Preclinical evidence of reno-protective effect of quercetin on acute kidney injury: a meta-analysis of animal studies.

Objective: This study evaluated the reno-protective effects of quercetin in animal models of acute kidney injury (AKI). Methods: We conducted a systematic search of literature published before April 2023 in PubMed, Web of Science, and EMBASE databases. Methodological quality was assessed by SYRCLE's RoB tool. Funnel plot, Egger's test, and Begg's test were used to determine publication bias. Results: A total of 19 studies with 288 animals were included in this meta-analysis. The methodology quality scores of the included studies ranged from 4 to 7. The results indicated that quercetin reduced blood urea nitrogen (SMD = -4.78; 95% CI: 6.45, -3.12; p < 0.01; I2 = 84%) and serum creatinine (SMD: 2.73, 95% CI: 3.66, -1.80; p < 0.01; I2 = 80%) in AKI models. The result of sensitivity analysis was stable, while the results of funnel plot indicated asymmetric. In addition, we further analyzed inflammatory cytokines, oxidative stress levels, and kidney injury scores, and found that quercetin treatment had antioxidant and anti-inflammatory effects and improved kidney injury scores in animal models of AKI. Conclusion: Quercetin exhibited a promising reno-protective effect in AKI animal models. Systematic Review Registration: PROSPERO (CRD42023433333).

Effects of apolipoprotein E on regulating insulin sensitivity via regulating insulin receptor signalosome in caveolae.

AIMS: Although impaired insulin signaling at a post-receptor level was a well-established key driver of insulin resistance, the role of surface abnormal insulin receptor (INSR) location in insulin resistance pathogenesis tended to be ignored and its molecular mechanisms remained obscure. Herein, this study aimed to investigate hepatic apolipoprotein E (APOE) impaired cellular insulin action via reducing cell surface INSR, especially in caveolae. KEY FINDINGS: Downregulation of APOE enhanced the caveolae translocation of INSR and glucose transporter 2 (GLUT2), and improved hepatic cells' sensitivity to insulin. Consistently, mice with selective suppression of liver tissue APOE showed lower fasting insulin and fasting glucose levels, better homeostatic model assessment (HOMA) index (HOMA-IS, HOMA-IR, HOMA-ß) and quantitative insulin sensitivity check index (QUICKI). Furthermore, the co-localization of INSR and CAV1 in the liver of these mice were more substantial than controls. SIGNIFICANCE: APOE might adversely set the basal gain of INSR signaling implied that APOE could be a new endogenous INSR regulator.

[Microcirculation characteristics and humoral factors of healthy people from different populations at high altitude (4 100 m)].

The present study was aimed to observe the characteristics of sublingual microcirculation and the changes of humoral factors in healthy people of three different high altitude populations. Three groups of healthy subjects in Guoluo area of Qinghai province (4 100 m) were included: Tibetan group: 30 Tibetans, (45.62 ± 10.15) years old; Han group: 22 two-generation of Han immigrants, (46.23 ± 8.59) years old; migrant group: 23 migrants living at high altitude for 2-5 years, (43.45 ± 8.31) years old. Blood routine test was performed to determine white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), platelet (PLT) count, and neutrophil (NEUT) count. The changes of serum humoral factors including endothelin-1 (ET-1), CD31, CD34, CD105, vascular endothelial growth factor (VEGF), nitric oxide (NO) and noradrenaline (NE) were detected by ELISA. Continuous noninvasive hemodynamics monitor was used to continuously measure the changes of systemic circulation indexes: cardiac output (CO), cardiac index (CI), heart rate (HR), stroke volume (SV), pulse pressure variation (PPV), systemic vascular resistance index (SVRI), and mean arterial pressure (MAP). Blood oxygen was measured by pulse oximeter. Sublingual microcirculation indexes including total vascular density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV), and microvascular flow index (MFI) were determined by sidestream dark field imaging. The results showed that there were no difference in systemic circulation among the 3 groups. Compared with Tibetan group, TVD and PVD of microcirculation in Han group and migrant group were significantly increased (P < 0.05). Compared with Tibetan group and Han group, WBC, RBC, HGB and HCT of migrant group were significantly increased (P < 0.05). Compared with Han group and Migrant group, PLT of Tibetan group was significantly increased (P < 0.05). Compared with the Tibetan group, the levels of serum humoral factors CD105 and VEGF were significantly higher in the migrant group (P < 0.05), while compared with Han and migration groups, NO in Tibetan group was significantly increased (P < 0.05). It is suggested that there were significant differences in microcirculation (TVD, PVD), blood routine (WBC, RBC, HGB, HCT) and humoral factors (CD105, VEGF) among different populations in high altitude area. Importantly, the increased microcirculation, erythrocytosis and increased pro-angiogenic factors due to hypoxic environment were observed in long-term residents and migrants, except for permanent residents. These physiological changes have clinical significance in the treatment of septic shock and chronic altitude sickness for different plateau populations.

Case series of COVID-19 patients from the Qinghai-Tibetan Plateau Area in China.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a serious infection caused by the new coronavirus severe acute respiratory syndrome coronavirus 2. The disease was first identified in December 2019 and has caused significant morbidity and mortality worldwide. AIM: To explore the clinical characteristics and treatments for COVID-19 in the Qinghai-Tibetan Plateau Area in China. METHODS: We retrospectively analyzed the blood cell counts (neutrophils and lymphocytes), blood gas analysis, and thoracic computed tomography changes of patients from Qinghai Province before, during, and after treatment (January 23, 2020 to February 21, 2020). In addition, we summarized and analyzed the information of critical patients. All data were analyzed using SPSS 17.0 (SPSS Inc., Chicago, IL, United States). The quantitative and count variables are represented as the mean ± SD and n (%), respectively. RESULTS: The main symptoms and signs of patients with COVID-19 were fever, dry cough, cough with phlegm, difficulty breathing, and respiratory distress with a respiration rate ≥ 30 times/min, finger oxygen saturation ≤ 93% in the resting state, and oxygenation index less than 200 but greater than 100 (after altitude correction). Eighteen patients with COVID-19, of whom three were critical, and the others were in a mild condition, were included. The main manifestations included fever, dry cough, and fatigue. Three patients developed difficulty breathing and had a fever. They were eventually cured and discharged. Adjuvant examinations showed one case with reduced white cell count (6%) (< 4 × 109/L), six with reduced count of lymphocytes (33%) (< 0.8 × 109/L), and one with abnormal blood glucose level. All 18 patients were discharged, and no death occurred. CONCLUSION: Our findings provide critical insight into assessing the clinical diagnosis and treatment for COVID-19 in the Tibetan plateau area.

[Characteristics of circulation and microcirculation in healthy people of Han nationality at different altitudes].

Objective: To observe the circulation and microcirculation characteristics of healthy han people in Qinghai at different Guoluo (4 100 m) and Huzhu (2 600 m) and in Shanghai in plain area (4 m). Methods: The 28 healthy han people aged (45.62±10.15) from Guoluo in Qinghai, 27 healthy han people aged (47.25±8.43) from Huzhu in Qinghai and 20 healthy han people aged (43.12±8.28) from Shanghai were divided into three groups: Guoluo group (GL), Huzhu group (HZ) and Shanghai group (SH); Venous blood was collected for routine blood test: red blood cells count(RBC), hemoglobin(HGB), hematocrit(HCT), platelet(PLT); and coagulation index: prothrombin time(PT), interntionl normlized ratio(INR), fibrin(Fib), activated partial thromboplastin time (APTT), thrombin time(TT), continuous non - invasive hemodynamic monitor (CNAP) was used for continuous measurement: cardiac output (CO), heart rate (HR), stroke volume (SV), pulse pressure variation rate (PPV), systemic vascular resistance index (SVRI), mean arterial pressure (MAP); pulse oxygen monitoring instrument is used for monitoring SPO2 (pulse oxygen); the total vascular density (TVD), perfusion vascular density (PVD), proportion of perfused vascular(PPV), and microvascular flow index (MFI) of sublingual microcirculation were observed by using peripheral dark field imaging (SDF) monitoring technique. Results: Compared with the Shanghai group, the RBC and HGB levels in the Huzhu group and the Guoluo group were significantly increased (P＜0.05), while PLT levels were significantly decreased (P＜0.05); The levels of PT, Fib, APTT, TT, CO, HR, SV, MAP and SPO2 in the Huzhu group were significantly decreased (P＜0.05), while the levels of TVD, PVD, PPV and MFI were significantly increased (P＜0.05). In Guoluo group, the levels of HCT, Fib, CO, SV, PPV, MAP, TVD and PVD were significantly increased (P＜0.05), while the levels of PT, INR, TT and SPO2 were significantly decreased (P＜0.05). Compared with the Huzhu group, the levels of RBC, HGB, HCT, Fib and APTT of Guoluo group were significantly increased (P＜0.05); while the levels of SPO2, TVD, PVD, INR and TT were significantly decreased (P＜0.05). Conclusion: The microcirculation of healthy people in different altitude areas is significantly different, and the microcirculation density of healthy people in high altitude areas is significantly higher than that in plain areas, especially in moderate altitude areas. Its special physiological significance is of guiding significance for the treatment of infectious shock and chronic altitude disease in plateau areas.

Dynamic changes in peripheral blood-targeted miRNA expression profiles in patients with severe traumatic brain injury at high altitude.

BACKGROUND: The aim of this work is to detect and compare the peripheral blood miRNA expression profiles in patients with severe traumatic brain injury (sTBI) 2, 12, 24, 48, and 72 h after injury at high altitude and to predict the target genes of differential expressed miRNAs. METHODS: Twenty sTBI patients from high-altitude areas were randomly selected according to the inclusion and exclusion criteria and were divided into five groups: the 2-h group, 12-h group, 24-h group, 48-h group, and 72-h group. Peripheral blood miRNA expression profiles were detected using real-time quantitative PCR (qRT-PCR). RESULTS: The expression levels of miR-18a, miR-203, miR-146a, miR-149, miR-23b, and miR-let-7b in peripheral blood showed significant differences between the 2-h group and the 12-h group. The expression levels of miR-203, miR-146a, miR-149, miR-23b, and miR-let-7f in peripheral blood were up-regulated in the 24-h group. In the 48-h group, the expression levels of miR-181d, miR-29a, and miR-18b were upregulated. In the 72-h group, the expression levels of miR-203, miR-146a, miR-149, miR-23b, and miR-let-7f changed. The main target genes of the differentiation expressed miRNAs were genes that regulate inflammatory responses, apoptosis, and DNA damage/repair. CONCLUSIONS: miRNAs may be involved in the pathogenesis of sTBI by dynamically regulating the target genes that regulate inflammatory responses, apoptosis, and DNA damage/repair pathways.

Clinicopathological and molecular characteristics of synchronous gastric adenocarcinoma and gastrointestinal stromal tumors.

Synchronous gastric tumors that consist of both gastrointestinal stromal tumor (GIST) and adenocarcinoma are rare. We studied the clinicopathological and molecular characteristics of six cases containing both gastric adenocarcinoma and GIST. By means of immunohistochemical analysis, all GIST cells expressed CD117, CD34 and Dog1 in all six synchronous gastric adenocarcinomas with GIST, and in GIST alone. Sequencing analysis demonstrated that exon 11 c-kit mutations were present in two of six synchronous tumors and four of five GISTs. One of the two exon 11 c-kit mutations in synchronous adenocarcinomas with GISTs was an uncommon mutation of CTT > CCA at amino acid 576, and the other was a GTT deletion at amino acid 560. The mutation was a homozygous A > G mutation in exon 12 (amino acid 567) of PDGFR-α. We concluded that the exon 11 mutations were the most important in both cases of synchronous gastric adenocarcinoma with GIST and GIST alone. The mutation rate was higher in GIST alone than in synchronous adenocarcinoma with GIST.

[Effect of high altitude hypoxia on fetal development during pregnancy and the reason analysis].

High altitude hypoxia is an important factor to affect fetal development during pregnancy. In the special environment, maternal physiological functions are regulated to maintain the maternal and fetal homeostasis, so that limited oxygen is to meet the needs of fetal growth and development. In this review, the literatures about the effects of hypoxic environment on fetal development during pregnancy in recent years were summarized, in which the fetal growth characteristics, maternal physiological regulation, genetic and placental influencing factors in high altitude areas were involved. This may be helpful for the reproductive healthcare of women in high altitude region, and also for the treatment and prevention of fetal growth retardation in the hypoxic environment.

Roles of long noncoding RNAs in colorectal cancer metastasis.

Colorectal cancer (CRC) is the 3rd most common malignancies worldwide. Metastasis is responsible for more than 90% CRC patients' death. Long noncoding RNAs (lncRNAs) are an important class of transcribed RNA molecules greater than 200 nucleotides in length. With the development of whole genome sequencing technologies, they have been gained more attention. Accumulating evidences suggest that abnormal expression of lncRNAs in diverse diseases are involved in various biological functions such as proliferation, apoptosis, metastasis and differentiation by acting as epigenetic, splicing, transcriptional or post-transcriptional regulators. Aberrant expression of lncRNAs has also been found in CRC. Besides, recent studies have indicated that lncRNAs play important roles in tumourigenesis and cancer metastasis. They participate in the process of metastasis by activing or inhibiting the metastatic pathways. However, their functions on the development of cancer metastasis are poorly understood. In this review, we highlight the findings of roles for lncRNAs in CRC metastasis and review the metastatic pathways of lncRNAs leading to cancer metastasis in CRC, including escape of apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis and invasion, migration and proliferation. Furthermore, we also discuss the potential clinical application of lncRNAs in CRC as diagnostic markers and therapeutic targets.

A high mean arterial pressure target is associated with improved microcirculation in septic shock patients with previous hypertension: a prospective open label study.

INTRODUCTION: The effect of mean arterial pressure titration to a higher level on microcirculation in septic shock patients with previous hypertension remains unknown. Our goal is to assess the effect of mean arterial pressure titration to a higher level on microcirculation in hypertensive septic shock patients. METHODS: This is a single-center, open-label study. Hypertensive patients with septic shock for less than 24 hours after adequate fluid resuscitation and requiring norepinephrine to maintain a mean arterial pressure of 65 mmHg were enrolled. Mean arterial pressure was then titrated by norepinephrine from 65 mmHg to the normal level of the patient. In addition to hemodynamic variables, sublingual microcirculation was evaluated by sidestream dark field imaging. RESULTS: Nineteen patients were enrolled in the study. Increasing mean arterial pressure from 65 mmHg to normal levels was associated with increased central venous pressure (from 11 ± 4 to 13 ± 4 mmHg, P = 0.002), cardiac output (from 5.4 ± 1.4 to 6.4 ± 2.1 l/minute, P = 0.001), and central venous oxygen saturation (from 81 ± 7 to 83 ± 7%, P = 0.001). There were significant increases in small perfused vessel density (from 10.96 ± 2.98 to 11.99 ± 2.55 vessels/mm(2), P = 0.009), proportion of small perfused vessels (from 85 ± 18 to 92 ± 14%, P = 0.002), and small microvascular flow index (from 2.45 ± 0.61 to 2.80 ± 0.68, P = 0.009) when compared with a mean arterial pressure of 65 mmHg. CONCLUSIONS: Increasing mean arterial pressure from 65 mmHg to normal levels is associated with improved microcirculation in hypertensive septic shock patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01443494; registered 28 September 2011.

[Effects of early mechanical ventilation on oxygenation and hemodynamics in acute high altitude pulmonary edema patients complicated by acute respiratory distress syndrome].

OBJECTIVE: To investigate the effect of early mechanical ventilation on oxygenation and hemodynamic of acute high altitude pulmonary edema (HAPE) patients complicated by acute respiratory distress syndrome (ARDS). METHODS: From May 2001 to December 2006, 8 HAPE patients with secondary ARDS admitted to Germud City People's Hospital were enrolled in the study. All the patients received early invasive mechanical ventilation within 24 hours of HAPE. Hemodynamics, cardiac output, arterial and mixed venous blood gas and oxygen dynamics parameters were determined before and after 96 hours of mechanical ventilation. RESULTS: Before treatment the right atrial pressure (RAP), mean pulmonary artery pressure (mPAP), pulmonary vascular resistance index (PVRI) and shunt (Qs/Qt) were above normal values. Oxygen delivery (DO2), oxygen extraction rate (O2ER), and oxygenation index (PaO2/FiO2) were lower than normal values. After treatment with mechanical ventilation, arterial partial pressure of oxygen (PaO2), PaO2/FiO2, arterial oxygen saturation (SaO2), partial pressure of oxygen of mixed venous blood (PVO2) and mixed venous oxygen saturation (SVO2) were increased significantly compared with those before treatment [PaO2: 70.3±2.9 mm Hg (1 mm Hg=0.133 kPa) vs. 49.9±3.5 mm Hg, t=15.292, P=0.001; PaO2/FiO2: 201.6 ± 4.8 mm Hg vs. 134.5±5.2 mm Hg, t=19.618, P=0.004; SaO2: 0.929±0.021 vs. 0.780±0.073, t=6.226, P=0.002; PVO2: 54.8±2.9 mm Hg vs. 44.9±2.6 mm Hg, t=6.767, P=0.002; SVO2: 0.726±0.017 vs. 0.663±0.053, t=3.262, P=0.008]. Heart rate (HR), RAP, mPAP, pulmonary wedge pressure (PAWP), PVRI, right ventricular stroke work index (RVSWI) and Qs/Qt were decreased significantly compared with those before mechanical ventilation [HR: 73±2 bpm vs. 102±13 bpm, t=6.228, P=0.000; RAP: 6.9±1.0 mm Hg vs. 13.9±1.5 mm Hg, t=3.609, P=0.008; mPAP: 18.5±2.9 mm Hg vs. 41.6±3.0 mm Hg, t=4.773, P=0.000; PAWP: 6.9±2.2 mm Hg vs. 14.0±4.2 mm Hg, t=2.747, P=0.030; PVRI: 26.3±1.7 kPa×s×L(-1) vs. 49.6±10.0 kPa×s×L(-1), t=9.861, P=0.000; RVSWI: 11.0±1.9 g×cm(-1)×min×m(2) vs. 22.0±1.5 g×cm(-1)×min×m(2), t=12.704, P=0.000; Qs/Qt: (26±18)% vs. (35±15)%, t=7.603, P=0.000], and cardiac index (CI), DO2, oxygen consumption (VO2) and O2ER were also increased [CI: 71.68±6.67 mL×s(-1)×m(-2) vs. 70.01±6.67 mL×s(-1)×m(-2), t=2.832, P=0.036; DO2 (L×min(-1)×m(-2)): 460.9±14.0 vs. 410.0±3.1, t=9.268, P=0.000; VO2 (L×min(-1)×m(-2)): 158.5±9.2 vs. 129.9±5.3, t=2.818, P=0.004; O2ER: (20±1)% vs. (18±1)%, t=7.652, P=0.000]. All of the 8 patients survived. CONCLUSIONS: Pulmonary circulation hemodynamic and oxygen dynamic disorders were found in HAPE patients with secondary ARDS. Treatment with early mechanical ventilation not only improved oxygenation but also reduced pulmonary hypertension and increased cardiac output and DO2.

[Bundle program of treatment for acute severe type high altitude disease].

OBJECTIVE: To discuss Bundle treatment of the acute severe type high altitude disease. METHODS: The prospective and randomized controlled trial was conducted. Two hundred and three patients with high altitude pulmonary edema (HAPE) or high altitude cerebral edema (HACE) met inclusion criteria were included, and were randomly divided into Bundle treatment group (n = 125) and conventional treatment control group (n = 78). Critical patients with multiple organ dysfunction syndrome (MODS) were admitted to intensive care unit (ICU); with respiratory failure or serious hypoxia of the patients were given mechanical ventilation (invasive or noninvasive); fluid resuscitation and vasoactive agents were given in the unstable hemodynamics patients; diuretics and continuous veno-venous hemofiltration were given in acute renal dysfunction or failure. The gastrointestinal bleeding and blood coagulation disorders were concerned. The hospital stay time, cure rate and mortality were compared according to the stages and classification of HAPE or HACE among two groups. RESULTS: The hospital stay time was significantly decreased 1.66 days in the Bundle treatment group (days: 5.28 ± 3.17) compared with conventional treatment control group (6.94 ± 4.05, P < 0.05), the cure rate was significantly increased 7.06% (96.80% vs. 89.74%, P < 0.05), mortality of severe and fatal patients were decreased 5.59% and 31.15%, the mortality of patients in Bundle treatment group was significantly lower than conventional treatment control group (3.20% vs. 10.26%, P < 0.05). CONCLUSION: The standardized treatment which was integrated with plateau medicine and critical care medicine can effectively reduce the mortality of critical or severe patients with HAPE or HACE.