Black phosphorous nanosheet: A novel immune-potentiating nanoadjuvant for near-infrared-improved immunotherapy.

Intrinsic immune behaviors of nanomaterials and immune systems promote research on their adjuvanticity and the design of next generation nanovaccine-based immunotherapies. Herein, we report a promising multifunctional nanoadjuvant by exploring the immune-potentiating effects of black phosphorus nanosheets (BPs) in vitro and in vivo. The facile coating of BPs with phenylalanine-lysine-phenylalanine (FKF) tripeptide-modified antigen epitopes (FKF-OVAp@BP) enables the generation of a minimalized nanovaccine by integrating high loading capacity, efficient drug delivery, comprehensive dendritic cell (DC) activation, and biocompatibility for cancer immunotherapy. Systemic immunization elicits potent antitumor cellular immunity and significantly augments checkpoint blockade (CPB) against melanoma in a mouse model. Furthermore, near-infrared (NIR) photothermal effects of BPs create an immune-favorable microenvironment for improved local immunization. This study offers new insight into the integration of immunoactivity and photothermal effects for enhanced cancer immunotherapy by using a nanoadjuvant and thus potentially advances the design and application of multifunctional adjuvant materials for cancer nanotreatment.

Efficacy and Safety of Tongning Gel for Knee Osteoarthritis: A Multicentre, Randomized, Double-Blinded, Parallel, Placebo-Controlled, Clinical Trial.

OBJECTIVE: To evaluate the efficacy and safety of Tongning Gel (TNG) compared to placebo-controlled (PC) for knee osteoarthritis (KOA). METHODS: A multicentre, randomized, double-blinded, parallel, placebo-controlled, clinical trial was performed in 576 patients (432 patients in the TNG group, 144 patients in the PC group), and 1 in the experimental group withdrew due to nonuse of drug. Patients were randomized to receive TNG or PC applied to knee skin at 3g per time, 2 times per day, which lasted for 3 weeks. The Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain score was used to evaluate the primary efficacy of TNG and WOMAC stiffness and physical function and total scores were used to evaluate the secondary efficacy of TNG. All participants who received at least one dose of study drug were included in the safety analysis. This trial has been registered in Chinese Clinical Trial Registry (no. CTR20131276). RESULTS: Primary efficiency outcome: there were significant differences in the decreased value of WOMAC pain score between two groups (P < 0.05), and the decreased value of WOMAC pain score in the TNG group were better than those in the PC group (P < 0.05). Secondary efficiency outcome: the WOMAC total score, WOMAC stiffness score, WOMAC physical function score, and the decrease of the above indexes of the two groups of patients after treatment were statistically significant (P < 0.05), and the improvement of the above indexes in the TNG group was better than that of the PC group (P < 0.05). Safety Evaluation. A total of 42 adverse events were reported by 29 patients: 25 adverse events reported by 16 patients (3.71%) in the experimental group and 17 adverse events were reported by 13 patients (9.03%) in the control group. And 8 adverse reactions were reported by 6 patients including 2 adverse reactions by 2 patients (0.46%) in the experimental group and 6 adverse reactions by 4 patients (2.78%) in the control group. Two cases of significant adverse events occurred in the experimental group. Both groups had one serious adverse event, respectively, which were not relevant to the intervention. CONCLUSION: These results of the trial demonstrate that TNG is superior to placebo in the treatment of patients with KOA, and TNG can improve other symptoms of KOA, such as stiffness and physical function. TNG is safe for the treatment of knee osteoarthritis as a whole.

A group of serum proteins as potential diagnostic biomarkers for Yin-deficiency-heat syndrome.

Yin-deficiency-heat (YDH) syndrome is a very common subhealth status in Traditional Chinese Medicine. However, currently, there is no unified standard for diagnosing YDH syndrome. We applied the iTRAQ-2D LC-MS/MS method to explore the potential of serum protein profiles as biomarker for YDH syndrome. A total of 120 differentially expressed proteins (79 downregulated and 41 upregulated) were identified by the proteomic profiling. The results of KEGG pathway analysis showed that the functions of the differentially expressed proteins were mainly involved in complement and coagulation cascades. The clinical data showed that YDH syndrome was closely related to inflammation and coagulation, compared with the healthy controls. The ELISA validation results indicated that the expression levels of ALB, CFI, and KLKB1 were downregulated in the YDH syndrome group (p < .05). Moreover, we established a decision tree model based on the combination of these three proteins and achieved a sensitivity of 87.5%, a specificity of 84.4%, and AUC of 0.891. The results indicated that the combination of ALB, CFI, and KLKB1 may serve as potential biomarkers for diagnosing YDH syndrome. Our study can provide a new method for YDH syndrome diagnosis, and may also provide an experimental basis to understand the molecular mechanism of YDH syndrome.

Screening of potential biomarkers for Yin-deficiency-heat syndrome based on UHPLC-MS method and the mechanism of Zhibai Dihuang granule therapeutic effect.

BACKGROUND: Yin-deficiency-heat (YDH) syndrome is a subhealth state of the individual, mainly manifested as oral ulcers, dry mouth, constipation, and other symptoms. Zhibai Dihuang granule (ZDG), as a classic traditional Chinese medicine, is effective in treating YDH syndrome. We screened the potential biomarkers for diagnosing YDH syndrome, and explored the mechanisms of the therapeutic effect of ZDG. METHODS: Plasma samples from the Pinghe (PH, healthy control) group, the Shanghuo (SH, YDH syndrome) group, and the ZDG treated group (therapeutic group) were analyzed by using metabolomics profiling. The data were analyzed by multivariate statistical and bioinformatics analyses. RESULTS: We screened four differential metabolites such as, decanoylcarnitine, dodecanoylcarnitine, phosphatidylcholine (PC), and Aspartate (Asp) Arginine (Arg) Proline (Pro) in the SH group and the PH group. The results showed that the combination of above four metabolites could serve as a potential biomarker for the early diagnosis of YDH syndrome. The metabolites decanoylcarnitine and glucose were found to be differentially expressed in the YDH syndrome group and tended to be normalized after ZDG treatment. CONCLUSION: The increased levels of four differential metabolites (decanoylcarnitine, dodecanoylcarnitine, PC, and Asp Arg Pro) revealed that individuals with YDH syndrome may have increased energy metabolism in the body, which could lead to disorders of fatty acids ß-oxidation and immune function. The levels of two differential metabolites including decanoylcarnitine and glucose returned to normal after ZDG treatment, indicating that ZDG could treat YDH syndrome by regulating glucose metabolism and fatty acids ß-oxidation. Our study provides a new method for the diagnosis of YDH syndrome, and may provide theoretical basis for novel therapeutic strategies of YDH syndrome.

Serum proteins TGFBI, PCSK9, and CCL14 are potential biomarkers for different traditional Chinese medicine syndromes of multidrug-resistant tuberculosis.

Patients with multidrug-resistant tuberculosis (MDR-TB) tend to have a long course of anti-TB treatment and severe side effects. Traditional Chinese Medicine (TCM) has a synergistic effect in attenuation of MDR-TB. However, the lack of objective biological standards to classify and diagnose MDR-TB TCM syndromes could result in less effective TCM treatment. Therefore, in this study, we identified differentially expressed proteins (DEPs) in serum of individuals with MDR-TB TCM syndromes by applying isobaric tags for relative and absolute quantification coupled with two-dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS) method and bioinformatics analysis. The functional analysis of DEPs was also performed. Additionally, DEPs among three different TCM syndromes of MDR-TB were validated by enzyme-linked immunosorbent assay (ELISA). Finally, a receiver operating characteristic (ROC) curve was performed to estimate the diagnostic ability of DEPs. A total of 71 DEPs were identified in the three different MDR-TB TCM syndrome groups such as the pulmonary Yin deficiency (PYD) syndrome group, the Hyperactivity of Fire due to Yin deficiency (HFYD) syndrome group, and the deficiency of Qi and Yin (DQY) syndrome group. The results showed that the expression level of transforming growth factor-beta-induced protein ig-h3 (TGFBI) was lower in the PYD syndrome group (p = .002), the proprotein convertase subtilisin/kexin type 9 (PCSK9) was overexpressed in the HFYD syndrome group (p < .0001), and the C-C motif chemokine ligand 14 (CCL14) expression level was reduced in the DQY syndrome group (p = .004). Our study demonstrated that serum TGFBI, PCSK9, and CCL14 may serve as potential novel biomarkers for PYD syndrome, HFYD syndrome and DQY syndrome of MDR-TB, respectively. The study provides a biological basis for MDR-TB TCM syndromes classification and can be of great significance for the treatment of different TCM syndromes.

Study on potential biomarkers of energy metabolism-related to early-stage Yin-deficiency-heat syndrome based on metabolomics and transcriptomics.

Yin-deficiency-heat (YDH) syndrome is a common sub-health state of the human body in traditional Chinese medicine (TCM). However, due to the lack of objective quantitative diagnostic indicators, patients with early-stage YDH syndrome cannot be treated in time and can develop a pathological (disease) state. Therefore, it is necessary to apply modern diagnostic techniques in order to identify the biological markers for the diagnosis of early-stage YDH syndrome. In the present study, we performed Solexa sequencing and non-targeted metabolomics analysis using high-performance liquid chromatography coupled with mass spectrometry to screen differentially expressed mRNAs and differential metabolites in individuals with early-stage YDH syndrome and healthy controls. Bioinformatics methods were used to perform enrichment analysis of differentially expressed mRNAs and differential metabolites for biological functions and signaling pathways. Furthermore, we found that differentially expressed mRNAs and differential metabolites were related to energy metabolism. Real-time PCR was used to validate the mRNA expression in the serum of subjects with early-stage YDH syndrome. We found that the mitochondrially encoded NADH dehydrogenase 2 (MT-ND2) mRNA was differentially expressed in the serum of individuals with early-stage YDH syndrome. Receiver operating characteristic (ROC) curve and logistic regression analysis were used to evaluate the efficacy of the diagnostic model based on eight differential metabolites. We combined the three metabolites such as Glycine, Sphingomyelin, and Isocitrate to establish the diagnostic model with a sensitivity of 0.853 and a specificity of 0.800. The combination of the above three metabolites may serve as a potential biomarker for the diagnosis of early-stage YDH syndrome. Our study reveals potential biomarker for the diagnosis of early-stage YDH syndrome and also provides a new method for the quantification and objectification of TCM syndromes.

Effect of Chinese Herbal Medicine Jinlida Granule in Treatment of Patients with Impaired Glucose Tolerance.

BACKGROUND: Diabetes mellitus (DM) remains a major health problem worldwide. Several clinical trials have shown the superiority of the Traditional Chinese Medicine in delaying or reversing the development and progression of DM. This study aimed to evaluate the efficacy of Jinlida (JLD) granule, a Chinese herbal recipe, in the treatment of impaired glucose tolerance (IGT) and its effect on the prevention of DM. METHODS: Sixty-five IGT patients were randomized to receive one bag of JLD granules three times daily (JLD group, n = 34) or no drug intervention (control group, n = 31) for 12 weeks. Oral glucose tolerance test, glycated hemoglobin A1c (HbA1c), body mass index, blood lipids levels, fasting insulin, and insulin resistance calculated using homeostatic model assessment (HOMA-IR) of all the patients were observed and compared before and after the treatment. RESULTS: Sixty-one participants completed the trial (32 in JLD group and 29 in the control group). There were statistically significant decreases in HbA1c (P < 0.001), 2-h plasma glucose (P < 0.001), and HOMA-IR (P = 0.029) in JLD group compared with the control group after 12 weeks of treatment. After 12 weeks of treatment, two (6.9%) patients returned to normal blood glucose, and five (17.2%) patients turned into DM in control group, while in the JLD group, 14 (43.8%) returned to normal blood glucose and 2 (6.2%) turned into DM. There was a significant difference in the number of subjects who had normal glucose at the end of the study between two groups (P = 0.001). CONCLUSIONS: JLD granule effectively improved glucose control, increased the conversion of IGT to normal glucose, and improved the insulin resistance in patients with IGT. This Chinese herbal medicine may have a clinical value for IGT.

Gold-nanorods-siRNA nanoplex for improved photothermal therapy by gene silencing.

Nanomaterials-mediated photothermal therapy (PTT) often suffers from the fundamental cellular defense mechanism of heat shock response which leads to therapeutic resistance of cancer cells and reduces the therapeutic efficacy. Herein, a gold nanorods (GNRs)-siRNA platform with gene silencing capability is produced to improve the PTT efficiency. After surface modification, the GNRs show the ability to deliver siRNA oligos targeting BAG3 which is an efficient gene to block the heat-shock response. The synthesized GNRs-siRNA nanoplex exhibits excellent ability in the delivery of siRNA into cancer cells with high silencing efficiency which is even better than that of commercial Lipofectamine 2000. The in vitro and in vivo studies demonstrate the ability of the GNRs-siRNA nanoplex to sensitize the cancer cells to PTT under moderate laser irradiation by down-regulating the increased BAG3 expression and enhancing apoptosis. The GNRs-siRNA mediated PTT has large potential in clinical cancer therapy due to the elimination of therapeutic resistance and enhanced photothermal therapeutic efficacy by means of gene silencing. It also suggests an efficient platform for gene delivery and controllable gene therapy.

Benefits of iron supplementation for low birth weight infants: a systematic review.

BACKGROUND: A number of studies have reported on the effects of iron supplementation in low birth weight infants; however, no systematic review of the available evidence has been conducted to date. Hence, we performed a systematic review of the literature to examine the effects of iron supplementation on hematologic iron status, growth, neurodevelopment, and adverse effects in low birth weight/premature infants. METHODS: We searched the Cochrane Library, Medline, and PubMed for articles reporting on the effects of iron supplementation in low weight infants. The following search terms were used: "preterm born infant(s)/children"; "preterm infants"; "prematurely born children" "weight less than 1500 g at birth"; "born prematurely"; "low birth weight infant(s)"; "infants born preterm"; "prematurity"; "small-for-gestational age"; "very small gestational age infants"; "iron supplementation"; "iron intake"; "iron supplements"; "ferric and/or ferrous compounds"; and "ferrous sulphate/fumarate/sulfate". RESULTS: A total of 15 studies were identified and included in the systematic review. Supplemental iron was given orally or as an iron-fortified formula in 14/15 studies. The duration of treatment ranged from 1 week to 18 months. Iron supplementation significantly increased hematologic measures of iron status (including hemoglobin, hematocrit, serum ferritin) relative to placebo or over time in most studies. All controlled studies that examined iron-deficiency anemia (IDA)/ID reported a decreased prevalence of IDA/ID with iron supplementation. Dose dependent decreases in the prevalence of IDA/ID were reported in several studies. Of the 5 studies reporting on growth, none found any significant effect on growth-related parameters (length, height, weight, and head circumference). Only 2 studies reported on neurodevelopment; no marked effects were reported. There were no consistently reported adverse effects, including oxidative stress, inhibited nutrient absorption, morbidity, or the requirement for blood transfusion. CONCLUSION: The available data suggest that iron supplementation increases the levels of hematologic indicators of iron status and reduces the prevalence of IDA/ID in low birth weight/premature infants. There is insufficient evidence to make a definitive statement regarding the effects of iron supplementation on growth, neurodevelopment, or the occurrence of adverse effects in low birth weight/premature infants.

[Effect of the mixed liquor of danshen and magnesium sulfate injection on IgG and IgM in serum of rabbits with lumbar intervertebral disc herniation].

OBJECTIVE: To explore the effect of the mixed liquor of danshen and magnesium sulfate injection on inflammatory reaction caused by autoimmune response of rabbits with lumbar intervertebral disc herniation. METHODS: Sixty rabbits were divided into blank group (10 rabbits), sham operation group (10 rabbits), model group (40 rabbits) according to method of random digits table. Then model group was divided into made group (group A, 10 rabbits), normal saline group (group B, 10 rabbits), aescin natrium group (group C, 10 rabbits) and danshen and magnesium sulfate injection group (group D,10 rabbits). After model success of lumbar intervertebral disc herniation, different drugs were given to rabbits with lumbar intervertebral disc herniation by ear margin vein. The rabbits of the group C,B,D were respectively given aescin natriu (0.5 mg/kg), normal saline (5 ml/kg), danshen and magnesium sulfate injection (2.0 mg/kg). The rabbits of blank group, sham operation group and group A were not given any disposal. The IgG and IgM level in serum of different groups were determined with ELISA method in fourteen day after model success and drugs given. RESULTS: The level of IgG and IgM in the group A was higher than that of blank group and sham operation group (P < 0.05). The level of IgG and IgM in the group D was lower than that of group B,C (P < 0.05). CONCLUSION: The mixed liquor of danshen () and magnesium sulfate injection could inhibit inflammatory reaction caused by autoimmune response of lumbar intervertebral disc herniation,which provides a new alternative for lumbar intervertebral disc herniation.

[Randomized controlled clinical study on ginger-partitioned moxibustion for patients with cold-damp stagnation type primary dysmenorrhea].

OBJECTIVE: To observe the effect of ginger-partitioned moxibustion in the treatment of patients with primary dysmenorrhea (PD) of cold-damp stagnation type. METHODS: A total of 209 PD patients were randomized into moxibustion group (n=105) and control group (medication group, n=104). Patients of the former group were treated with ginger-partitioned moxibustion at Shenque (CV 8) and Guanyuan (CV 4), once daily for 3 days in the first menstrual cycle, and 3 days before menstruation and once daily for 6 days in the 2nd and 3rd menstrual cycles, and those of control group were asked to take Yueyueshu Granules (a Chinese herbal patent drug for relieving PD). Clinical symptom scores were assessed before and after the treatment. RESULTS: After the treatment, of the 105 and 104 cases in the moxibustion and control groups, the cured, markedly effective, effective and failed cases were 58 (55.24%) and 32 (30.77%), 37 (35.24%) and 33 (31.73%), 5 (4.76%) and 24 (23.08%), and 5 (4.76%) and 15 (14.42%), respectively. The total therapeutic effect of moxibustion group wassignificantly better than that of control group (P<0.01). The effects of moxibustion for relieving mild, moderate and severe dysmenorrhea were evidently superior to those of medication (P<0.01). The symptom scores after the treatment and 3 months of post-treatment in moxibustion group were significantly lower than those of control group (P<0.01). CONCLUSION: Ginger-partitioned moxibustion therapy was effective for PD of cold-damp stagnation type.