An Activatable Dual Polymer Nanosystem for Photoimmunotherapy and Metabolic Modulation of Deep-Seated Tumors.

Nanomedicine in combination with immunotherapy has shown great potential in the cancer treatment, but phototherapeutic nanomaterials that specifically activate the immunopharmacological effects in deep tumors have rarely been developed due to limited laser penetration depth and tumor immune microenvironment. Herein, this work reports a newly synthesized semiconducting polymer (SP) grafted with imiquimod R837 and indoxmid encapsulated micelle (SPRIN-micelle) with strong absorption in the second near infrared window (NIR-II) that can relieve tumor immunosuppression and enhance the photothermal immunotherapy and catabolic modulation on tumors. Immune agonists (Imiquimod R837) and immunometabolic modulators (indoxmid) are covalently attached to NIR-II SP sensors via a glutathione (GSH) responsive self-immolation linker and then loaded into Pluronic F127 (F127) micelles by a temperature-sensitive critical micelle concentration (CMC)-switching method. Using this method, photothermal effect of SPRIN-micelles in deep-seated tumors can be activated, leading to effective tumor ablation and immunogenic cell death (ICD). Meanwhile, imiquimod and indoxmid are tracelessly released in response to the tumor microenvironment, resulting in dendritic cell (DC) maturation by imiquimod R837 and inhibition of both indoleamine 2,3-dioxygenase (IDO) activity and Treg cell expression by indoxmid. Ultimately, cytotoxic T-lymphocyte infiltration and tumor metastasis inhibition in deep solid tumors (9 mm) are achieved. In summary, this work demonstrates a new strategy for the combination of photothermal immunotherapy and metabolic modulation by developing a dual functional polymer system including activable SP and temperature-sensitive F127 for the treatment of deep solid tumors.

Metal coordination micelles for anti-cancer treatment by gene-editing and phototherapy.

CRISPR-Cas9 is a central focus of the emerging field of gene editing and photodynamic therapy (PDT) is a clinical-stage ablation modality combining photosensitizers with light irradiation. But metal coordination biomaterials for the applications of both have rarely been investigated. Herein, Chlorin-e6 (Ce6) Manganese (Mn) coordination micelles loaded with Cas9, termed Ce6-Mn-Cas9, were developed for augmented combination anti-cancer treatment. Manganese played multiple roles to facilitate Cas9 and single guide RNA (sgRNA) ribonucleoprotein (RNP) delivery, Fenton-like effect, and enhanced endonuclease activity of RNP. Histidine (His)-tagged RNP could be coordinated to Ce6 encapsulated in Pluronic F127 (F127) micelles by simple admixture. Triggered by ATP and endolysosomal acidic pH, Ce6-Mn-Cas9 released Cas9 without altering protein structure or function. Dual guide RNAs were designed to target the antioxidant regulator MTH1 and the DNA repair protein APE1, resulting in increased oxygen and enhanced PDT effect. In a murine tumor model, Ce6-Mn-Cas9 inhibited tumor growth with the combination therapy of PDT and gene editing. Taken together, Ce6-Mn-Cas9 represents a new biomaterial with a high degree of versatility to enable photo- and gene-therapy approaches.

Antibiotic Cross-linked Micelles with Reduced Toxicity for Multidrug-Resistant Bacterial Sepsis Treatment.

One potential approach to address the rising threat of antibiotic resistance is through novel formulations of established drugs. We designed antibiotic cross-linked micelles (ABC-micelles) by cross-linking the Pluronic F127 block copolymers with an antibiotic itself, via a novel one-pot synthesis in aqueous solution. ABC-micelles enhanced antibiotic encapsulation while also reducing systemic toxicity in mice. Using colistin, a hydrophilic, potent ″last-resort" antibiotic, ABC-micelle encapsulation yield was 80%, with good storage stability. ABC-micelles exhibited an improved safety profile, with a maximum tolerated dose of over 100 mg/kg colistin in mice, at least 16 times higher than the free drug. Colistin-induced nephrotoxicity and neurotoxicity were reduced in ABC-micelles by 10-50-fold. Despite reduced toxicity, ABC-micelles preserved bactericidal activity, and the clinically relevant combination of colistin and rifampicin (co-loaded in the micelles) showed a synergistic antimicrobial effect against antibiotic-resistant strains of Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. In a mouse model of sepsis, colistin ABC-micelles showed equivalent efficacy as free colistin but with a substantially higher therapeutic index. Microscopic single-cell imaging of bacteria revealed that ABC-micelles could kill bacteria in a more rapid manner with distinct cell membrane disruption, possibly reflecting a different antimicrobial mechanism from free colistin. This work shows the potential of drug cross-linked micelles as a new class of biomaterials formed from existing antibiotics and represents a new and generalized approach for formulating amine-containing drugs.

COVID-19: what has been learned and to be learned about the novel coronavirus disease.

The outbreak of Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), has thus far killed over 3,000 people and infected over 80,000 in China and elsewhere in the world, resulting in catastrophe for humans. Similar to its homologous virus, SARS-CoV, which caused SARS in thousands of people in 2003, SARS-CoV-2 might also be transmitted from the bats and causes similar symptoms through a similar mechanism. However, COVID-19 has lower severity and mortality than SARS but is much more transmissive and affects more elderly individuals than youth and more men than women. In response to the rapidly increasing number of publications on the emerging disease, this article attempts to provide a timely and comprehensive review of the swiftly developing research subject. We will cover the basics about the epidemiology, etiology, virology, diagnosis, treatment, prognosis, and prevention of the disease. Although many questions still require answers, we hope that this review helps in the understanding and eradication of the threatening disease.

Effect of Modified Buzhong Yiqitang on Cardiac Function of Diabetic Cardiomyopathy Rats and FABP3 and PPARγ Proteins of Rat Cardiac Myocytes / 中国实验方剂学杂志

Objective: To study the effects of modified Buzhong Yiqitang on cardiac function and fat acid binding protein3 (FABP3)and peroxisome proliferator-activated receptor gamma(PPARγ) protein of cardiac myocytes in type 2 diabetic mellitus (T2DM) rats, and to explore the mechanism of this prescription to protect T2DM cardiomyopathy. Method: After 6 weeks of high-glucose and high-fat diet, streptozotocin (STZ) was intraperitoneally injected (50 mg·kg-1) to establish a diabetic rat model, and then randomly divided into normal group, model group, modified Buzhong Yiqitang group (21 g·kg-1) and metformin hydrochloride group (2 g·kg-1). After continuous administration for 6 weeks, echocardiography was used to detect the cardiac structure and function of the rats in each group. Combined with the measured blood glucose level, it was judged that the rat model building of diabetic cardiomyopathy was successful.Rat heart tissue was dissected, and rat myocardial morphology was observed by hematoxylin-eosin(HE)staining. Western blot was used to detect the expression levels of FABP3 and PPARγ proteins in rat myocardium. Result: Compared with normal group, levels of blood sugar, total triglyceride(TC), triglyceride(TG),insulin (INS) in model group rats increased significantly (PPγ protein expression levels were significantly lower (PPPγ protein expression was significantly increased (PConclusion: Modified Buzhong Yiqitang can improve glucose and lipid metabolism disorder in diabetic cardiomyopathy rats, improve cardiac function in diabetic cardiomyopathy rats, increase the expression of PPARγ in cardiomyocytes, and reduce the expression of FABP3 protein.

Anti-atherosclerosis and cardio-protective effects of the Angong Niuhuang Pill on a high fat and vitamin D3 induced rodent model of atherosclerosis.

ETHNOPHARMACOLOGICAL RELEVANCE: The Angong Niuhuang Pill (ANP) is a well known Chinese traditional therapeutic for the treatment for diseases affecting the Central Nervous System (CNS). Components of the ANP formulation, including Bovis Calculus Sativus, Pulvis Bubali Comus Concentratus, Moschus, Margarita, Cinnabaris, Realgar, Coptidis Rhizoma, Scutellariae Radix, Gardeniae Fructus, Curcumae Radix, and Bomeolum Syntheticum, have been used for the treatment of stroke, encephalitis and emergency meningitis across Asia, especially in China for hundreds of years. OBJECTIVE: The goal of this study was to investigate the anti-atherosclerosis and cardio-protective effects of ANP administration using a rodent model of atherosclerosis induced by a high fat and vitamin D3. METHODS: Specific Pathogen-Free (SPF) 78 male SD rats were randomly divided into a control group and 5 atherosclerotic model groups. The atherosclerotic groups were divided to receive either Simvastatin (SVTT, 0.005g/kg), Low-dose ANP (0.125g/kg), Medium-dose ANP (0.25g/kg), and High-dose ANP (0.5g/kg). Following adaptive feeding for one week, atherosclerosis was induced and the atherosclerosis model was established. Experimental drugs (either simvastatin or ANP) or normal saline were administered intragastrically once daily for 9 weeks starting from the 8th week. A carotid artery ultrasound was performed at the 17th week to determine whether atherosclerosis had been induced. After the atherosclerosis model was successfully established, platelet aggregation rates, serum biochemical indices, apoptosis-related Bcl-2, Bax proteins levels in the heart were assayed. Pathological and histological analysis was completed using artery tissue from different experimental different groups to assess the effects of ANP. RESULTS: ANP significantly decreased aortic membrane thickness, the maximum platelet aggregation rates, and the ratio of low density lipoprotein cholesterol (LDL) to high density lipoprotein cholesterol (HDL). In addition, ANP significantly reduced serum contents of total cholesterol, low density lipoprotein, malondialdehyde, troponin I, high-sensitivity C-reactive protein, and lactate dehydrogenase. ANP markedly improved abnormal pathological conditions of the aorta and heart, and helped to prevent myocardial apoptosis. CONCLUSIONS: We have demonstrated that ANP has robust ant-atherosclerosis and cardio-protective effects on a high-fat and vitamin D3 - induced rodent model of atherosclerosis due to its antiplatelet aggregation, lipid regulatory, antioxidant, anti-inflammatory and anti-apoptotic properties.

Phytoremediation potentiality of garlic roots for 2,4-dichlorophenol removal from aqueous solutions.

2,4-Dichlorophenol (2,4-DCP) is considered as an important pollutant because of its high toxicity and wide distribution in wastewaters. Innocuous remediation technologies have been studied for the removal of this pollutant. This study investigated the feasibility of using garlic roots as a plant system for the removal of 2,4-DCP. The optimal conditions for its removal were established based on orthogonal experiments (OA25 matrix). Significant factors that affect removal efficiency, arranged from high to low importance, include pH, reaction time, 2,4-DCP concentration, and H2O2 concentration. In addition, garlic roots could be re-used for as much as three consecutive cycles. The decrease in pH and the increase of Cl(-) ion content in the post-removal solutions indicated that 2,4-DCP dehalogenation occurred during transformation. Changes in the deposition pattern of lignin in roots exposed to 2,4-DCP suggested that several of the products deposited were lignin-type polymers. The acute toxicity test revealed that the post-removal solutions were less toxic than the parent solutions. Therefore, garlic roots have considerable potential to effectively and safely remove 2,4-DCP from wastewater.

Changes of soluble CD40 ligand in patients with hyperlipidemia of blood stasis syndrome and its clinical significance / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe changes of soluble CD40 ligand (sCD40L) in patients with hyperlipidemia of blood stasis syndrome and its correlation with blood stasis syndrome integral, P-selectin, and high sensitive creatine reactive protein (hs-CRP), to investigate the roles of platelet activation and inflammation in the physiopathologic process of blood-stasis type hyperlipidemia, and to explore the pathogenetic mechanism of blood-stasis syndrome (BSS).</p><p><b>METHODS</b>Seventy hyperlipidemia patients were assigned to two groups, 39 in the BSS group and 31 in the non-BSS group. Meanwhile, thirty healthy subjects were grouped as the control. Main physiochemical indices, blood levels of sCD40L, P-selectin, hs-CRP were detected in all. The correlations of the aforesaid indices were analyzed.</p><p><b>RESULTS</b>BSS score in the BSS group was higher than that in the non-BSS group and in the control group. Higher blood levels of P-selectin and sCD40L were shown in the BSS group than in the non-BSS group [(25.13 +/- 5.49) ng/L vs. (21.37 +/- 3.56) ng/L and (2.45 +/- 0.48) ng/L vs. (2.07 +/- 0. 41) ng/L] respectively, and the two indices were higher in hyperlipidemia patients than in healthy persons [(14.91 +/- 2.48) ng/L and (1.63 +/- 0.25) ng/L, P < 0.01]. Correlation analysis showed that in patients with hyperlipidemia, blood level of sCD40L was positively correlated with low-density lipoprotein cholesterol (LDL-C) level (r = 0.503, P < 0.01), P-selectin (r = 0.897, P < 0.01), and the BSS score (r = 0.603, P < 0.01).</p><p><b>CONCLUSIONS</b>The over-expressed sCD40L indicated persistent inflammatory state in patients with hyperlipidemia of BSS. BSS would further accelerate the chronic inflammation process of hyperlipidemia.</p>

[Efficiency analysis of two-stage SBR for phosphorus nitrogen and organic substrate removal].

Taking simulated domestic sewage as treatment object, the characteristics of separate-stage phosphorus, organic substrate and nitrogen removal were studied in two-stage SBR by contrast experiment and mechanism analysis under the normal temperature, its efficiency-predominance was analyzed. The results indicate that the heterotrophic PAOs and nitrobacteria can be dominant growth in individual reactor respectively, under the effluent quality is more superior, the treatment efficiency is one time higher than that in the single SBR by controlling the sludge age (the phosphorus removal stage 5-7 d, the nitrogen removal stage about 50 d). The two-stage SBR can relieve the attack of organic load to nitrification process effectively, its nitrogen removal stage (SBR2) can still maintain stable nitrification rate under the higher COD concentration and the final effluent of the system is easy and stable to reach national standards (TP < or = 0.5 mg x L(-1)). In addition, the nitrogen removal stage (SBR2) of two-stage SBR not only can maintain nitrobacteria predominant, but also can cultivate heterotrophic bacteria which can remove difficult degraded organic substrate, that results in lower COD concentration than in the single's at the end of nitrification.

Summarization of professor He Pu-ren's channel syndrome differentiation for treatment of complicated and difficult diseases / 中国针灸

Channel syndrome differentiation is a more commonly-used syndrome differentiation method of Professor HE Pu-ren clinically, which includes the 3 aspects: differentiation of diseases and syndromes on the channel parts along the body surface; differentiation of diseases and syndromes of the internal organs connected with the channels; differentiation of qi and blood of the channels. According to results of the channel syndrome differentiation, with flexible application of the HE's Santong methods and selection of corresponding treatment program, many complicated and difficult diseases are cured.

Observation on therapeutic effects of red-hot needle therapy on nodules of breast of the type of stagnation of liver-qi and phlegm coagulation / 中国针灸

<p><b>OBJECTIVE</b>To compare therapeutic effects of red-hot needle therapy and filiform needle therapy on nodules of breast of the type of stagnation of liver-qi and phlegm coagulation.</p><p><b>METHODS</b>Six hundred cases were randomly divided into a treatment group and a control group, 300 cases in each group. The treatment group were treated with red-hot needle pricking at the proliferative parts and Ashi points as main, and the control group with filiform needle therapy.</p><p><b>RESULTS</b>In the treatment group, 240 cases were cured, 58 cases improved and 2 cases were not cured with an effective rate of 99.3%; and in the control group, 113 cases were cured, 165 cases improved and 22 were not cured with an effective rate of 92.7%, with a significant difference between the two groups (P = 0.001).</p><p><b>CONCLUSION</b>The therapeutic effect of red-hot needle therapy is better than that of filiform needle therapy on nodules of breast of the type of stagnation of liver-qi and phlegm coagulation.</p>

Effects of xinshuai mistura on plasma angiotensin II, atrial natriuretic peptide and N terminal pro-brain natriuretic peptide in patients with heart failure / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the effects of Xinshuai Mistura (XM) on plasma angiotensin II (Ang II), atrial natriuretic peptide (ANP) and N terminal pro- brain natriuretic peptide (Nt-proBNP) in patients with heart failure (HF).</p><p><b>METHODS</b>Fifty-nine patients with HF (NYHA class II-IV) were randomly divided into two groups, the treated group treated with XM and the control group with Wuling Pulvis (WP), both on the base of captopril treatment. The treatment course was two weeks. Plasma levels of Ang II , ANP and Nt-proBNP were observed.</p><p><b>RESULTS</b>The plasma levels of Ang I, ANP and Nt-proBNP showed an ascending tendency along with the increasing in severity of HF(P < 0.01), and significantly decreased after treatment in the treated group (P < 0.01), but with no remarkable difference as compared with those in the control group (P > 0.05).</p><p><b>CONCLUSION</b>XM had definite therapeutic effects on excessive neuroendocrine activation in HF patients.</p>