The Genetic Echo of the Tarim Mummies in Modern Central Asians.

The diversity of Central Asians has been shaped by multiple migrations and cultural diffusion. Although ancient DNA studies have revealed the demographic changes of the Central Asian since the Bronze Age, the contribution of the ancient populations to the modern Central Asian remains opaque. Herein, we performed high-coverage sequencing of 131 whole genomes of Indo-European-speaking Tajik and Turkic-speaking Kyrgyz populations to explore their genomic diversity and admixture history. By integrating the ancient DNA data, we revealed more details of the origins and admixture history of Central Asians. We found that the major ancestry of present-day Tajik populations can be traced back to the admixture of the Bronze Age Bactria-Margiana Archaeological Complex and Andronovo-related populations. Highland Tajik populations further received additional gene flow from the Tarim mummies, an isolated ancient North Eurasian-related population. The West Eurasian ancestry of Kyrgyz is mainly derived from Historical Era populations in Xinjiang of China. Furthermore, the recent admixture signals detected in both Tajik and Kyrgyz are ascribed to the expansions of Eastern Steppe nomadic pastoralists during the Historical Era.

Hematologic and spirometric characteristics of Tajik and Kyrgyz highlanders in the Pamir Mountains.

OBJECTIVES: In this study, we measured the hematologic and spirometric parameters of native Tajik and Kyrgyz highlanders in the Pamir Mountains to investigate adaptations to high altitude stressors. METHODS: Hematological parameters including arterial oxygen saturation (SaO2 ), red blood cell (RBC) counts, and hemoglobin (Hb) concentration were measured on Sarikoli Tajik (n = 80; 3100 m), Wakhi Tajik (n = 48; 3500 m), and Kyrgyz (n = 64; 3250 m) in comparison to lowland Uyghurs (n = 50; 1300 m). Spirometric parameters including forced vital capacity (FVC), the first second of forced expiration (FEV1), and forced expiratory flow between 25% and 75% (FEF25-75) were measured. We also reported mountain sickness symptoms in these highlanders and conducted a multivariate regression analysis to analyze the association between these symptoms and the measured parameters. RESULTS: SaO2 of Sarikoli Tajik, Wakhi Tajik, and Kyrgyz (91%-93.5%) are significantly lower than lowland Uyghurs, yet are comparable to other native highlanders at a similar altitude. RBC counts and Hb concentrations of all three highland populations are significantly increased compared to Uyghurs. FVC is lower in Sarikoli Tajik, Wakhi Tajik, and Kyrgyz (male: 3.48-3.86 L, female: 2.47-2.78 L) compared to Uyghurs. Combined with normal FEV1, elevated FEV1/FVC ratio, and FEF25-75, the spirometric patterns of these highlanders indicate restrictive lung disease. A high prevalence of mountain sickness symptoms such as headache and nausea was found in all three highland populations, and are attributed to low FVC and aging by regression analysis. CONCLUSION: Tajik and Kyrgyz highlanders showed adaptation in SaO2 , RBC, and Hb level, but poor performance in spirometry, which causes mountain sickness.

[Voltage-dependent potassium channel and calcium-activated potassium channel current changes of peripheral blood T-lymphocytes from hypertensive patients in Xinjiang Kazakh].

OBJECTIVE: To observe the current changes of voltage-dependent potassium channel (Kv1.3 potassium channel) and calcium-activated potassium channel (IKCa1 potassium channel) in peripheral blood T-lymphocyte derived from hypertensive patients of Xinjiang Kazakh. METHODS: Twenty randomly selected untreated Kazakh hypertensive patients and 20 Kazakh healthy subjects from Xinjiang were included in this study. T-lymphocytes were isolated from peripheral blood with magnetic cell sorting, the whole-cell currents of Kv1.3 and IKCa1 potassium channels were recorded with patch-clamp technique. RESULTS: (1) The current density of Kv1.3 potassium channel was significantly higher in the hypertensive group [(280 ± 74) pA/pF (n = 39)] than that in the control group [(179 ± 51) pA/pF (n = 38), P < 0.01], while the membrane capacitance was similar between the two groups. (2) The current density of IKCa1 potassium channel was also significantly higher in the hypertensive group [(198 ± 44) pA/pF (n = 28)] than that in the control group [(124 ± 43) pA/pF (n = 26), P < 0.01], while the membrane capacitance was also similar between the two groups. CONCLUSIONS: The T-lymphocytes Kv1.3 potassium channel and IKCa1 potassium channel current densities are higher in hypertensive patients in Xinjiang Kazakh suggesting a potential role of Kv1.3 and IKCa1 potassium channels activation in the pathophysiology of hypertension.

Corrigendum: Exploring the molecular mechanism of hepatitis virus inducing hepatocellular carcinoma by microarray data and immune infiltrates analysis.

[This corrects the article DOI: 10.3389/fimmu.2022.1032819.].

Exploring the molecular mechanism of hepatitis virus inducing hepatocellular carcinoma by microarray data and immune infiltrates analysis.

The number of new cases of hepatocellular carcinoma (HCC) worldwide reached 910,000, ranking the sixth, 80% HCC is associated with viruses, so exploring the molecular mechanism of viral carcinogenicity is imperative. The study showed that both HBV and HCV associated HCC and non-viral HCC have the same molecular phenotype (low gene expression and inhibition of immune pathways), but in the tumor immune micro-environment, there is excessive M2-type macrophage polarization in virus-associated hepatocellular carcinoma. To address this phenomenon, the data sets were analyzed and identified five hub genes (POLR2A, POLR2B, RPL5, RPS6, RPL23A) involved in viral gene expression and associated with PI3K-Akt-mTOR pathway activation by six algorithms. In addition, numerous studies have reported that M2-type macrophages participate in the hepatic fibro-pathological process of the development of HCC and are regulated by the PI3K-Akt-mTOR pathway. On this basis, the study showed that hepatitis virus causes abnormal expression of hub genes, leading to the activation of the pathway, which in turn promote the differentiation of M2-type macrophages and eventually promote the formation of liver fibrosis, leading to the occurrence of HCC. In addition, these hub genes are regulated by transcription factors and m6A enzyme, and have good prognosis and diagnostic value. With regard to drug reuse, the results suggest that patients with virus-related HCC for whom Cytidine triphosphate disodium salt and Guanosine-5'-Triphosphate are used as supplementary therapy, and may have a better prognosis. In conclusion, the study has identified novel molecules that are carcinogenic to hepatitis viruses and are expected to serve as molecular markers and targets for diagnosis and treatment.

The In Vitro Effect of Psoralen on Glioma Based on Network Pharmacology and Potential Target Research.

Glioma is an aggressive tumor, currently there is no satisfactory management available. Psoralen, as a natural product, has been found to have an effect of treating cancer in recent years, but its effect on glioma has not been explored. In this study, we investigated the in vitro inhibition effect and potential targets of psoralen on glioma through network pharmacology and in vitro glioma treatment experiments. First, we used network pharmacology to preliminarily predict the 21 core genes of psoralen in the treatment of glioma, including PIK3CA, PIK3CB, PIK3CG, and JAK2. The CCK-8 method was used to detect the effect of psoralen on the proliferation of glioma U87 and U251 cells, and the results showed that psoralen could significantly inhibit the proliferation of U87 and U251 cells. The flow cytometry was used to detect the apoptosis and cell cycle changes, and it was found that psoralen could significantly promote the early apoptosis of U87 and U251 cells and had a significant cycle arrest effect on the two cells. The cell scratch test showed that psoralen could significantly inhibit the migration of U87 and U251 cells. The relative expression levels of PIK3CA, PIK3CB, PIK3CG, and JAK2 were analyzed by Real-time Quantitative polymerase chain reaction (QT-PCR), and the results showed that psoralen could inhibit the gene expression of PIK3CA, PIK3CB, PIK3CG, and JAK2. Later, Western blotting (WB) experiments showed that psoralen could inhibit the protein expressions of PI3K and JAK2. This study has preliminarily explored and verified the antiglioma effect of psoralen in the form of inhibiting cell proliferation and migration, promoting cell apoptosis and organizing cell cycle in vitro. And may play a role by inhibiting the expression of PIK3CA, PIK3CB, PIK3CG, JAK2 gene and PI3K, JAK2 protein, psoralen has become a potential antiglioma drug.

Metabolic stress in isolated mouse ventricular myocytes leads to remodeling of t tubules.

Cardiac ventricular myocytes possess an extensive t-tubular system that facilitates the propagation of membrane potential across the cell body. It is well established that ionic currents at the restricted t-tubular space may lead to significant changes in ion concentrations, which, in turn, may affect t-tubular membrane potential. In this study, we used the whole cell patch-clamp technique to study accumulation and depletion of t-tubular potassium by measuring inward rectifier potassium tail currents (I(K1,tail)), and inward rectifier potassium current (I(K1)) "inactivation". At room temperatures and in the absence of Mg(2+) ions in pipette solution, the amplitude of I(K1,tail) measured ~10 min after the establishment of whole cell configuration was reduced by ~18%, but declined nearly twofold in the presence of 1 mM cyanide. At ~35°C I(K1,tail) was essentially preserved in intact cells, but its amplitude declined by ~85% within 5 min of cell dialysis, even in the absence of cyanide. Intracellular Mg(2+) ions played protective role at all temperatures. Decline of I(K1,tail) was accompanied by characteristic changes in its kinetics, as well as by changes in the kinetics of I(K1) inactivation, a marker of depletion of t-tubular K(+). The data point to remodeling of t tubules as the primary reason for the observed effects. Consistent with this, detubulation of myocytes using formamide-induced osmotic stress significantly reduced I(K1,tail), as well as the inactivation of inward I(K1). Overall, the data provide strong evidence that changes in t tubule volume/structure may occur on a short time scale in response to various types of stress.

[Hepatoprotective effect of Gossipium hirsutum extract on acute experimental hepatitis on rat liver injury].

OBJECTIVE: To investigate the protective effect on the mice acute experimental hepatic injury by Flos Gossypium herbaceum extracts (FGF-I, FGF-II). METHOD: Experimental hepatic injury model was established by a single intraperitoneal injection of 350 mg x kg(-1) D-CalN in Wistar rats. Serum samples for alanine aminotransferase (ALT), aspartate transferase (AST) level and liver homogenate samples for super oxide dismutase (SOD), malondialdehyde (MDA), Glutathione peroxidese (GSH-PX) activities were assayed. RESULT: For acute experimental hepatic injury, FGF-I and FGF-II significantly decrease the serum transaminase activities (P < 0.01). FGF-I increased the SOD activities (P < 0.01), and decreased MDA content only for 50 mg x kg(-1) FGF-I (P < 0.05), no effect on GSH-PX activity was found for them. FGF-II increased the SOD and GSH-PX activity (P < 0.05) with decreased MDA content (P < 0.05). CONCLUSION: FGF-I and FGF-II showed significant protective action in mice experimental hepatic injury.

Eplerenone Reverses Cardiac Fibrosis via the Suppression of Tregs by Inhibition of Kv1.3 Channel.

Background: Fibroblast proliferation is a critical feature during heart failure development. Previous studies reported regulatory T-lymphocytes (Tregs)' protective role against myocardial fibrosis. However, notably, Tregs also secrete fibrogenic cytokine TGF-ß when activated. This study aimed to clarify the intriguing link between Tregs and fibrosis, the role of Tregs Kv1.3 potassium channel (regulating T-lymphocytes activation) in the fibrosis process, and how selective aldosterone receptor antagonist Eplerenone affects Tregs and fibrosis through its action on Kv1.3 channel. Methods and Results: After co-incubation with Tregs, cardiac fibroblast proliferation (CCK-8 assay) and levels of collagen I, III, and Matrix metalloproteinase2 (ELISA) significantly elevated. Cell viability assays, Kv1.3 channel mRNA (RT-qPCR), and protein expression (In-Cell Western Blotting) revealed Tregs were activated/proliferated when co-cultured with fibroblasts. Treg intracellular TGF-ß level increased by 5.8-fold, far more than that of intracellular IL-10, extracellular TGF-ß and IL-10 (ELISA). And 30 µM eplerenone suppressed Tregs proliferation by 82.77% and furthermore, suppressed intracellular TGF-ß level to a significantly greater extent than that of intracellular IL-10, extracellular TGF-ß and IL-10. Moreover, the Kv1.3 current (whole-cell patch clamp) of Tregs in congestive heart failure patients and rats (induced by coronary artery ligation and exhaustive exercise) elevated by >4-fold than that of healthy volunteers and control rats, whereas 30 µM eplerenone suppressed the current by >60% in control Tregs. In addition, docking calculations (AutoDock software 4.0 suite) showed eplerenone has higher H-bond energy with Kv1.3 channel than other selective blockers. Conclusion: Immuno-regulation in the late stage of CHF activates Tregs proliferation via the upregulation of Kv1.3 channels, which promotes cardiac fibrosis by primarily secreting TGF-ß. Taken together, eplerenone's high affinity to Kv1.3 channel enables it to antagonize the Kv1.3 channels directly to suppress Tregs proliferation, which in turn may play an immuno-regulatory role during CHF.

Antiarthritic Activity of Qi-Wu Rheumatism Granule (a Chinese Herbal Compound) on Complete Freund's Adjuvant-Induced Arthritis in Rats.

OBJECTIVE: The aim was to study the therapeutic effects and mechanisms of QWRG on adjuvant-induced RA in rats. METHODS: The RA rat models were manipulated and subsequently divided into five experimental groups: AIA, DEX, and QWRG groups. The paw volume, body weight, arthritic score, and mechanical nociceptive threshold were assessed. The serum levels of the RF, MDA, ALP, AST, ALT, IL-1ß, IL-2, IL-16, and TNF-α were measured. The proliferative capacity of lymphocytes was evaluated, and the synovial tissue was histopathologically examined. RESULTS: The paw swelling and arthritic scores were relieved, and the variation of relative body weight and mechanical nociceptive threshold had improved in the AIA rats. The serum levels of RF, MDA, ALP, AST, and ALT were alleviated, and the inflammation and cartilage damage were effectively attenuated in the AIA rats. Simultaneously, the inflammation of the synovial cavity was alleviated, and the grading of synovitis reduced by inhibiting the expressions of IL-1ß, TNF-α, and IL-16 in the serum and synovium tissue. CONCLUSION: Our results suggested that the antiarthritic properties of QWRG may be due to immunodepression and downregulation of inflammatory cytokines, which may be a potential candidate for the treatment of RA.

Biphasic effects of haloperidol on sodium currents in guinea pig ventricular myocytes.

AIM: To study the effects of haloperidol on sodium currents (I(Na)) in guinea pig ventricular myocytes. METHOD: Whole-cell patch clamp technique was employed to evaluate the effects of haloperidol on I(Na) in individual ventricular myocytes. RESULTS: Haloperidol (0.1-3 micromol/L) inhibited I(Na) in a concentration-dependent manner with an IC50 of 0.253+/-0.015 micromol/L. The inhibition rate of haloperidol (0.3 micromol/L) on I(Na) was 22.14%+/-0.02%, and the maximum conductance was reduced. Haloperidol significantly reduced the midpoints for the activation and inactivation of I(Na) by 2.09 and 4.09 mV, respectively. The time constant of recovery was increased. The increase in time intervals could only recover by 90.14%+/-1.4% (n=6); however, haloperidol at 0.03 micromol/L enhanced I(Na) conductance. The midpoints for the activation and inactivation of I(Na) were shifted by 1.38 and 5.69 mV, respectively, at this concentration of haloperidol. CONCLUSION: Haloperidol displayed a biphasic effect on I(Na) in guinea pig cardiac myocytes. High concentrations of haloperidol inhibited I(Na), while lower concentrations of haloperidol shifted the activation and inactivation curve to the left. Full recovery of recovery curve was not achieved after 0.3 micromol/L haloperidol administration, indicating that the drug affects the inactivated state of sodium channels.

Electrophysiological effects of haloperidol on isolated rabbit Purkinje fibers and guinea pigs papillary muscles under normal and simulated ischemia.

AIM: Overdoses of haloperidol are associated with major ventricular arrhythmias, cardiac conduction block, and sudden death. The aim of this experiment was to study the effect of haloperidol on the action potentials in cardiac Purkinje fibers and papillary muscles under normal and simulated ischemia conditions in rabbits and guinea pigs. METHODS: Using the standard intracellular microelectrode technique, we examined the effects of haloperidol on the action potential parameters [action potential amplitude (APA), phase 0 maximum upstroke velocity (V(max)), action potential amplitude at 90% of repolarization (APD(90)), and effective refractory period (ERP)] in rabbit cardiac Purkinje fibers and guinea pig cardiac papillary cells, in which both tissues were under simulated ischemic conditions. RESULTS: Under ischemic conditions, different concentrations of haloperidol depressed APA and prolonged APD(90) in a concentration-dependent manner in rabbit Purkinje fibers. Haloperidol (3 micromol/L) significantly depressed APA and prolonged APD(90), and from 1 micromol/L, haloperidol showed significant depression on V(max); ERP was not significantly affected. In guinea pig cardiac papillary muscles, the thresholds of significant reduction in APA, V(max), EPR, and APD(90) were 10, 0.3, 1, and 1 mumol/L, respectively, for haloperidol. CONCLUSION: Compared with cardiac conductive tissues, papillary muscles were more sensitive to ischemic conditions. Under ischemia, haloperidol prolonged ERP and APD(90) in a concentration-dependent manner and precipitated the decrease in V(max) induced by ischemia. The shortening of ERP and APD(90) in papillary muscle action potentials may be inhibited by haloperidol.