[Effect of Nrf2/HO-1 signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis in mice].

The present study aimed to explore the effect of nuclear factor erythroid 2 related factor 2(Nrf2)/heme oxygenase-1(HO-1) signaling pathway in intestinal protection by Sishen Pills against ulcerative colitis(UC). After the UC model was induced by 3% dextran sodium sulfate(DSS), experimental animals were randomly divided into control group, model group, salazosulfapyridine(SASP) group, and low-and high-dose Sishen Pills groups. Drug intervention(ig) was performed for seven consecutive days during modeling. On the 7 th day, the mice were euthanized. The body weight and colon length were recorded, and the histopathological changes of the colon were observed by HE staining. Serum interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), total antioxidant capacity(T-AOC), malondialdehyde(MDA), and reactive oxygen species(ROS) were detected by ELISA. The protein and mRNA expression of Nrf2, HO-1, and NADPH quinine oxidoreductase-1(NQO-1) was determined by Western blot and reverse transcription-polymerase chain reaction(RT-PCR). Compared with the normal group, the model group exhibited reduced body weight, colon length, and T-AOC, increased IL-6, TNF-α, MDA, and ROS, and diminished protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. Compared with the model group, the SASP group and high-dose Sishen Pills group showed elevated body weight, colon length, and T-AOC, lowered IL-6, TNF-α, MDA, and ROS levels, and increased protein and mRNA expression of Nrf2, HO-1, and NQO-1 in the colon tissues. As assessed by HE staining, Sishen Pills could improve the pathological changes of the colon. The findings suggested that Sishen Pills could protect the colon against UC induced by 3% DSS. The specific mechanism of action may be related to the anti-inflammatory and anti-oxidative stress effects by the activation of the Nrf2/HO-1 signaling pathway.

Correction: Effect of Physician-Pharmacist Participation in the Management of Ambulatory Cancer Pain Through a Digital Health Platform: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/24555.].

Prevalence and modifiable risk factors of degenerative valvular heart disease among elderly population in southern China.

OBJECTIVE: To investigate the prevalence and modifiable risk factors of degenerative valvular heart disease (DVHD) among elderly population in southern China. METHODS: A stratified multistage sampling method was used to recruit subjects. The contents of the survey included the questionnaire, laboratory examination, echocardiography, and other auxiliary examinations. The possible risk factors of DVHD were analyzed by logistic regression analysis. RESULTS: A total of 3538 subjects ≥ 65 years of age were enrolled. One thousand three hundred and seven subjects (36.9%) were diagnosed with DVHD. Degenerative was the most common etiology of VHD. Prevalence of DVHD increased with advancing age. The prevalence of DVHD differed by living region (χ 2 = 45.594, P < 0.001), educational level ( χ 2 = 50.557, P < 0.001), and occupation ( χ 2 = 36.961, P < 0.001). Risk factors associated with DVHD included age (two-fold increased risk for each 10-year increase in age), elevated level C-reactive protein (OR = 1.346, 95% CI: 1.100-1.646), elevated level low density lipoprotein (OR = 1.243, 95% CI: 1.064-1.451), coronary artery disease (OR = 1.651, 95% CI: 1.085-2.513), smoking (OR = 1.341, 95% CI: 1.132-1.589), and hypertension (OR = 1.414, 95% CI: 1.221-1.638). Other significant risk factors included reduced or elevated level red blood cell (OR = 1.347, 95% CI: 1.031-1.761; OR = 1.599, 95% CI: 1.097-2.331; respectively), elevated level platelets (OR = 1.891, 95% CI: 1.118-3.198), elevated level uric acid (OR = 1.282, 95% CI: 1.112-1.479), and stroke (OR: 1.738, 95% CI = 1.085-2.513). CONCLUSIONS: The survey characterized the baseline conditions of DVHD cohort of elderly population in Guangzhou city. The established and emerging risk factors for DVHD may represent challenges and opportunities for therapy.

Effect of Physician-Pharmacist Participation in the Management of Ambulatory Cancer Pain Through a Digital Health Platform: Randomized Controlled Trial.

BACKGROUND: Self-management of ambulatory cancer pain is full of challenges. Motivated by the need for better pain management, we developed a WeChat-supported platform, Medication Housekeeper (MediHK), to enhance communication, optimize outcomes, and promote self-management in the home setting. OBJECTIVE: We conducted a randomized controlled trial to assess whether the joint physician-pharmacist team through MediHK would provide better self-management of ambulatory patients with cancer pain. METHODS: Patients were randomly assigned to either an intervention group or control group. During the 4-week study period, the pharmacist would send 24-hour pain diaries daily, adverse drug reaction (ADR) forms every 3 days, and the Brief Pain Inventory form every 15 days to patients in the intervention group via MediHK. If a patient needed a change in drug/dosage or treatment of an ADR after the comprehensive review, the pharmacist would propose pharmacological interventions to the attending physician, who was then responsible for prescribing or adjusting pain medications. If no adjustments were needed, the pharmacist provided appropriate targeted education based on knowledge deficits. Patients in the control group received conventional care and did not receive reminders to fill out the forms. However, if the control group patients filled out a form via MediHK, the pain management team would review and respond in the same way as for the intervention group. The primary outcomes included pain intensity and pain interference in daily life. Secondary outcomes included patient-reported outcome measures, medication adherence, ADRs, and rehospitalization rates. RESULTS: A total of 100 patients were included, with 51 (51%) in the intervention group and 49 (49%) in the control group. The worst pain scores, least pain scores, and average pain scores in the intervention group and the control group were statistically different, with median values of 4 (IQR 3-7) vs 7 (IQR 6-8; P=.001), 1 (IQR 0-2) vs 2 (IQR 1-3; P=.02), and 2 (IQR 2-4) vs 4 (IQR 3-5; P=.001), respectively, at the end of the study. The pain interference on patients' general activity, mood, relationships with others, and interests was reduced, but the difference was not statistically significant compared with the control group (Ps=.10-.76). The medication adherence rate increased from 43% to 63% in the intervention group, compared with an increase of 33% to 51% in the control group (P<.001). The overall number of ADRs increased at 4 weeks, and more ADRs were monitored in the intervention group (P=.003). Rehospitalization rates were similar between the 2 groups. CONCLUSIONS: The joint physician-pharmacist team operating through MediHK improved pain management. This study supports the feasibility of integrating the internet into the self-management of cancer pain. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900023075; https://www.chictr.org.cn/showproj.aspx?proj=36901.

A phosphatidic acid-binding lncRNA SNHG9 facilitates LATS1 liquid-liquid phase separation to promote oncogenic YAP signaling.

Long noncoding RNAs (lncRNAs) are emerging as a new class of important regulators of signal transduction in tissue homeostasis and cancer development. Liquid-liquid phase separation (LLPS) occurs in a wide range of biological processes, while its role in signal transduction remains largely undeciphered. In this study, we uncovered a lipid-associated lncRNA, small nucleolar RNA host gene 9 (SNHG9) as a tumor-promoting lncRNA driving liquid droplet formation of Large Tumor Suppressor Kinase 1 (LATS1) and inhibiting the Hippo pathway. Mechanistically, SNHG9 and its associated phosphatidic acids (PA) interact with the C-terminal domain of LATS1, promoting LATS1 phase separation and inhibiting LATS1-mediated YAP phosphorylation. Loss of SNHG9 suppresses xenograft breast tumor growth. Clinically, expression of SNHG9 positively correlates with YAP activity and breast cancer progression. Taken together, our results uncover a novel regulatory role of a tumor-promoting lncRNA (i.e., SNHG9) in signal transduction and cancer development by facilitating the LLPS of a signaling kinase (i.e., LATS1).

Development of a novel 7 immune-related genes prognostic model for oral cancer: A study based on TCGA database.

Oral squamous cell carcinoma (OSCC) is an aggressive tumor whose prognosis has little improvement in the last three decades. Various immune-related genes have been suggested as significant roles in the development and progression of malignant cancers. In this study, we acquired and integrated differentially expressed genes of OSCC patients, including immune-related genes and transcription factors (TFs), from The Cancer Genome Atlas (TCGA) database. TF-mediated network was established to exploring the regulatory mechanisms of prognostic immune-related genes. A 7 immune-related genes prognostic model for OSCC was obtained, including CGB8, CTLA4, TNFRSF19, CCL26, NRG1, TPM2 and PLAU, which was further proved to be an independent prognostic indicator after adjusting for other clinical factors. The immune-related genes prognostic index was significantly negatively correlated to the infiltration abundances of B cells (P < 0.05) and CD8+ T cells (P < 0.05). The novel proposed immune-based prognostic model not only provided a promising biomarker and a way to monitor the long-term treatment of OSCC, but also gave a new insight into a potential immunotherapy strategy.

High hydrostatic pressure induces atrial electrical remodeling through angiotensin upregulation mediating FAK/Src pathway activation.

Hypertension is an independent risk factor for atrial fibrillation (AF), although its specific mechanisms remain unclear. Previous research has been focused on cyclic stretch, ignoring the role of high hydrostatic pressure. The present study aimed to explore the effect of high hydrostatic pressure stimulation on electrical remodeling in atrial myocytes and its potential signaling pathways. Experiments were performed on left atrial appendages from patients with chronic AF or sinus rhythm, spontaneously hypertensive rats (SHRs) treated with or without valsartan (10 mg/kg/day) and HL-1 cells were exposed to high hydrostatic pressure using a self-developed device. Whole-cell patch-clamp recordings and western blots demonstrated that the amplitudes of ICa,L, Ito, and IKur were reduced in AF patients with corresponding changes in protein expression. Angiotensin protein levels increased and Ang1-7 decreased, while focal adhesion kinase (FAK) and Src kinase were enhanced in atrial tissue from AF patients and SHRs. After rapid atrial pacing, AF inducibility in SHR was significantly higher, accompanied by a decrease in ICa,L, upregulation of Ito and IKur, and a shortened action potential duration. Angiotensin upregulation and FAK/Src activation in SHR were inhibited by angiotensin type 1 receptor inhibitor valsartan, thus, preventing electrical remodeling and reducing AF susceptibility. These results were verified in HL-1 cells treated with high hydrostatic pressure, and demonstrated that electrical remodeling regulated by the FAK-Src pathway could be modulated by valsartan. The present study indicated that high hydrostatic pressure stimulation increases AF susceptibility by activating the renin-angiotensin system and FAK-Src pathway in atrial myocytes.

High hydrostatic pressure induces atrial electrical remodeling through upregulation of inflammatory cytokines.

AIMS: Hypertension is an independent risk factor for atrial fibrillation (AF). However, the direct effect of hydrostatic pressure on atrial electrical remodeling is unclear. The present study investigated whether hydrostatic pressure is responsible for atrial electrical remodeling and addressed a potential role of inflammation in this pathology. MAIN METHODS: Whole-cell patch-clamp recordings and biochemical assays were used to study the regulation and expression of ion channels in left atrial appendages in patients with AF, spontaneously hypertensive rats (SHRs), and atrium-derived cells (HL-1 cells) exposed to standard (0 mmHg) and elevated (20, 40 mmHg) hydrostatic pressure. KEY FINDINGS: Both TNF-α and MIF were highly expressed in patients with AF and SHRs. AF inducibility in SHRs was higher after atrial burst pacing, accompanied by a decrease in the L-type calcium current (ICa,L), an increase in the transient outward K+ current (Ito) and ultra-rapid delayed rectifier K+ current (IKur), and a shortened action potential duration (APD), which could be inhibited by atorvastatin. Furthermore, exposure to elevated pressure was associated with electrical remodeling of the HL-1 cells. The peak current density of ICa,L was reduced, while Ito and IKur were increased. Moreover, the expression levels of Kv4.3, Kv1.5, TNF-α, and MIF were upregulated, while the expression of Cav1.2 was downregulated in HL-1 cells after treatment with high hydrostatic pressure (40 mmHg). Atorvastatin alleviated the electrical remodeling and increased inflammatory markers in HL-1 cells induced by high hydrostatic pressure. SIGNIFICANCE: Elevated hydrostatic pressure led to atrial electrical remodeling and increased AF susceptibility by upregulating inflammation.

Characteristics, Mechanism and Long-Term Ablation Outcome of Atrial Tachycardias After Mitral Valvular Surgery and Concomitant Cox-MAZE IV Procedure.

The incidence of atrial tachycardia (AT) after rheumatic mitral valvular (RMV) surgery has been well described. However, there have been few reports on the characteristics, mechanism, and long-term ablation outcome of ATs after RMV surgery and concomitant Cox-MAZE IV procedure.The present study reviewed consecutive patients who underwent AT ablation between May 2008 and July 2013. All patients were refractory to antiarrhythmic drugs (AADs) and had a history of RMV surgery and Cox-MAZE IV procedure. A total of 34 patients underwent AT ablation after RMV surgery and concomitant Cox-MAZE IV procedure, and presented 57 mappable and 2 unmappable ATs. The 57 mappable ATs included 14 focal-ATs and 43 reentry-ATs. Ten of the 14 focal-like ATs were located at the pulmonary vein (PV) antrum and border of a box lesion. Of the 43 reentry-ATs, 16 were marco-reentrant around the mitral annulus (MA) and 16 around the tricuspid annulus. There were 41 atypical ATs (non-cavotricuspid isthmus related) including 16 ATs related to the box lesion and 21 ATs related to other Cox-MAZE IV lesions. The AT were successfully terminated in 33 (97.1%) patients. After mean follow-up of 46.9 ± 15.7 months, 25 (73.5%) patients maintained sinus rhythm without AADs after a single procedure and 28 (82.4%) patients after repeated procedures.The recurrent ATs after RMV surgery and concomitant Cox-MAZE IV were mainly reentry mechanism, and largely related to LA. An incomplete lesion or re-conductive gaps in a prior lesion might be the predominant mechanisms for these ATs. Catheter-based mapping and ablation of these ATs seems to be effective and safe during a long-term follow-up.

Electrocardiographic conduction and repolarization markers associated with sudden cardiac death: moving along the electrocardiography waveform.

The QT interval along with its heart rate corrected form (QTc) are well-established ECG markers that have been found to be associated with malignant ventricular arrhythmogenesis. However, extensive preclinical and clinical investigations over the years have allowed for novel clinical ECG markers to be generated as predictors of arrhythmogenesis and sudden cardiac death. Repolarization markers include the older QTc, QT dispersion and newer Tpeak - Tend intervals, (Tpeak - Tend) / QT ratios, T-wave alternans (TWA), microvolt TWA and T-wave area dispersion. Meanwhile, conduction markers dissecting the QRS complex, such as QRS dispersion (QRSD) and fragmented QRS, were also found to correlate conduction velocity and unidirectional block with re-entrant substrates in various cardiac conditions. Both repolarization and conduction parameters can be combined into the excitation wavelength (λ). A surrogate marker for λ is the index of Cardiac Electrophysiological Balance (iCEB: QT / QRSd). Other markers based on conduction-repolarization are [QRSD x (Tpeak-Tend) / QRSd] and [QRSD x (Tpeak-Tend) / (QRSd x QT)]. Advancement in technology permitted sophisticated electrophysiological analyses such as principal component analysis and periodic repolarization dynamics to further improve risk stratification. This was closely followed by other novel indices including ventricular ectopic QRS interval, the f99 index and EntropyXQT, which integrates mathematical and physical calculations for determining the risk markers. Though proven to be effective in limited patient cohorts, more clinical studies across different cardiac pathologies are required to confirm their validity. As such, this review seeks to encapsulate the development of old and new ECG markers along with their associated utility and shortcomings in clinical practice.

Association between thyroglobulin polymorphisms and autoimmune thyroid disease: a systematic review and meta-analysis of case-control studies.

Emerging evidence revealed that thyroglobulin (TG) contributes to the development of autoimmune disease, and the relationship between TG and autoimmune thyroid disease (AITD) is still controversial. The aim of this study was to quantify the association between rs2076740, rs853326, rs180223, and rs2069550 TG polymorphisms and risk of AITD using a meta-analysis approach. We identified all studies that assessed the association between TG polymorphisms and AITD from PubMed, Embase, and Web of Science databases. A total of 3013 cases and 1812 controls from ten case-control studies were included. There was no significant associations found between rs2069550, rs180223, and rs853326 polymorphisms and AITD risk. The association between the rs2076740 polymorphism and AITD risk was significant in the codominant model (P = 0.005), suggesting the CC rs2076740 genotype might be a protective factor for AITD. Sensitivity analysis by removing one or two study changed the results in dominant rs2076740 and rs853326 and rs2069550 allele models (P = 0.016, 0.024, 0.027). Latitude and ethnicity significantly affected the association between rs2076740 and rs2069550 polymorphisms and AITD, indicating their protective effects in allele or dominant model (P = 0.012, 0.012, 0.012, 0.009, 0.009). The association between rs2076740, rs2069550, and rs853326 polymorphisms and AITD risk is significantly affected by study characteristics.

Matrine promotes oligodendrocyte development in CNS autoimmunity through the PI3K/Akt signaling pathway.

AIMS: Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae flavescens, has been recently found to be beneficial in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, mainly through its anti-inflammatory effect. In the present study, we tested the effect of MAT on ongoing EAE and defined possible mechanisms underlying its effects on myelination and oligodendrocytes. MAIN METHODS: EAE was induced in C57BL/6 mice and MAT treatment was started at disease onset. Clinical scores were monitored daily; spinal cords and the corpus callosum brain region of mice were harvested on day 23 p.i. for inflammatory infiltration and demyelination of the central nervous system. Myelin content and the development of oligodendrocytes and their precursors were determined by immunostaining, and expression of p-Akt, p-mTOR, p-PI3K, and p-P70S6 was determined by Western blot. KEY FINDINGS: MAT effectively suppressed EAE severity and increased the expression of proteolipid protein, a myelin protein that is a marker of CNS myelin. MAT treatment largely increased the number of mature oligodendrocytes, and significantly activated the PI3K/Akt/mTOR signaling pathway, which is required for oligodendrocyte survival and axon myelination. SIGNIFICANCE: These findings demonstrate a beneficial effect of MAT on oligodendrocyte differentiation and myelination during EAE, most likely through activating the PI3K/Akt/mTOR signaling pathway.

Role of tumour necrosis factor-a in the regulation of T-type calcium channel current in HL-1 cells.

Increasing evidence indicates that inflammation contributes to the initiation and perpetuation of atrial fibrillation (AF). Although tumour necrosis factor (TNF)-α levels are increased in patients with AF, the role of TNF-α in the pathogenesis of AF remains unclear. Besides L-type Ca(2+) currents (IC a,L ), T-type Ca(2+) currents (IC a,T ) also plays an important role in the pathogenesis of AF. This study was designed to use the whole-cell voltage-clamp technique and biochemical assays to explore if TNF-α is involved in the pathogenesis of AF through regulating IC a,T in atrial myocytes. It was found that compared with sinus rhythm (SR) controls, T-type calcium channel (TCC) subunit mRNA levels were decreased, while TNF-α expression levels were increased, in human atrial tissue from patients with AF. In murine atrial myocyte HL-1 cells, after culturing for 24 h, 12.5, 25 and 50 ng/mL TNF-α significantly reduced the protein expression levels of the TCC α1G subunit in a concentration-dependent manner. The peak current was reduced by the application of 12.5 or 25 ng/mL TNF-α in a concentration-dependent manner (from -15.08 ± 1.11 pA/pF in controls to -11.89 ± 0.83 pA/pF and -8.54 ± 1.55 pA/pF in 12.5 or 25 ng/mL TNF-α group respectively). TNF-α application also inhibited voltage-dependent inactivation of IC a,T, shifted the inactivation curve to the left. These results suggest that TNF-α is involved in the pathogenesis of AF, probably via decreasing IC a,T current density in atrium-derived myocytes through impaired channel function and down-regulation of channel protein expression. This pathway thus represents a potential pathogenic mechanism in AF.

Five-year epidemiological survey of valvular heart disease: changes in morbidity, etiological spectrum and management in a cardiovascular center of Southern China.

OBJECTIVE: The objective of the present study is to analyze the epidemiological profile of patients with abnormal valvular structure and function and highlight the etiological spectrum and management of valvular heart disease (VHD) in a single cardiovascular center of Southern China in five years. METHODS: The retrospective study included 19,428 consecutive patients (9,441 men and 9,987 women with a mean age of 52.03±20.50 years) with abnormal valvular structure and function who were screened by transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE) at the in-patient department of Guangdong General Hospital from January 2009 to December 2013. Data on baseline characteristics, potential etiology, treatment strategies and discharge outcomes were collected from electronic medical records. RESULTS: There were 13,549 (69.7%) patients with relatively definite etiology for VHD. VHD was rheumatic in 7,197 (37.0%) patients, congenital in 2,697 (13.9%), degenerative in 2,241 (11.5%), ischemic in 2,460 (12.7%). The prevalence decreased significantly in rheumatic VHD from 2009 to 2013 (from 42.8% to 32.8%, P<0.001), but increased markedly in congenital VHD (from 9.0% to 12.3%, P<0.001), ischemic VHD (from 9.2% to 11.3%, P=0.003) and degenerative VHD (from 8.8% to 14.5%, P<0.001). Meantime, the prevalence of ischemic VHD increased after the age of 45, similar to that of degenerative VHD. From 2009 to 2013, the proportion of patients with VHD undergoing open cardiac valvular surgery decreased (from 49.5% to 44.3%, P<0.001) and that of patients treated with general medication increased (from 49.2% to 54.1%, P<0.001). However, there was markedly increment in video-assisted thoracoscopic surgery (VATS) from 2009 to 2013 (from 0.3% to 4.4%, P<0.001). Increasing tendencies were showed in aortic mechanical valve replacement (from 32.1% to 34.5%, P=0.001) and double mechanical valve replacement (from 20.9% to 22.3%, P=0.035), especially in mitral valvuloplasty (from 8.5% to 15.7%, P<0.001). However, the proportion of patients undergoing bioprosthetic valve replacement decreased from 2009 to 2013 (from 26.3% to 15.5%, P<0.001). CONCLUSIONS: Despite a significant shift from rheumatic towards degenerative etiology from 2009 to 2013, rheumatic VHD remains the leading etiology in Southern China, with a significant increase in the prevalence of ischemic, congenital and degenerative VHD. General medication and cardiac valvular surgery remain the main treatment options. The proportion of VATS increased markedly from 2009 to 2013, and mechanical valve replacement and mitral valvuloplasty showed an increasing tendency.

[Clinical features of parathyroid space-occupying lesions].

OBJECTIVE: To investigate the clinical manifestation, diagnosis, treatment of parathyroid occupying lesions. METHODS: The clinical data of 42 patients with parathyroid occupying lesions were retrospectively analyzed, including the clinical symptoms and signs, laboratory results, pathologic and imaging results and treatment. RESULTS: The number of males and females were 8 and 34, with females: males ratio being 1:5.25. The median age was 39 years. There were 2 cases of parathyroid cancer, 29 cases of parathyroid adenoma, 11 cases of parathyroid cysts in this study. The symptoms were as follows: 40 cases of neck lump, 34 cases of osteoporosis/osteitis fibrosa cystica, 29 cases of urinary symptom, 7 cases of voice hoarseness, 4 cases of peptic ulcer, 3 cases of dyspnoea and dysphagia, 3 cases of thoracic cavity lump, 2 cases of enhanced amylase activity. Serum calcium ion level and serum parathyroid hormone (PTH) level were examined qualitatively before operation. Ultrasonography, ECT-99mTc-MIBI, CT, MRI were used in diagnosing and locating parathyroid occupying lesions before operation. Twenty nine cases of parathyroid adenoma were treated with operation, 28 patients achieved complete remission, 1 suffered relapse after 23 months postoperative follow up. Eleven cases of parathyroid cysts were treated with operation and the outcome was no recurrence. Two cases of parathyroid cancer survived with out recurrence during follow up for 28 months and 50 months after operation. CONCLUSIONS: Examination of serum calcium and PTH level together with ultrasonography, ECT-99mTc-MIBI, CT, MRI is helpful to diagnose parathyroid occupying lesions. Surgery should be done as primary treatment. Tumor resection can be performed for parathyroid cysts, intraoperative exploration of bilateral neck is indicated for parathyroid adenoma, and a radical resection should be performed primarily for the parathyroid cancer.