of LDD was associated with fatty infiltration of paraspinal muscles and preliminarily explored the underlying mechanism. METHODS: A retrospective study was conducted on 109 patients with chronic LBP. The degree of LDD was assessed by the Pfirrmann classification. Total muscle cross-sectional area, L4 vertebral body endplate area, and fat cross-sectional area at axial T2-weighted MRI were measured. Multifidus and lumbar disc specimens were taken from eight individuals undergoing discectomy for disc herniation. Gene and protein expression levels of TNF were quantified through qPCR assays and ELISA, respectively. RESULTS: The relative cross-sectional area, total muscle cross-sectional area, and muscle cross-sectional area asymmetry were not related to LDD. Pfirrmann grades correlated strongly with fatty infiltration of the multifidus and moderately with fatty infiltration of the erector spinae and the psoas muscles. Linear regression analysis suggested that Pfirrmann grades were most associated with fatty infiltration of the multifidus. Compared with II-degree degeneration discs (mild-degeneration group), fatty infiltration of the multifidus in IV-degree degeneration discs (severe-degeneration group) significantly increased, accompanied by increased mRNA expression of TNF. Meanwhile, the protein expression levels of TNF (pg/g protein) in discs (16.62 ± 4.33) and multifidus (13.10 ± 2.76) of the severe-degeneration group were higher than those in the mild-degeneration group (disc: 9.75 ± 2.18; multifidus: 7.84 ± 2.43). However, the mRNA expression of TNF in the multifidus was not significantly different between the two groups. CONCLUSIONS: The results suggest that LDD is associated with fatty infiltration of the multifidus. The possible underlying mechanism is that LDD induces fatty infiltration by inflammation. Furthermore, compared with the erector spinae and the psoas muscles, fatty infiltration of the multifidus shows an optimal correlation with LDD, which may contribute to further understanding of LDD pathology.

Propionibacterium acnes contributes to low back pain via upregulation of NGF in TLR2-NF-κB/JNK or ROS pathway.

Propionibacterium acnes infection in intervertebral discs (IVDs) is a newly identified cause of low back pain (LBP). In the present study, we aimed to determine whether the nerve growth factor (NGF), a critical pro-algesic factor, is involved in P. acnes-induced LBP. After co-culturing with P. acnes, nucleus pulposus cells (NPCs) produced NGF, which was upregulated after inoculation of P. acnes into IVDs of rats. In addition, administration of P. acnes into rat IVDs leads to significant mechanical allodynia and cold hyperreflexia, and significant upregulation of the pain-related factors, including substance P (SP), calcitonin gene-related peptide (CGRP), and Transient Receptor Potential Vanilloid 1 (TRPV1), in rat dorsal root ganglia (DRG), suggesting that P. acnes-inoculated rats had obvious discogenic LBP. However, inhibition of NGF bioactivity significantly ameliorated P. acnes-induced discogenic LBP, suggesting that P. acnes induced LBP via NGF. Finally, an in vitro mechanism study demonstrated that P. acnes stimulated NPCs to secrete NGF via TLR-2 receptor and NF-κB p65/JNK pathway, or ROS-related pathway. Therefore, P. acnes had a strong association with LBP by stimulating NPCs to secrete NGF via the TLR2-NF- κB/JNK or ROS-related pathway. These findings propose a novel potential therapeutic strategy for LBP.

Huangqi Guizhi Wuwu Decoction attenuates Podocyte cytoskeletal protein damage in IgA nephropathy rats by regulating AT1R/Nephrin/c-Abl pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqi Guizhi Wuwu Decoction(HQGZWWD) is a Traditional Chinese Medicine formula from Synopsis of Golden Chamber used to treat blood arthralgia. According to the principle that the same treatment can be used for different diseases, HQGZWWD has proven effective for IgA nephropathy (IgAN) associated with spleen and kidney yang deficiency. AIM OF THE STUDY: In this study, we investigated the mechanism by which HQGZWWD alleviates proteinuria and protects renal function in rats with IgAN by regulating the AT1R/Nephrin/c-Abl pathway. METHODS: Rats were randomly divided into six groups: control, IgAN model, IgAN model treated with low-dose HQGZWWD, IgAN model treated with medium-dose HQGZWWD, IgAN model treated with high-dose HQGZWWD, and IgAN model treated with valsartan. IgAN was induced using bovine γ-globulin. We evaluated the mediating effects of HQGZWWD on podocyte cytoskeletal proteins, the AT1R/Nephrin/c-Abl pathway, upstream tumor necrosis factor-α (TNF-α), and TNF-α receptor-1 (TNFR1). RESULTS: The IgAN rats displayed proteinuria, IgA deposition in the mesangial region, and podocyte cytoskeletal protein damage. The expression of TNF-α, TNFR1, AT1R, and c-Abl was increased in the IgAN rat kidney, whereas the expression of nephrin, podocin, ACTN4, and phosphorylated nephrin (p-nephrin) was reduced. HQGZWWD treatment significantly alleviated podocyte cytoskeletal protein damage in the IgAN rats, upregulated the expression of nephrin, podocin, and ACTN4, and the colocalized expression of F-actin and nephrin. This study demonstrates that HQGZWWD attenuates podocyte cytoskeletal protein damage by regulating the AT1R-nephrin- c-Abl pathway, upregulating the expression of p-nephrin, and downregulating the expression of AT1R and c-Abl. CONCLUSIONS: These results indicate that HQGZWWD attenuates podocyte cytoskeletal protein damage in IgAN rats by regulating the AT1R/Nephrin/c-Abl pathway, providing a potential therapeutic approach for IgAN.

Protective effect of Sika Deer bone polypeptide extract on dexamethasone-induced osteoporosis in rats

BACKGROUND: Osteoporosis attacks approximately 10% of the population worldwide. Sika Deer (Cervus nippon), one of China's precious traditional medicinal animals, has been widely recorded in ancient Chinese medical books and claimed for centuries to have numerous medical benefits including bone strengthening. This study aimed to find the use of Sika Deer bone in treating osteoporosis according to traditional records and to investigate the protective effect of Sika Deer bone polypeptide extract on glucocorticoidinduced osteoporosis (GIOP) in rats. RESULTS: Sika Deer bone polypeptide extract could increase serum Ca2+ and BGP, decrease serum P3+, ALP, PTH, and CT, but had no effect on serum NO in rats with GIOP. The immunohistochemical iNOS results of the rats' distal femur were negative in each group. Besides the model group, the eNOS color reaction in osteoblasts was strongly positive in the other three groups. CONCLUSIONS: Sika Deer bone polypeptide extract can improve pathological changes in the microstructure and stimulate the expression of eNOS in osteoblasts. The protective effect on bone might be mediated by eNOS-dependent NO generation.

In situ rotation surgery for correction of growing, inversely impacted maxillary central incisors.

Treatment of an impacted incisor with a dilacerated root is challenging for clinicians because of the position of the impacted incisor, the abnormality of the root, unfavorable prognosis, and, especially, the long treatment duration. We report on 2 young patients who had inversely impacted maxillary central incisors with developing labially dilacerated roots. Both patients were treated by a novel surgical approach, in situ rotation, by which the crowns of the inversely impacted incisors were carefully rotated to a relatively normal position, whereas the apical location remained relatively unchanged. About 2 weeks after surgery, spontaneous eruption of the treated incisors was observed. Three months later, the postoperative central incisors were further aligned into the maxillary arch with a fixed orthodontic appliance. Follow-up visits 2 or 3 years after surgery indicated that the positions of the dilacerated incisors maintained stability with good gingival esthetics, and the pulpal vitality was favorable. The roots grew further in a relatively normal direction of the incisor's longitudinal axis, which was different from the initial curvature angle. Moreover, with the in situ rotation surgery, treatment time was greatly reduced and resulted in a favorable prognosis compared with conventional treatment.

Four-octyl itaconate activates Nrf2 cascade to protect osteoblasts from hydrogen peroxide-induced oxidative injury.

Four-octyl itaconate (4-OI) is the cell-permeable derivative of itaconate that can activate Nrf2 signaling by alkylating Keap1's cysteine residues. Here, we tested the potential effect of 4-OI on hydrogen peroxide (H2O2)-induced oxidative injury in osteoblasts. In OB-6 cells and primary murine osteoblasts, 4-OI was able to activate Nrf2 signaling cascade and cause Keap1-Nrf2 disassociation, Nrf2 protein stabilization, cytosol accumulation, and nuclear translocation. 4-OI also augmented antioxidant-response element reporter activity and promoted expression of Nrf2-dependent genes (HO1, NQO1, and GCLC). Pretreatment with 4-OI inhibited H2O2-induced reactive oxygen species production, cell death, and apoptosis in osteoblasts. Furthermore, 4-OI inhibited H2O2-induced programmed necrosis by suppressing mitochondrial depolarization, mitochondrial cyclophilin D-ANT1 (adenine nucleotide translocase 1)-p53 association, and cytosol lactate dehydrogenase release in osteoblasts. Ectopic overexpression of immunoresponsive gene 1 (IRG1) increased endogenous itaconate production and activated Nrf2 signaling cascade, thereby inhibiting H2O2-induced oxidative injury and cell death. In OB-6 cells, Nrf2 silencing or CRISPR/Cas9-induced Nrf2 knockout blocked 4-OI-induced osteoblast cytoprotection against H2O2. Conversely, forced Nrf2 activation, by CRISPR/Cas9-induced Keap1 knockout, mimicked 4-OI-induced actions in OB-6 cells. Importantly, 4-OI was ineffective against H2O2 in Keap1-knockout cells. Collectively, 4-OI efficiently activates Nrf2 signaling to inhibit H2O2-induced oxidative injury and death of osteoblasts.

A rapid protocol to distinguish between Citri Exocarpium Rubrum and Citri Reticulatae Pericarpium based on the characteristic fingerprint and UHPLC-Q-TOF MS methods.

Citri Exocarpium Rubrum (CER) and Citri Reticulatae Pericarpium (CRP) are used as common functional foods and traditional Chinese medicine (TCM). As different parts of the same fruit, CER and CRP have different effects in clinical applications. However, they are commonly confused due to the similarity of the chemical compounds and a lack of scientific method to distinguish them in the finished product. In this study, an ultra-high performance liquid chromatography-diode array detector (UHPLC-DAD) technique and an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF MS) method were employed to generate the characteristic fingerprint under the optimum analytical conditions. Principal component analysis (PCA) and orthogonal partial least squares discrimination analysis (OPLS-DA) were applied to represent different chemical markers for CER and CRP. 44 potential markers including 15 polymethoxylated flavanones (PMFs), 5 flavone-C-glycosides, 6 flavanone-O-glycosides, 3 flavonoid-O-glycosides, 8 organic acids, 5 limonoids and 2 alkaloids were successfully identified by using UNIFI software. The heat map showed that there were significant differences in the CER and CRP samples. Furthermore, 12 potential markers were screened out by characteristic fingerprint and UHPLC-Q-TOF MS methods and were analyzed by quantitative analysis of multicomponents by a single marker (QAMS) method. Finally, a prediction model based on the discovered chemical markers was established for discrimination between CER and CRP. Using these markers can significantly distinguish the unknown processed products of CER and CRP. In conclusion, an effective way to quickly and easily distinguish CER and CRP was successfully established based on the characteristic fingerprint and UHPLC-Q-TOF MS. It could also be a new strategy for analysis of different processed products of the same plant source.

Study on the therapeutic material basis and effect of Acanthopanax senticosus (Rupr. et Maxim.) Harms leaves in the treatment of ischemic stroke by PK-PD analysis based on online microdialysis-LC-MS/MS method.

Leaves of Acanthopanax senticosus (Rupr. et Maxim.) Harms (ASL) have revealed significant biological activity in the treatment of ischemic stroke diseases. However, there was no in-depth study of the therapeutic material basis and effect of ASL from the pharmacokinetics-pharmacodynamics (PK-PD) analysis level. In this study, a method based on microdialysis coupled with ultra-performance liquid chromatography combined with triple quadruple mass spectrometry (MD-UPLC-QQQ-MS) was established to simultaneously and continuously collect and quantify the active compounds and endogenous neuroactive substances related to therapeutic effect in plasma and hippocampus of fully awake ischemic stroke rats. The acquired data were analyzed by the PK-PD analysis method. It was found that hyperoside, quercitrin, quercetin, and caffeic acid could pass through the blood-brain barrier, and quercetin needed a longer intake time than quercitrin and hyperoside, but the passage rate was higher. The exposure of the four compounds in the hippocampus affected the contents of seven neuroactive substances in different ways and was depicted graphically (concentration-time effect). In addition, the study found that the brain index and brain water content of ischemic stroke rats were significantly reduced after the oral administration of ASL. ASL observably regulated the content or activity of six important biochemical indexes in rats. On the one hand, this study verified that ASL could regulate ischemic stroke in many aspects. On the other hand, a visualized method to express the relationship between pharmacokinetics and pharmacodynamics in the hippocampus of cerebral ischemic areas was established. This research gives a hand to the study on the therapeutic material basis and effect of traditional Chinese medicine mechanism.

Early growth response 1 reduction in peripheral blood involving condylar subchondral bone loss.

OBJECTIVES: To detect whether early growth response 1 (EGR1) in peripheral blood leucocytes (PBLs) indicates temporomandibular joint (TMJ) osteoarthritis (OA) lesions. MATERIALS AND METHODS: Egr1 mRNA expression levels in PBLs were detected in eight malocclusion patients without temporomandibular disorder (TMD) signs and 16 malocclusion patients with clinical TMD signs with (eight) or without (eight) imaging signs of TMJ OA. Twelve 6-week-old rats were randomized to a control group and a unilateral anterior crossbite (UAC) group and were sampled at 4 weeks. The Egr1 mRNA expression levels in PBLs and protein expression levels in different orofacial tissues were measured. RESULTS: Patients with TMD signs with/without TMJ OA diagnosis showed lower Egr1 mRNA expression levels in PBLs than patients without TMD signs. The lower Egr1 mRNA expression was also found in the PBLs of UAC rats, which were induced to exhibit early histo-morphological signs of TMJ OA lesions. In subchondral bone of UAC rats, EGR1 protein expression was decreased, co-localization of EGR1 with osterix or dentin matrix protein-1 was identified, and the number of EGR1 and osterix double-positive cells was reduced (all p < .05). CONCLUSION: Egr1 reduction in PBLs potentially indicates subchondral bone OA lesions at an early stage.

Mass spectrometry-based urinary metabolomics for the investigation on the mechanism of action of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves against ischemic stroke in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine, Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) can treat ischemic, neurasthenia, and hypertension diseases. However, only few studies have been conducted on the mechanism of action of ESL for ischemic disease treatment. AIM OF THE STUDY: This study aimed to discover the potential biomarkers in the rats caused by ischemic stroke and build a gene-enzyme-biomarker network to explore the mechanism of ESL treatment on ischemic stroke further. MATERIALS AND METHODS: The urinary metabolomics strategy was developed by combining UPLC-Q-TOF/MS with multivariate data analysis. The gene-enzyme-biomarker network was built by Cytoscape 3.6.0 on the basis of the potential biomarkers filtered out via urinary metabolomic analysis. Then, the potential target enzymes of ESL in the treatment of ischemic stroke were selected for further validation analysis via the ELISA kits. RESULTS: A total of 42 biomarkers associated with ischemic stroke have been identified, among which 38 species can be adjusted by ESL, including 5'-methylthioadenosine, prostaglandin A2, l-methionine, aldosterone, 11b-hydroxyprogesterone, prostaglandin E3, dehydroepiandrosterone, taurine, 5-methoxyindoleacetate, and p-cresol glucuronide. These biomarkers were involved in several metabolic pathways, including taurine and hypotaurine, arachidonic acid, cysteine and methionine, steroid hormone biosynthesis, tryptophan, and tyrosine metabolism pathways. The gene-enzyme-biomarker network was built, and three predicted target proteins, including cyclooxygenase-2 (COX-2), monoamine oxidase (MAO), and nitric oxide synthase (NOS), were selected as the potential target enzymes for ESL in ischemic stroke treatment. CONCLUSIONS: All results showed that ESL can play a therapeutic role in treating ischemic stroke through different pathways. This study will provide an overall view of the mechanism underlying the action of ESL against ischemic stroke.

Siwu Granules and Erythropoietin Synergistically Ameliorated Anemia in Adenine-Induced Chronic Renal Failure Rats.

OBJECTIVE: Renal anemia in patients with end-stage chronic kidney disease is closely related to the deterioration of cardiac function, renal function, and quality of life. This study involved adenine-induced renal anemic rat models and evaluated the treatment effect of Siwu granules and/or erythropoietin (EPO). METHODS: Fifty SD rats were randomly divided into 5 groups: control, model, Siwu, EPO, and Siwu plus EPO groups. The expression levels of NO, MDA, SOD, CAT, IL-6, TNF-α, EPO, EPOR, α-SMA, and TGF-ß1 were detected in rats after 8 weeks of treatment with Siwu granules and/or EPO. RESULTS: After modeling, 47 rats entered the stage of treatment. Siwu plus EPO treatment significantly increased the rat hemoglobin content (p < 0.05) and reduced blood urea nitrogen (p < 0.05) and serum creatinine (p < 0.001). Compared with the control group, the expression of EPO and EPOR in the kidney of rats with renal failure was significantly decreased (p < 0.05). Moreover, the Siwu plus EPO group improved the level of oxidative stress in rats with chronic renal failure and reduced the expression of inflammatory factors. The expression of α-SMA and TGF-ß1 in rats with renal failure was higher, but there was no expression in the control group. CONCLUSION: Combined treatment of Siwu granules with EPO increased the expression of EPO and EPOR in the renal tissues and inhibited oxidative stress and inflammatory factors, improving the renal function and anemia.

Gorham disease of the mandible: a report of two cases and a literature review.

Gorham disease, a rare disorder of unknown etiology, is characterized by the clinical and radiologic disappearance of bone. Because the etiology is unknown, diagnosis is difficult. Therefore, radiographic manifestations play a vital role in the diagnosis of this disease. Thus far, there has been no completely effective treatment. Most remedies are limited to symptom management. Despite the fact that any bone can be affected, one of the most prevalent sites is the maxillofacial region. In this paper, 2 cases of Gorham disease involving the maxillofacial region are reported, including preoperative and postoperative radiographic features.

Systematic studies on the in vivo substance basis and the pharmacological mechanism of Acanthopanax Senticosus Harms leaves by UPLC-Q-TOF-MS coupled with a target-network method.

The leaves of Acanthopanax Senticosus Harms (ASL) can be used as a food ingredient and also as raw materials for making tea and wine. As a traditional Chinese medicine (TCM), ASL has demonstrated significant effects in the treatment of ischemic stroke, but the substance basis and the pharmacological mechanism of ASL are unclear. In this study, a sensitive and rapid method was constructed for the separation and identification of the absorbed prototype components and metabolites from ASL in rat plasma and brain using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). A database of ASL active ingredients was established, which comprised 27 prototype ingredients and 20 metabolites from the rat plasma and 10 prototype ingredients and 7 metabolites from the rat brain. A comprehensive and effective target-network pharmacological method for tracing co-related targets and pathways between ASL and ischemic stroke was also set up. As a result, 34 targets and 30 pathways were obtained. TNF, NF-κB, IL-6, IL-1B, ICAM, and MMP-9 targets are all critical factors related to ischemic stroke, while the NF-κB signaling pathway, MAPK signaling pathway, TNF signaling pathway, and arachidonic acid metabolism play significant roles in the development of ischemic stroke. The visualized relationship between ASL and ischemic stroke was demonstrated by compound-target networks and compound-target-pathway networks, which revealed the therapeutic targets around the signaling pathways of ASL in the treatment of ischemic stroke. This research method will open a window for the mechanistic studies of TCM in the treatment of diseases.

Effect and Mechanism of ShiZhiFang on Uric Acid Metabolism in Hyperuricemic Rats.

OBJECTIVE: To explore the effect and mechanism of ShiZhiFang on uric acid metabolism. METHODS: 40 rats were divided into normal group, model group, ShiZhiFang group, and benzbromarone group. The hyperuricemic rat model was induced by yeast gavage at 15 g/kg and potassium oxonate intraperitoneal injection at 600 mg/kg for two weeks. During the next two weeks, ShiZhiFang group rats were given ShiZhiFang by gavage, and benzbromarone group rats were given benzbromarone by gavage. The serum uric acid, creatinine, blood urea nitrogen, XOD activity, urinary uric acid, urinary ß2-MG, and histopathological changes were observed in the rats of each group after treatment. RESULTS: The hyperuricemic model was established successfully and did not show the increase of serum creatinine and blood urea nitrogen. Compared with the model group, the serum uric acid, serum XOD activity, and urinary ß2-MG were significantly decreased (p < 0.05), and 24 h urinary uric acid excretion was significantly decreased (p < 0.01) in ShiZhiFang group, whereas the two treatment groups were of no statistical significant in above indicators (p > 0.05); renal histopathology showed that the lesions in two treatment groups were reduced compared to the model groups. The gene and protein expression of uric acid anion transporters rOAT1 and rOAT3 in the kidney was significantly higher than that in model group (p < 0.01). CONCLUSION: The model is suitable for the study of primary hyperuricemia. The mechanisms of ShiZhiFang on uric acid metabolism in hyperuricemic rats may be involved in reducing the activity of serum XOD and promoting the transcription and expression of rOAT1 and rOAT3 in the kidney.

Myosin Light Chain Kinase: A Potential Target for Treatment of Inflammatory Diseases.

Myosin light chain kinase (MLCK) induces contraction of the perijunctional apical actomyosin ring in response to phosphorylation of the myosin light chain. Abnormal expression of MLCK has been observed in respiratory diseases, pancreatitis, cardiovascular diseases, cancer, and inflammatory bowel disease. The signaling pathways involved in MLCK activation and triggering of endothelial barrier dysfunction are discussed in this review. The pharmacological effects of regulating MLCK expression by inhibitors such as ML-9, ML-7, microbial products, naturally occurring products, and microRNAs are also discussed. The influence of MLCK in inflammatory diseases starts with endothelial barrier dysfunction. The effectiveness of anti-MLCK treatment may depend on alleviation of that primary pathological mechanism. This review summarizes evidence for the potential benefits of anti-MLCK agents in the treatment of inflammatory disease and the importance of avoiding treatment-related side effects, as MLCK is widely expressed in many different tissues.