Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial.

Importance: Previous research has suggested that Xuebijing injection (XBJ), an herbal-based intravenous preparation, may reduce mortality among patients with sepsis. Objective: To determine the effect of XBJ vs placebo on 28-day mortality among patients with sepsis. Design, Setting, and Participants: The Efficacy of Xuebijing Injection in Patients With Sepsis (EXIT-SEP) trial was a multicenter, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites and included 1817 randomized patients with sepsis (sepsis 3.0) present for less than 48 hours. Patients aged 18 to 75 years with a Sequential Organ Failure Assessment score of 2 to 13 were enrolled. The study was conducted from October 2017 to June 2019. The final date of follow-up was July 26, 2019. Data analysis was performed from January 2020 to August 2022. Interventions: The patients were randomized to receive either intravenous infusion of XBJ (100 mL, n = 911) or volume-matched saline placebo (n = 906) every 12 hours for 5 days. Main Outcomes and Measures: The primary outcome was 28-day mortality. Results: Among the 1817 patients who were randomized (mean [SD] age, 56.5 [13.5] years; 1199 [66.0%] men), 1760 (96.9%) completed the trial. In these patients, the 28-day mortality rate was significantly different between the placebo group and the XBJ group (230 of 882 patients [26.1%] vs 165 of 878 patients [18.8%], respectively; P < .001). The absolute risk difference was 7.3 (95% CI, 3.4-11.2) percentage points. The incidence of adverse events was 222 of 878 patients (25.3%) in the placebo group and 200 of 872 patients (22.9%) in the XBJ group. Conclusions and Relevance: In this randomized clinical trial among patients with sepsis, the administration of XBJ reduced 28-day mortality compared with placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT03238742.

Effects of a low-sodium diet in patients with idiopathic hyperaldosteronism: a randomized controlled trial.

Background: Idiopathic hyperaldosteronism (IHA) is one of the most common types of primary aldosteronism (PA), an important cause of hypertension. Although high dietary sodium is a major risk factor for hypertension, there is no consensus on the recommended dietary sodium intake for IHA. Objective: This study investigated the effect of a low-sodium diet on hemodynamic variables and relevant disease biomarkers in IHA patients, with the aim of providing a useful reference for clinical treatment. Methods: Fifty IHA patients were evenly randomized into two groups and provided, after a 7-day run-in period (100 mmol/d sodium), either a low-sodium diet (50 mmol/d sodium) or a normal sodium diet (100 mmol/d sodium) for an additional 7 days. After the 14-day intervention (conducted without potassium supplementation), changes in blood pressure (BP) and serum potassium were evaluated in both groups. Results: After the dietary intervention, the low sodium group exhibited, compared to the normal sodium group, decreased BP (SBP: 121.8 ± 12.8 vs. 129.9 ± 12.1 mmHg, p < 0.05; DBP: 82.6 ± 7.6 vs. 86.4 ± 8.2 mmHg, p < 0.05; MAP: 95.7 ± 8.8 vs. 100.9 ± 8.4 mmHg, p < 0.05) and increased serum potassium levels (3.38 ± 0.33 vs. 3.07 ± 0.27 mmol/L, p < 0.001). The low sodium group showed also better control of both BP and serum potassium: BP <140/90 mmHg in 70.0% of total patients (76.0% vs. 64.0%, in the low and normal sodium groups, respectively; p > 0.05), BP <130/85 mmHg in 38.0% of total patients (56.0% vs. 20.0%, p < 0.05), BP <120/80 mmHg in 28.0% of total patients (44.0% vs. 12.0%, p < 0.05); serum potassium ≥3.5 mmol/L in 22.0% of total patients (32.0% vs. 12.0% in the low and normal sodium groups, respectively; p = 0.088). There were differences between the controlled BP group (<120/80 mmHg) and the non-controlled BP group (≥120/80 mmHg) in gender, BP at baseline, and type of diet (low vs. normal sodium). Female gender and low-sodium diet were protective factors for BP control. Conclusions: A low-sodium diet is effective in lowering BP and elevating serum potassium in IHA patients. Female patients on a low-sodium diet are more likely to achieve BP control (<120/80 mmHg). We advocate a dietary sodium intake of 50 mmol/d for IHA patients. Clinical trial registration: https://clinicaltrials.gov, Identifier NCT05649631.

Facet Dependence of Biosynthesis of Vivianite from Iron Oxides by Geobacter sulfurreducens.

Vivianite plays an important role in alleviating the phosphorus crisis and phosphorus pollution. The dissimilatory iron reduction has been found to trigger the biosynthesis of vivianite in soil environments, but the mechanism behind this remains largely unexplored. Herein, by regulating the crystal surfaces of iron oxides, we explored the influence of different crystal surface structures on the synthesis of vivianite driven by microbial dissimilatory iron reduction. The results showed that different crystal faces significantly affect the reduction and dissolution of iron oxides by microorganisms and the subsequent formation of vivianite. In general, goethite is more easily reduced by Geobacter sulfurreducens than hematite. Compared with Hem_{100} and Goe_L{110}, Hem_{001} and Goe_H{110} have higher initial reduction rates (approximately 2.25 and 1.5 times, respectively) and final Fe(II) content (approximately 1.56 and 1.20 times, respectively). In addition, in the presence of sufficient PO43-, Fe(II) combined to produce phosphorus crystal products. The final phosphorus recoveries of Hem_{001} and Goe_H{110} systems were about 5.2 and 13.6%, which were 1.3 and 1.6 times of those of Hem_{100} and Goe_L{110}, respectively. Material characterization analyses indicated that these phosphorous crystal products are vivianite and that different iron oxide crystal surfaces significantly affected the size of the vivianite crystals. This study demonstrates that different crystal faces can affect the biological reduction dissolution of iron oxides and the secondary biological mineralization process driven by dissimilatory iron reduction.

Surfactant-sodium dodecyl sulfate enhanced degradation of polystyrene microplastics with an energy-saving electrochemical advanced oxidation process (EAOP) strategy.

Microplastics have been identified as a kind of emerging pollutant with potential ecological risks, and it is an urgent endeavor to find proper technologies for their remediation. Electrochemical advanced oxidation process (EAOP) technology has exhibited robust performance in the removal of various refractory organic pollutants. In this study, we explored a new remediation strategy for polystyrene microplastics (PS MPs), introducing sodium dodecyl sulfate (SDS) to enhance its degradation performance in boron-doped diamond (BDD) anode adopted EAOP. At first, we investigated the degradation behaviors of SDS in the BDD electrolysis. According to the SDS half-life under various current densities, the SDS addition strategy into EAOP is proposed; that is, supplement SDS to 500 mg/L at every half-life during electrolysis except the last cycle. Results indicated that SDS addition greatly enhanced MPs degradation rate in 72 h of EAOP, about 1.35-2.29 times higher than that in BDD electrolysis alone. The SDS assisted EAOP also led to more obvious changes in the particle size, morphology, and functional groups of the MPs. After treatment, a variety of alkyl-cleavage and oxidation products were identified, which attributed to the strong attack of oxidants (i.e., persulfate) on the MPs. The enhanced persulfate generation and oxidants adsorption on MPs can explain the enhancement effect in the EAOP strategy. Cost analysis results showed the surfactant only accounts for < 0.05% of the total operating costs in the SDS assisted EAOP. In general, the current study provided new insight into the effective way to improve the EAOP efficiency of microplastics.

Magnolol effectively ameliorates diabetic peripheral neuropathy in mice.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking efficient treatment. Magnolol (MG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is a natural product derived from Magnolia officinalis and widely used to treat a variety of diseases as a traditional Chinese medicine and Japanese Kampo medicine. PURPOSE: Here, we aimed to investigate the potential of MG in ameliorating DPN-like pathology in mice and decipher the mechanism of MG in treating DPN. MATERIALS AND METHODS: 12-week-old male streptozotocin (STZ)-induced type 1 diabetic (T1DM) mice and 15-week-old male BKS Cg-m+/+Lepr db/J (db/db) type 2 diabetic mice (T2DM) were used as DPN mice. MG was administrated (i.p) daily for 4 weeks. Peripheral nerve functions of mice were evaluated by measuring mechanical response latency, thermal response latency and motor nerve conduction velocity (MNCV). The mechanisms underlying the amelioration of MG on DPN-like pathology were examined by qRT-PCR, western blot and immunohistochemistry assays, and verified in the DPN mice with PPARγ-specific knockdown in dorsal root ganglia (DRG) neuron and sciatic nerve tissues by injecting adeno-associated virus (AAV)8-PPARγ-RNAi. RESULTS: MG promoted DRG neuronal neurite outgrowth and effectively ameliorated neurological dysfunctions in both T1DM and T2DM diabetic mice, including improvement of paw withdrawal threshold, thermal response latency and MNCV. Additionally, MG promoted neurite outgrowth of DRG neurons, protected sciatic nerve myelin sheath structure, and ameliorated foot skin intraepidermal nerve fiber (IENF) density in DPN mice by targeting PPARγ. Mechanism research results indicated that MG improved mitochondrial dysfunction involving PPARγ/MKP-7/JNK/SIRT1/LKB1/AMPK/PGC-1α pathway in DRG neurons, repressed inflammation via PPARγ/NF-κB signaling and inhibited apoptosis through regulation of PPARγ-mediated Bcl-2 family proteins in DRG neurons and sciatic nerves. CONCLUSIONS: Our work has detailed the mechanism underlying the amelioration of PPARγ agonist on DPN-like pathology in mice with MG as a probe, and highlighted the potential of MG in the treatment of DPN.

Scutellarin acts on the AR-NOX axis to remediate oxidative stress injury in a mouse model of cerebral ischemia/reperfusion injury.

BACKGROUND: Oxidative stress plays an important role in the pathology of ischemic stroke. Studies have confirmedthat scutellarin has antioxidant effects against ischemic injury, and we also reported that the involvement of Aldose reductase (AR) in oxidative stress and cerebral ischemic injury, in this study we furtherly explicit whether the antioxidant effect of scutellarin on cerebral ischemia injury is related to AR gene regulation and its specific mechanism. METHODS: C57BL/6N mice (Wild-type, WT) and AR knockout (AR-/-) mice suffered from transient middle cerebral artery occlusion (tMCAO) injury (1 h occlusion followed by 3 days reperfusion), and scutellarin was administered from 2 h before surgery to 3 days after surgery. Subsequently, neurological function was assessed by the modified Longa score method, the histopathological morphology observed with 2,3,5-triphenyltetrazolium chloride (TTC) and hematoxylin-eosin (HE) staining. Enzyme-linked immunosorbent assay (Elisa) was used to detect the levels of ROS, 4-hydroxynonenal (4-HNE), 8-hydroxydeoxyguanosine (8-OHDG), Neurotrophin-3 (NT-3), poly ADP-ribose polymerase-1 (PARP1) and 3-nitrotyrosine (3-NT) in the ischemic penumbra regions. Quantitative proteomics profiling using quantitative nano-HPLC-MS/MS were performed to compare the protein expression difference between AR-/- and WT mice with or without tMCAO injury. The expression of AR, nicotinamide adenine dinucleotide phosphate oxidases (NOX1, NOX2 and NOX4) in the ipsilateral side of ischemic brain were detected by qRT-PCR, Western blot and immunofluorescence co-staining with NeuN. RESULTS: Scutellarin treatment alleviated brain damage in tMCAO stroke model such as improved neurological function deficit, brain infarct area and neuronal injury and reduced the expression of oxidation-related products, moreover, also down-regulated tMCAO induced AR mRNA and protein expression. In addition, the therapeutic effect of scutellarin on the reduction of cerebral infarction area and neurological function deficits abolished in AR-/- mice under ischemia cerebral injury, which indicated that the effect of scutellarin treatment on tMCAO injury is through regulating AR gene. Proteomic analysis of AR-/- and WT mice indicated AR knockout would affect oxidation reaction even as NADPH related process and activity in mice under cerebral ischemia conditions. Moreover, NOX isoforms (NOX1, NOX2 and NOX4) mRNA and protein expression were significant decreased in neurons of penumbra region in AR-/- mice compared with that in WT mice at 3d after tMCAO injury, which indicated that AR should be the upstream protein regulating NOX after cerebral ischemia. CONCLUSIONS: We first reported that AR directly regulates NOX subtypes (not only NOX2 but also NOX1 and NOX4) after cerebral ischaemic injury. Scutellarin specifically targets the AR-NOX axis and has antioxidant effects in mice with cerebral ischaemic injury, providing a theoretical basis and accurate molecular targets for the clinical application of scutellarin.

Network pharmacology to unveil the mechanism of Moluodan in the treatment of chronic atrophic gastritis.

BACKGROUND: Moluodan (MLD) is a traditional Chinese patent medicine for the treatment of chronic atrophic gastritis (CAG). However, the mechanism of action (MoA) of MLD for treating CAG still remain unclear. PURPOSE: Elucidate the MoA of MLD for treating CAG based on network pharmacology. STUDY DESIGN: Integrate computational prediction and experimental validation based on network pharmacology. METHODS: Computationally, compounds of MLD were scanned by LC-MS/MS and the target profiles of compounds were identified based on network-based target prediction method. Compounds in MLD were compared with western drugs used for gastritis by hierarchical clustering of target profile. Key biological functional modules of MLD were analyzed, and herb-biological functional module network was constructed to elucidate combinatorial rules of MLD herbs for CAG. Experimentally, MLD's effect on different biological functional modules were validated from both phenotypic level and molecular level in 1- Methyl-3-nitro-1-nitrosoguanidine (MNNG)-induced GES-1 cells. RESULTS: Computational results show that the target profiles of compounds in MLD can cover most of the biomolecules reported in literature. The MoA of MLD can cover most types of MoA of western drugs for CAG. The treatment of CAG by MLD involved the regulation of various biological functional modules, e.g., inflammation/immune, cell proliferation, cell apoptosis, cell differentiation, digestion and metabolism. Experimental results show that MLD can inhibit cell proliferation, promote cell apoptosis and differentiation, reduce the inflammation level and promote lipid droplet accumulation in MNNG-induced GES-1 cells. CONCLUSION: The network pharmacology framework integrating computational prediction and experimental validation provides a novel way for exploring the MoA of MLD.

Intelligent Bimetallic Nanoagents as Reactive Oxygen Species Initiator System for Effective Combination Phototherapy.

Phototherapy is a promising oncotherapy method. However, there are various factors greatly restricted phototherapy development, including poor tumor-specific accumulation, the hypoxia in solid tumor, and the systemic phototoxicity of photosensitizer. Herein, a tumor microenvironment (TME)-responsive intelligent bimetallic nanoagents (HSA-Pd-Fe-Ce6 NAs) composed of human serum albumin (HSA), palladium-iron (Pd-Fe) bimetallic particles, and chlorin e6 (Ce6) was designed for effective combination phototherapy. The Pd-Fe part in the HSA-Pd-Fe-Ce6 NAs would react with the endogenous hydrogen peroxide (H2O2) in an acidic ambiance within tumor to generate cytotoxic superoxide anion free radical through the "Fenton-like reaction." H2O2, coupled with highly toxic singlet oxygen (1O2) caused by the Ce6 component under the irradiation of 660 nm laser, resulted in synergistic cancer therapy effects in hypoxia surroundings. Besides, this nanoagents could result in hyperpyrexia-induced cell apoptosis because of superior absorption performance in near-infrared wavelength window bringing about excellent photothermal conversion efficiency. The cell cytotoxicity results showed that the survival rate after treated by 40 µg mL-1 nanoagents was only 17%, which reveals that the HSA-Pd-Fe-Ce6 NAs had the advantage of efficient and controllable phototherapy. In short, it exhibited excellent hypoxia-resistant combination phototherapy efficacy in vitro. Therefore, the multifunctional nanoagents are powerful and provide a new avenue for effective combination phototherapy.

Dye-Anchored MnO Nanoparticles Targeting Tumor and Inducing Enhanced Phototherapy Effect via Mitochondria-Mediated Pathway.

Phototherapy is a promising treatment method for cancer therapy. However, the various factors have greatly restricted phototherapy development, including the poor accumulation of photosensitizer in tumor, hypoxia in solid tumor tissue and systemic phototoxicity. Herein, a mitochondrial-targeted multifunctional dye-anchored manganese oxide nanoparticle (IR808@MnO NP) is developed for enhancing phototherapy of cancer. In this nanoplatform, IR808 as a small molecule dye acts as a tumor targeting ligand to make IR808@MnO NPs with capacity to actively target tumor cells and relocate finally in the mitochondria. Meanwhile, continuous production of oxygen (O2 ) and regulation of pH induced by the high reactivity and specificity of MnO NPs toward mitochondrial endogenous hydrogen peroxide (H2 O2 ) could effectively modulate tumor hypoxia and lessen the tumor subacid environment. Large amounts of reactive oxide species (ROS) are generated during the reaction process between H2 O2 and MnO NPs. Furthermore, under laser irradiation, IR808 in IR808@MnO NPs turns O2 into a highly toxic singlet oxygen (1 O2 ) and generates hyperthermia. The results indicate that IR808@MnO NPs have the high efficiency of specific targeting of tumors, relieving tumor subacid environment, improving the tumor hypoxia environment, and generating large amounts of ROS to kill tumor cells. It is expected to have a wide application in treating cancer.

Label-free quantitative proteomics reveals fibrinopeptide B and heparin cofactor II as potential serum biomarkers in respiratory syncytial virus-infected mice treated with Qingfei oral liquid formula.

Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections. Qingfei oral liquid (QFOL), a traditional Chinese medicine, is widely used in clinical treatment for RSV-induced pneumonia. The present study was designed to reveal the potential targets and mechanism of action for QFOL by exploring its influence on the host cellular network following RSV infection. We investigated the serum proteomic changes and potential biomarkers in an RSV-infected mouse pneumonia model treated with QFOL. Eighteen BALB/c mice were randomly divided into three groups: RSV pneumonia model group (M), QFOL-treated group (Q) and the control group (C). Serum proteomes were analyzed and compared using a label-free quantitative LC-MS/MS approach. A total of 172 protein groups, 1009 proteins, and 1073 unique peptides were successfully identified. 51 differentially expressed proteins (DEPs) were identified (15 DEPs when M/C and 43 DEPs when Q/M; 7 DEPs in common). Classification and interaction network showed that these proteins participated in various biological processes including immune response, blood coagulation, complement activation, and so forth. Particularly, fibrinopeptide B (FpB) and heparin cofactor II (HCII) were evaluated as important nodes in the interaction network, which was closely involved in coagulation and inflammation. Further, the FpB level was increased in Group M but decreased in Group Q, while the HCII level exhibited the opposite trend. These findings not only indicated FpB and HCII as potential biomarkers and targets of QFOL in the treatment of RSV pneumonia, but also suggested a regulatory role of QFOL in the RSV-induced disturbance of coagulation and inflammation-coagulation interactions.

Hypoxia-triggered single molecule probe for high-contrast NIR II/PA tumor imaging and robust photothermal therapy.

Hypoxia is a common characteristic of solid tumors. This important feature is associated with resistance to radio-chemotherapy, which results in poor prognosis and probability of tumor recurrence. Taking advantage of background-free NIR II fluorescence imaging and deeper-penetrating photoacoustic (PA) imaging, we developed a hypoxia-triggered and nitroreductase (NTR) enzyme-responsive single molecule probe for high-contrast NIR II/PA tumor imaging and hypoxia-activated photothermal therapy (PTT), which will overcome cellular resistance during hypoxia. Methods: The single molecule probe IR1048-MZ was synthesized by conjugating a nitro imidazole group as a specific hypoxia trigger with an IR-1048 dye as a NIR II/PA signal reporter. We investigated the NIR II fluorescence, NIR absorbance and photothermal effect in different hypoxia conditions in vitro, and performed NIR II/PA tumor imaging and hypoxia-activated photothermal therapy in mice. Results: This versatile molecular probe IR1048-MZ not only realized high-contrast tumor visualization with a clear boundary by NIR II fluorescence imaging, but also afforded deep-tissue penetration at the centimeter level by 3D PA imaging. Moreover, after being activated by NTR that is overexpressed in hypoxic tumors, the probe exhibited a significant photothermal effect for curative tumor ablation with no recurrence. Conclusions: We have developed the first hypoxia-triggered and NTR enzyme-responsive single molecule probe for high-contrast NIR II/PA tumor imaging and hypoxia-activated photothermal therapy. By tracing the activity of NTR, IR1048-MZ may be a promising contrast agent and theranostic formulation for other hypoxia-related diseases (such as cancer, inflammation, stroke, and cardiac ischemia).

Protective effects of Tongxinluo on cerebral ischemia/reperfusion injury related to Connexin 43/Calpain II/Bax/Caspase-3 pathway in rat.

ETHNOPHARMACOLOGICAL RELEVANCE: Tongxinluo (TXL) is a multifunctional traditional Chinese medicine and has been widely used in the treatment of cardiovascular and cerebrovascular diseases. Numerous studies demonstrate that TXL is a novel neuroprotective drug, however, the mechanisms are largely unknown. AIM OF THE STUDY: we aimed to demonstrate the protective effect of TXL on cerebral ischemia/reperfusion (I/R) injury and provide the evidence for the involvement of Connexin 43/Calpain II/ Bax/Caspase-3 pathway in TXL-mediated neuroprotection. METHODS: Focal cerebral I/R injury were induced by transient middle cerebral artery occlusion (MCAO, for 90min) in adult male Sprague-Dawley rats. We estimated the effects of TXL on I/R injury including neurological deficit assessment and cerebral infarct volume measurement via TTC staining, and detected the protein expression of Connexin 43 (Cx43) by western blot. Furthermore, after the intracerebroventricular injection of carbenoxolone (CBX, the inhibitor of Cx43) at 30min before MCAO surgery, Calpain II, Bax and cleaved Caspased-3 immunoreactivity in ischemic penumbra region was detected by immunofluorescent staining, and cell apoptosis was detected by TUNEL staining. RESULTS: TXL treatment greatly improved neurological deficit and reduced the infarction volume compared to MCAO with buffer treatment (P<0.05), and TXL pre-post treatment showed better results than TXL pre-treatment. TXL pre-post treatment significantly up-regulated Cx43 protein expression at 3d, 7d and 14d post-injury compared to MCAO with buffer treatment (P<0.05). Meanwhile, the immunoreactivity of Calpain II, Bax and cleaved Caspase-3 in ischemic penumbra region was obviously decreased by TXL pre-post treatment compared to MCAO group (P<0.05). However, with the treatment of the Cx43 inhibitor, CBX, the down-regulated effect of TXL on Calpain II, Bax and cleaved Caspase-3 immunoreactivity was abolished (P<0.05). Moreover, the protective effect of TXL against neuron apoptosis in penumbra region was conteracted by CBX (P<0.05). CONCLUSIONS: TXL could effectively protect against I/R injury and reduced cell death via Cx43/Calpain II/Bax/Caspase-3 pathway, which contribute to I/R injury prevention and therapy.

Tumor-targeted small molecule for dual-modal imaging-guided phototherapy upon near-infrared excitation.

Near-infrared (NIR) organic dyes have received increasing attention in recent years as diagnostic and therapeutic agents in the field of tumor research. In this study, IR-822, a near-infrared fluorescence (NIRF) heptamethine cyanine dye, was chosen as a fluorophore due to its high extinction coefficients, and native preferential tumor accumulation property. To enhance its specificity in tumor imaging, N1-(pyridin-4-ylmethyl)ethane-1,2-diamine (PY) was conjugated to IR-822 as a pH-sensing receptor, forming a fluorophore-spacer-receptor molecular probe (IR-PY) that can modulate the fluorescence emission intensity through a fast photoinduced electron-transfer process, which allowed the probe to "switch on" significantly in an acidic tumor microenvironment and which realized enhanced NIRF imaging in vivo. Having a strong NIR absorption at 600-850 nm, this small-molecule IR-PY showed not only high spatial resolution photoacoustic (PA) imaging in mice, but also effective tumor photothermal ablation in vivo. After photothermal therapy (PTT) with IR-PY under NIR 808 nm laser irradiation, the mice exhibited remarkable ablation with no tumor recurrence after treatment. Therefore, a single smart small-molecule probe IR-PY has been designed, synthesized and verified as an "all in one" multifunctional agent, including pH sensitivity, tumor targeting, "switch-on" near-infrared fluorescence imaging, high-spatial-resolution PA imaging and efficient near-infrared photothermal therapy, which is promising for clinical application in NIRF/PA dual-modal imaging-guided cancer diagnosis and treatment.

The Influence of Diabetes Mellitus on Proliferation and Osteoblastic Differentiation of MSCs.

BACKGROUND: Diabetes mellitus (DM) is a widespread chronic metabolic disease which has high mortality due to its complications. In addition to traditional medication, stem cell transplantation therapeutics has become a brand-new and prospective remedy for DM. With strong self-renewal and multi-potential ability, mesenchymal stem cells (MSCs) are considered as ideal cell sources of cell therapy for DM and many other diseases. However, not only do endogenous MSCs fail to replace the impaired islet cells, but also transplanted MSCs fail to cure many patients complicated with DM. Besides, quite a few DM patients suffer from high risk of fracture and low efficiency of bone regeneration, which are often associated with the osteoblastic differentiation of MSCs. Recently, a number of researches have investigated that the changes in micro-environment by DM can affect biological characteristics of MSCs through many factors. SUMMARY: In this review, we summarize the developments in the influence of DM on proliferation and osteoblastic differentiation of MSCs, and moreover, osteoporosis, obesity and metabolism syndrome, as they are closely related to DM.

[Study on effect of voltage-gated calcium channel protein in meridian tissue cells exciting conduction].

OBJECTIVE: To explore the material basis of conduction along meridian. METHODS: Sixty SD rats(30 males,30 females) were randomly assigned into a normal group,an acupuncture group,a verapamil blocking group and a 0.9%NaCl blocking group(control group),15 rats in each one. Fluo 3-AM(calcium fluorescence probe) was injected at the observation part in femoral stomach meridian of foot-yangming(meridian part) and the approaching femoral meridian part(non-meridian part) in the normal group and the acupuncture group,and then incubation was applied. In the verapamil blocking group,verapamil was injected at local meridian part and non-meridian part,and in the control group 0.9%NaCl was injected. Then Fluo 3-AM was injected at the meridian part and non-meridian part in the two groups,and incubation was implemented. Ca2+ imaging changes in cells were recorded for more than 20 min after injection of every part in each group respectively. After the above operations in the last three groups,acupuncture was used at "Zusanli"(ST 36) immediately,with electroacupuncture for one min,then Ca2+ imaging changes in cells at the meridian and non-meridian parts were recorded for more than 20 min. RESULTS: In the normal group, Ca2+ fluorescence intensity at the meridian part was higher than that at the non-meridian part. In the acupuncture group,after acupuncture Ca2+ fluorescence intensity at the meridian part was obviously higher than before,but the change before and after acupuncture was not apparent at the non-meridian part. After verapamil blocking local calcium channel and acupuncture,the Ca2+ fluorescence of the meridian part did not strengthen,and the change of that before and after acupuncture at the non-meridian part was not obvious. In the control group,after injecting 0.9%NaCl at local part,Ca2+ fluorescence intensities of the meridian and non-meridian parts showed no obvious change,so was that before and after acupuncture. CONCLUSIONS: The voltage-gated calcium channel at the meridian part is highly correlated with its tissue cells exciting conduction.

Electroacupuncture Pretreatment Attenuates Cerebral Ischemic Injury via Notch Pathway-Mediated Up-Regulation of Hypoxia Inducible Factor-1α in Rats.

We have reported electroacupuncture (EA) pretreatment induced the tolerance against focal cerebral ischemia through activation of canonical Notch pathway. However, the underlying mechanisms have not been fully understood. Evidences suggest that up-regulation of hypoxia inducible factor-1α (HIF-1α) contributes to neuroprotection against ischemia which could interact with Notch signaling pathway in this process. Therefore, the current study is to test that up-regulation of HIF-1α associated with Notch pathway contributes to the neuroprotection of EA pretreatment. Sprague-Dawley rats were treated with EA at the acupoint "Baihui (GV 20)" 30 min per day for successive 5 days before MCAO. HIF-1α levels were measured before and after reperfusion. Then, HIF-1α antagonist 2ME2 and γ-secretase inhibitor MW167 were used. Neurologic deficit scores, infarction volumes, neuronal apoptosis, and Bcl2/Bax were evaluated. HIF-1α and Notch1 intracellular domain (NICD) were assessed. The results showed EA pretreatment enhanced the neuronal expression of HIF-1α, reduced infarct volume, improved neurological outcome, inhibited neuronal apoptosis, up-regulated expression of Bcl-2, and down-regulated expression of Bax after reperfusion in the penumbra, while the beneficial effects were attenuated by 2ME2. Furthermore, intraventricular injection with MW167 efficiently suppressed both up-regulation of NICD and HIF-1α after reperfusion. However, administration with 2ME2 could only decrease the expression of HIF-1α in the penumbra. In conclusion, EA pretreatment exerts neuroprotection against ischemic injury through Notch pathway-mediated up-regulation of HIF-1α.

Neuroprotective effect of the traditional Chinese herbal formula Tongxinluo: a PET imaging study in rats.

Tongxinluo has been widely used in China for the treatment of acute stroke and for neuroprotection. However, there are few positron emission tomography (PET) studies on the neuroprotective effect of Tongxinluo on cerebral ischemia/reperfusion in small animals. In the present study, Tongxinluo superfine powder suspension or its vehicle was administered intragastrically to rats for 5 successive days before middle cerebral artery occlusion. (18)F-fluorodeoxyglucose (FDG) small animal PET imaging showed that at 1 and 2 weeks after cerebral ischemia/reperfusion, glucose metabolism in the ischemic area was greater in rats that had received Tongxinluo than in those that had received the vehicle. Nissl staining showed that 2 weeks after cerebral ischemia/reperfusion, there was less neuronal loss in the prefrontal cortex in Tongxinluo-treated rats than in controls. In addition, Tongxinluo-treated animals showed better neurologic function and lower cerebral infarct volume than rats that received the vehicle. These findings suggest that Tongxinluo exhibits neuroprotective effects in cerebral ischemia/reperfusion injury and demonstrates that (18)F-FDG small animal PET imaging is a useful tool with which to study the molecular pharmacology of traditional Chinese medicine.

[Vegetative state treated with acupoint injection combined with plum-blossom needle in children: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy difference on vegetative state in children between acupoint injection combined with plum-blossom needle and western medication based on basic treatment. METHODS: Forty-eight children of vegetative state were randomized into an observation group and a control group, 24 cases in each one. On the basis of the treatment of transcranial magnetic stimulation apparatus, balancing treatment apparatus and massage, the acupoint injection and tapping method with plum-blossom needle were adopted in the observation group, in which Xingnaojing injection, mouse nerve growth factor (mNGF) injection, monosialotetrahexosylganglioside sodium injection (MSI), compound Danshen injection were divided in 6 pairs and were injected respectively in Baihui (GV 20), Yongquan (KI 1), Fengfu (GV 16), Yamen (GV 15) and the others, 0.5 mL in each acupoint, once a day for continuous 10 days. Additionally, the tapping method with plum-blossom needle was used on the Governor Vessel and Jiaji (EX-B 2) on the back. In the control group, the intravenous infusion was adopted with citicoline sodium injection, mannitol injection and dexamethasone injection. The treatment was given once a day, 20 days of treatment made one session and totally 3 sessions were required in the two groups. The clinical efficacy, the vegetative state score and the mean curing time were observed after 20 days, 40 days and 60 days of treatment between the two groups. RESULTS: The effective rates were 58.3% (14/24), 70.8% (17/24) and 79.2% (19/24) in 20 days, 40 days and 60 days of treatment in the observation group and 20.8% (5/24), 45.8% (11/24) and 58.3% (14/24) in the control group respectively. The efficacy in the observation group was superior to those in the control group (P < 0.01, P < 0.05). The vegetative state score was improved apparently after 20 days, 40 days and 60 days of treatment as compared with those before treatment separately (all P < 0.05). It was improved obviously at the each time point after treatment in the observation group as compared with that in the control group (3.34 +/- 2.41 vs 2.64 +/- 11.56, 6.20 +/- 1.46 vs 4.34 +/- 1.64, 11.26 +/- 2.63 vs 8.75 +/- 2.18, all P < 0.05). The mean curing time was (45.67 +/- 16.24) days in the observation group, which was shorter apparently than that of (55.34 +/- 4.57) days in the control group (P < 0.05). CONCLUSION: Based on basic treatment acupoint injection combined with tapping method of plum-blossom needle achieve the reliable efficacy on vegetative state in children.

Electroacupuncture treatment contributes to the downregulation of neuronal nitric oxide synthase and motoneuron death in injured spinal cords following root avulsion of the brachial plexus.

This study was performed in order to investigate the effect of electroacupuncture (EA) on motoneurons and the expression of neuronal nitric oxide synthase (nNOS) following brachial plexus root avulsion (BPRA). A total of 40 female Sprague-Dawley rats underwent BPRA (5th cervical-1st thoracic) and were randomly divided into the avulsion plus EA stimulation (AV+EA) and AV groups. The AV+EA group received a continuous 20-Hz asymmetric bidirectional disperse-dense wave at the acupuncture points (acupoints) of Dazhui (DU4) and Shousanli (LI10) for 15 min on alternate days until the animals were sacrificed, at 1, 2, 3 and 6 weeks. The AV group received no treatment. The cryostat sections of the 7th cervical segments were prepared and stained with neuronal nitric oxide synthase nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) and histochemically stained and counterstained with neutral red (NR). The number of nNOS-positive motoneurons on the lesion side and survived motoneurons on both sides of the 7th cervical segments were blindly counted and compared between the two groups. The results demonstrated that the number of nNOS-positive motoneurons was significantly lower in the AV+EA group compared with that in the AV group and the percentage of survived motoneurons was significantly higher compared with that of the AV group at 2 and 3 weeks. However, the number of nNOS-positive motoneurons and the percentage of survived motoneurons were not significantly different between the two groups at 1 and 6 weeks. These results indicated that, during the early period after BPRA, EA stimulation at the acupoints of Dazhui (DU4) and Shousanli (LI10) may significantly reduce the number of nNOS-positive motoneurons and protect against motoneuron death.

[Formation mechanism of high-energy metabolism along meridians].

According to the analysis and integration on prior research results regarding meridian essence, it is believed that high-energy metabolism is one of the main characteristics of along-meridian specificity. With discussion on the formation mechanism of along-meridians high-energy metabolism as entry point, it is found out that proteins of voltage-gated calcium channel along the meridians are likely to play an essential role of starting and coupling during the along-meridians functional activity. Thus, the hypothesis "proteins coupling in the meridians" is modified to the hypothesis "calcium channels proteins coupling in the meridians", which opens new path to reveal material basis and action mechanism of meridians.