Study on the effect and mechanism of Zhenzhu Tongluo pills in treating diabetic peripheral neuropathy injury.

BACKGROUND: As a traditional Mongolian medicine, Zhenzhu Tongluo pills has played a good neuroprotective function in clinic. However, the key mechanisms by which it works are poorly studied. OBJECTIVES: To study the effect and mechanism of Zhenzhu Tongluo pills in treating diabetic peripheral neuropathy injury. METHODS: Diabetic peripheral neuropathy model was established by injecting STZ into rats. Physiological, behavioral, morphological and functional analyses were used to evaluate that the overall therapeutic effect of rats, ELISA, qRT-PCR, Western blot, immunohistochemical staining, HE staining and TUNEL staining were used to further study the related mechanism. RESULTS: Zhenzhu Tongluo pills can significantly improve the physiological changes, behavioral abnormalities, structural and functional damage in diabetic peripheral neuropathy rats, which may be related to the anti-inflammatory and anti-apoptotic effects that realized by regulating PI3K/AKT, MAPK, NF-κB signaling pathways. CONCLUSIONS: Zhenzhu Tongluo pills has neuroprotective effect, and anti-inflammatory and anti-apoptosis may be the important way of its function.

Glucose-Regulated Protein 78 Targeting ICG and DOX Loaded Hollow Fe3O4 Nanoparticles for Hepatocellular Carcinoma Diagnosis and Therapy.

Purpose: Liver cancer is considered as the third leading cause of cancer-related deaths, with hepatocellular carcinoma (HCC) accounting for approximately 90% of liver cancers. Improving the treatment of HCC is a serious challenge today. The primary objective of this study was to construct SP94-Fe3O4@ICG&DOX nanoparticles and investigate their potential diagnosis and treatment effect benefits on HCC. Methods: Firstly, we synthesized and characterized SP94-Fe3O4@ICG&DOX nanoparticles and confirmed their in vitro release behavior, photothermal and photodynamic performance. Moreover, the in vivo imaging capability was also observed. Finally, the inhibitory effects on Hepa1-6 in vitro and in vivo were observed as well as biosafety. Results: SP94-Fe3O4@ICG&DOX nanoparticles have a size of ~22.1 nm, with an encapsulation efficiency of 45.2% for ICG and 42.7% for DOX, showing excellent in vivo MPI and fluorescence imaging capabilities for precise tumor localization, and synergistic photo-chemotherapy (pH- and thermal-sensitive drug release) against tumors under irradiation. With the assistance of a fluorescence molecular imaging system or MPI scanner, the location and contours of the tumor were clearly visible. Under a constant laser irradiation (808 nm, 0.6 W/cm2) and a set concentration (50 µg/mL), the temperature of the solution could rapidly increase to ~45 °C, which could effectively kill the tumor cells. It could be effectively uptaken by HCC cells and significantly inhibit their proliferation under the laser irradiation (100% inhibition rate for HCC tumors). And most importantly, our nanoparticles exhibited favorable biocompatibility with normal tissues and cells. Conclusion: This versatile agent can serve as an intelligent and promising nanoplatform that integrates multiple accurate diagnoses, precise positioning of cancer tissue, and effective coordination with synergistic tumor photodynamic therapy.

Anti-depression-like effect of Mogroside V is related to the inhibition of inflammatory and oxidative stress pathways.

Siraitia grosvenorii (SG) is an edible medicinal plant found mainly in Guangxi, China, and Mogroside V (MGV) is the main component of SG extract. Previous research has shown that SG and MGV exert anti-inflammatory, antioxidative and neuroprotective effects. However, it is not clear whether MGV has anti-depression-like effect. In this study, we evaluated the neuroprotective effects and anti-depression-like effect of MGV both in vitro and in vivo. By performing in vitro tests, we evaluated the protective effects of MGV on PC12 cells with corticosterone-induced injury. In vivo tests, we used the chronic unpredictable mild stress (CUMS) depression model. Fluoxetine (10 mg/kg/day) and MGV (10 or 30 mg/kg/day) were administered by gavage for 21 days, and the open field test (OFT), novelty suppressed feeding test (NSFT), Tail suspension test (TST), and forced Swimming test (FST) were used to evaluate the depressive-like behaviors. In addition, we investigated the role of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and anti-inflammatory cytokine (IL-4) in the hippocampal and cortex tissues. The levels of Superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-PX) in hippocampal and cortex tissues were also measured. Pathological changes in the hippocampal dentate gyrus and cortex regions were detected by immunofluorescence and Western blotting was used to measure the protein expression of BDNF, TrkB, TNF-α, and AKT. The results showed that MGV had a protective effect on PC12 cells with corticosterone-induced incurred injury. In addition, MGV treatment relieved the depressive symptoms and significantly reduced inflammatory levels (IL-1ß, IL-6, and TNF-α). MGV also significantly reduced oxidative stress damage and reduced the levels of apoptosis in hippocampal nerve cells. These results suggested that the anti-depressive effect of MGV may occur through the inhibition of inflammatory and oxidative stress pathways and the BDNF/TrkB/AKT pathway. These findings provide a new concept for the identification of new anti-depressive strategies.

Treatment of polycystic ovary syndrome and its associated psychiatric symptoms with the Mongolian medicine Nuangong Qiwei Pill and macelignan.

ETHNOPHARMACOLOGICAL RELEVANCE: The Mongolian medicine Nuangong Qiwei Pill (NGQW) is a folk prescription with a long history of use by the Mongolian people. NGQW comprises seven Mongolian medicines, which have the effects of regulating and nourishing blood, warming the uterus, dispelling cold and relieving pain. For a long time, it has been used as a good remedy for gynecological diseases, with remarkable curative effects, favored by the majority of patients and recommended by doctors. Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder that can lead to menstrual disorders or infertility. In the gynecological classification of Mongolian medicine, polycystic ovary syndrome has not been distinguished in detail, and the mechanism of NGQW in the treatment of polycystic ovary syndrome has not been scientifically studied and standardized. AIM OF THE STUDY: The aim of this study was to clarify the mechanism of action of NGQW and macelignan in the treatment of PCOS and to provide a reference for the clinical application of these drugs. MATERIALS AND METHODS: The effect of intragastric administration of NGQW and macelignan on PCOS model mice was observed. The mental status of mice was examined behaviorally, and serum hormone levels and oxidative stress parameters were measured by ELISA. Giemsa staining was used to detect the reproductive cycle, and HE staining was used to observe the ovarian status. Immunofluorescence staining was performed to observe the proliferation and apoptosis of ovarian granulosa cells. qRT‒PCR was conducted to measure the expression of IL-6, BAX, BCL-2, and estrogen synthesis-related genes in ovarian tissue and particle cells. RESULTS: In the dehydroepiandrosterone (DHEA)-induced PCOS model mice, both NGQW and macelignan improved the estrous cycle; increased the estradiol (E2) content; lowered testosterone (T), progesterone (P) and luteinizing hormone (LH) levels; reduced the number of polycystic follicles; promoted granulosa cell proliferation; reduced granulosa cell apoptosis; and alleviated depression and anxiety. In addition, Nuangong Qiwei Pill and macelignan reduced the mRNA levels of the ovarian inflammatory factor IL-6; improved the disordered levels of the antioxidant indicators GSH, MDA, and SOD; and activated the TGF-ß3 signaling pathway to increase the transcription of Cyp19a1, which increases estrogen secretion. CONCLUSION: NGQW and macelignan can treat PCOS through the TGF-ß3/Smad/Cyp19a1 signaling pathway to regulate the secretion ability of ovarian granulosa cells. Our research justifies the traditional use of NGQW to treat PCOS and enriches the scope of action of macelignan.

Anti-depressant-like effects of rannasangpei and its active ingredient crocin-1 on chronic unpredictable mild stress mice.

Major depressive disorder is one of the most common neuropsychiatric diseases and it is a global public health problem that leads to disabilities. Currently, there is a growing need to explore novel strategy to cure major depressive disorder due to the limitation of available treatments. Rannasangpei (RSNP) is a traditional Tibetan medicine which acts as a therapeutic agent in various acute or chronic diseases, including cardiovascular diseases and neurodegenerative diseases. Crocin-1 a coloring ingredient of saffron which exhibited anti-oxidative and anti-inflammatory properties. Here, we aimed to illustrate whether RSNP and its active ingredient crocin-1 rescue depressive-like phenotypes in chronic unpredictable mild stress (CUMS) induced mouse model of depression. Our results showed that peripheral administration of RSNP or crocin-1 ameliorated the depressive-like behaviors in CUMS-treated mice, as demonstrated by the forced swimming test and tail suspension test. Furthermore, RSNP or crocin-1 treatment reduced oxidative stress in the peripheral blood and hippocampus of the CUMS-treated mice. Additionally, the dysregulated immune system response, as demonstrated by the increased expression of the pro-inflammatory factors (tumor necrosis factor-α and interleukin-6) and the decreased expression of the anti-inflammatory factor-interleukin-10 in the prefrontal cortex and/or hippocampus of CUMS-treated mice, were at least partially restored by RSNP or crocin-1 treatment. RSNP or crocin-1 also restored apoptotic protein marker (Bcl-2 and Bax) levels in the prefrontal cortex and hippocampus of the CUMS-treated mice. Moreover, our data indicated that RSNP or crocin-1 increased astrocyte number and brain-derived neurotrophic factor levels in the hippocampus of CUMS-treated mice after RSNP or crocin-1 administration. Taken together, our study for the first time revealed an anti-depressant effect of RSNP and its active ingredient crocin-1 in a mouse model of depression, with involvement of oxidative stress, inflammatory response and apoptotic pathway.

A biomimetic nanoplatform for precise reprogramming of tumor-associated macrophages and NIR-II mediated antitumor immune activation.

The therapeutic effects of photothermal therapy (PTT) are dependent on the photothermal conversion efficiency of photothermal agents (PTAs) in tumors and the subsequent activation of the antitumor immune system. However, the insufficient tumor accumulation of current PTAs and the inevitable recruitment of tumor-associated macrophages (TAMs) could further compromise the antitumor activities of PTT. To address these issues, a biomimetic photothermal nanoplatform Au@Fe-PM is developed for the targeted remodeling of TAMs, which promotes the antitumor immunity of PTT. Au nanorods with second near-infrared (NIR-II) absorptions are fabricated to serve as PTAs to induce immunogenic cell death in tumor cells. The ferric hydroxide shell coated on Au nanorods can release iron ions to repolarize M2-like TAMs into the tumoricidal M1 phenotype via P38 and STAT1-mediated signaling pathways. Moreover, the surface decoration of platelet membranes endows biomimetic nanoplatform with enhanced tumor targeting ability for precise tumor ablation and TAM regulation. Consequently, Au@Fe-PM under NIR-II laser irradiation exhibits significantly higher inhibitory effects in a poor immunogenic 4T1 tumor-bearing mouse model with a 50% complete remission rate compared to conventional PTT (0%). By simultaneously reversing the immunosuppressive tumor microenvironment, this biomimetic nanoplatform offers a promising strategy for enhancing the antitumor efficacy of PTT. STATEMENT OF SIGNIFICANCE: The therapeutic effects of current photothermal therapy (PTT) are hindered by the insufficient tumor accumulation of conventional photothermal agents and the recruitment of immunosuppressive tumor-associated macrophages (TAMs) after PTT. Herein, we report a biomimetic iron-based second near-infrared (NIR-II) photothermal nanoplatform (Au@Fe-PM) for targeted TAMs reprogramming and NIR-II mediated anti-tumor immunity. Au@Fe-PM can actively target the tumor site with the help of surface-decorated platelet membranes. Meanwhile, iron ions would be released from Au@Fe-PM in acidic lysosomes to reprogram TAMs into tumoricidal M1-like macrophages, which promotes the antitumor responses elicited by NIR-II PTT, thereby contributing to remarkable tumor inhibitory effects, with 50% higher complete remission rate than that of conventional PTT.

3D Microfluidic System for Evaluating Inhibitory Effect of Chinese Herbal Medicine Oldenlandia diffusa on Human Malignant Glioma Invasion Combined with Network Pharmacology Analysis.

OBJECTIVE: To investigate the anti-invasion efficacy of the ethanol extract of Oldenlandia diffusa Will. (EEOD) on a three-dimensional (3D) human malignant glioma (MG) cell invasion and perfusion model based on microfluidic chip culture and the possible mechanism of action of Oldenlandia diffusa Will. (OD). METHODS: The comprehensive pharmacodynamic analysis method in this study was based on microfluidic chip 3D cell perfusion culture technology, and the action mechanism of Chinese medicine (CM) on human MG cells was investigated through network pharmacology analysis. First, the components of EEOD were analyzed by ultraperformance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Then, cell viability and apoptosis were assessed to determine the optimum concentration of EEOD for invasion experiments, and two-dimensional (2D) migration and invasion abilities of U87 and U251 MG cells were evaluated using scratch wound and Transwell assays. The possible mechanism underlying the effects of EEOD on glioma was analyzed through a network pharmacology approach. RESULTS: Thirty-five compounds of EEOD were detected by UPLC-Q-TOF/MS. EEOD suppressed the viability of MG cells, promoted their apoptosis, and inhibited their migratory and invasive potentials (all P<0.05). Network pharmacology analysis showed that OD inhibited the invasion of MG cells by directly regulating MAPK and Wnt pathways through MAPK, EGFR, MYC, GSK3B, and other targets. The anti-invasion effect of OD was also found to be related to the indirect regulation of microtubule cytoskeleton organization. CONCLUSIONS: ]EEOD could inhibit the invasion of human MG cells, and the anti-invasion mechanism of OD might be regulating MAPK and Wnt signaling pathways and microtubule cytoskeleton organization.

The relationship between different iodine sources and nutrition in pregnant women and adults.

Background: Different iodine supplement measures emerge along with the economy development in China. The article objectives are to compare and explore the relationship between iodine sources and nutrition of pregnant women and adults. Methods: A total of 2,145 pregnant women and 1,660 adults were investigated by multi-stage random method. Questionnaire was used to collect basic information and the consumption of food, water, and iodine preparations. Household salt and individual urine and blood samples were collected, and thyroid function and morphology of pregnant women were measured. Results: The median urinary iodine concentration (MUIC) of pregnant women (164.49 µg/L) was lower than adults (187.30 µg/L, p < 0.05). Iodine supplement with IS (iodized salt) was the main measure for pregnant women and adults, and the difference was mainly on the consumption of iodine preparations between pregnant women (5.19%) and adults (0.85%). Moreover, adults' dietary iodine intake from food (100.6 µg/day), IS (140.8 µg/day), and drinking water (6.0 µg/day) was higher than those of pregnant women (86.5, 107.2, and 3.5 µg/day, respectively). Compared with iodine supplement with IS, ISFP (IS + iodine-rich food + iodine preparations) could reduce the risk of iodine deficiency for pregnant women. The MUICs for pregnant women and adults of iodine supplements with IF (iodine-rich food) and ISF (IS + iodine-rich food) were lower. For pregnant women, thyroid nodule (11.90%) and peroxidase antibody (TPOAb) positive (9.32%) were high prevalent thyroid diseases, and habitation (urban/rural), gestation, annual income, and drinking water type would affect them. Conclusion: Pregnant women and adults had adequate iodine nutrition in four provinces. Their iodine supplement measures were different, the consumption of iodine preparations in pregnant women was higher, and their dietary iodine intake was lower than adults. ISFP was an effect measure for pregnant women to supplement iodine.

[Research on function of Feilike Mixture in stopping cough, eliminating phlegm and relieving asthma based on animal experiments and network pharmacology].

This study observed the pharmacological effects of Feilike Mixture(FLKM) in stopping cough, eliminating phlegm, and relieving asthma through animal experiments, and explored its mechanism using network pharmacology. The antitussive effect was detected by citric acid-induced guinea pig cough model, the expectorant effect by mouse phenol red excretion experiment and lipopolysaccharide-induced mucus hypersecretion rat model, and the antiasthmatic effect by histamine phosphate-induced guinea pig asthma model. The chemical components of FLKM were collected by TCMSP, TCMID, TCMIP, and BATMAN-TCM databases and literature search, and the potential active components were screened through ADMETlab 2.0. The targets of FLKM were obtained by STITCH, SwissTargetPrediction, and TCMSP, and the symptom targets of cough, phlegm, and asthma were acquired through SymMap database. After taking the intersection of FLKM targets and symptom targets, this study used the OECloud tool to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. RESULTS:: demonstrated that FLKM 0.43-1.74 g·kg~(-1) reduced the number of coughs in guinea pigs within 3 min(P<0.05, P<0.01), and FLKM 6-12 g·kg~(-1) increased the tracheal phenol red excretion in mice(P<0.01). Moreover, FLKM 2-8 g·kg~(-1) inhibited the number of goblet cells(P<0.05, P<0.01), and FLKM 7-11.2 g·kg~(-1) prolonged the incubation period of asthma(P<0.05). A total of 115 potential active components and 910 targets of FLKM were obtained through network pharmacological analysis. FLKM had 27, 12, and 7 targets for stopping cough, eliminating phlegm, and relieving asthma, respectively. The GO and KEGG enrichment analysis found that there were commonalities and characteristics, among which cytokine-cytokine receptor interaction and infectious disease-related signaling pathway were shared. FLKM has a good effect of stopping cough, eliminating phlegm, and relieving asthma through animal experiments and network pharmacology.

Study on association between height, weight, iodine supplementation and thyroid volume.

The policy of Universal Salt Iodisation (USI) could reduce population's thyroid volume (TVOL) in iodine deficiency areas. Conversely, the improved growth and developmental status of children might increase the TVOL accordingly. Whether the decreased TVOL by USI conceals the increase effect of height and weight on TVOL is unclear. The aim of this study was to analyse the association between height, weight, iodine supplementation and TVOL. Five national Iodine Deficiency Disorder surveys were matched into four pairs according to the purpose of analysis. County-level data of both detected by paired surveys were incorporated; 1:1 random pairing method was used to match counties or individuals. The difference of TVOL between different height, weight, different iodine supplementation measures groups and the association between TVOL and them were studied. The mean height and weight of children aged 8-10 years increased from 129·9 cm and 26·9 kg in 2002 to 136·2 cm and 32·1 kg in 2019, while the median TVOL decreased from 3·10 ml to 2·61 ml. Iodine supplementation measures can affect TVOL; after excluding iodine effects, the median TVOL was increased with the height and weight. On the other side, after excluding the influence of height and weight, the median TVOL remained decreased. Only age, weight and salt iodine were significantly associated with TVOL in multiple linear models. Development of height and weight in children is the evidence of improved nutrition. The decreased TVOL caused by iodised salt measures conceals the increase effect of height and weight on TVOL. Age, weight and salt iodine affect TVOL significantly.

Association of Seafood Consumption and Mercury Exposure With Cardiovascular and All-Cause Mortality Among US Adults.

Importance: Although seafood is known to contain heart-healthy omega-3 fatty acids, many people choose to limit their seafood consumption because of fear of mercury exposure from seafood. It is imperative to clarify the potential health effects of current mercury exposure in contemporary populations. Objective: To examine the association of seafood consumption and mercury exposure with all-cause and cardiovascular disease (CVD)-related mortality in the US general population. Design, Setting, and Participants: This prospective cohort study included adults 20 years or older who participated in the 2003 to 2012 cycles of the National Health and Nutrition Examination Survey; data were linked to mortality records through December 31, 2015. Data analysis was performed from January to March 10, 2021. Exposures: Seafood consumption was assessed through two 24-hour dietary recalls, and mercury exposure was assessed by blood mercury levels. Main Outcomes and Measures: All-cause and CVD-related mortality. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs of mortality associated with usual seafood consumption and blood mercury concentration quartiles. Results: This study included 17 294 participants (mean [SD] age, 45.9 [17.1] years; 9217 [53.3%] female) with a mean (SD) blood mercury concentration of 1.62 (2.46) µg/L. During 131 276 person-years of follow-up, 1076 deaths occurred, including 181 deaths from CVD. The multivariable-adjusted HR for an increase in seafood consumption of 1 oz equivalent per day and all-cause mortality was 0.84 (95% CI, 0.66-1.07) and for CVD-related mortality was 0.89 (95% CI, 0.54-1.47). Blood mercury level was not associated with all-cause or CVD-related mortality. Comparing the highest with the lowest quartile of blood mercury concentration, the multivariable-adjusted HRs were 0.82 (95% CI, 0.66-1.05) for all-cause mortality and 0.90 (95% CI, 0.53-1.52) for CVD-related mortality. Conclusions and Relevance: In this cohort study of US adults, seafood consumption and mercury exposure with the current seafood consumption level were not significantly associated with the risk of all-cause or CVD-related mortality. These findings may inform future public health guidelines regarding mercury exposure, seafood consumption, and cardiovascular health promotion.

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate.

SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine (NSDP) as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

A Hepatocellular Carcinoma Targeting Nanostrategy with Hypoxia-Ameliorating and Photothermal Abilities that, Combined with Immunotherapy, Inhibits Metastasis and Recurrence.

Hepatocellular carcinoma (HCC) is a common and highly malignant tumor that is prone to recurrence and metastasis and has no effective treatment. Unsurprisingly, its prognosis is quite poor; early detection methods and effective low-toxicity treatments are urgently needed. To achieve these goals, we designed a multifunctional, U.S. Food and Drug Administration-approved Prussian blue (PB) nanoparticle (NP) with a porous metal organic frame loaded with sorafenib (SF), conjugated with HCC-specific targeting peptide SP94 and the near-infrared dye cyanine (Cy)5.5. These NPs are amenable to multimodal imaging for dynamic monitoring of their biodistribution and tumor-targeting effects. The SP94-PB-SF-Cy5.5 NPs achieved targeted delivery and controlled SF release and exhibited good photothermal effects. In this strategy, photothermal therapy and SF treatment complement each other, reducing the side effects of SF and achieving a therapeutic effect without local tumor recurrence. In addition, the catalase-like ability of the NPs alleviates tumor hypoxia, and their photothermal effects induce immunogenic cell death, leading to the release of tumor-associated antigens. These effects combine to trigger an antitumor immune response; the NPs also displayed promising inhibitory effects on tumor metastasis and recurrence and produced an abscopal effect and long-term immunological memory when combined with antiprogrammed death-ligand 1 (PD-L1) immunotherapy. These safe, multifunctional NPs represent a valuable treatment option for HCC. In addition, this next-generation treatment model may provide some ideas for the management of HCC and other cancers.

[Effects of hedyotis diffusa on mitochondrial membrane potential and expressions of apoptosis-related genes in human gastric cancer cell line MNK-45].

Objective: To investigate the effects of hedyotis diffusa (injection) on mitochondrial membrane potential and expressions of apoptosis-related genes in human gastric cancer cell line MNK-45 cells. Methods: The human gastric cancer MNK-45 cells were divided into 4 groups, each group was set with 3 replicates. The control group was MNK-45 cells without added hedyotis diffusa; the 3 groups of experimental groups were treated with hedyotis diffusa at final concentrations of 20 , 30, 40 µg / ml respectively; each group was incubated for 48 h in a 5% carbon dioxide incubator, and the morphological changes of the cells were observed under a laser confocal microscope. Mitochondrial membrane potential was detected by flow cytometry. The expressions of Cytochrome C (Cyt c), caspase3 and caspase9 genes and proteins were detected by qRT-PCR and Western blot respectively. Results: Compared with the control group, the mitochondrial membrane potentials of MNK-45 cells were significantly reduced in the hedyotis diffusa treated groups at final concentrations of 20, 30, and 40 µg / ml (P＜0. 01). The gene expressions of Cyt c, caspase3, and caspase9 were significantly up-regulated (P＜0. 01) and their protein expressions were also significantly increased (P＜0. 05 or P＜0. 01). The 40 µg / ml hedyotis diffusa treatment group performed best. Conclusion: In the final concentration range of 20 ~ 40 µg / ml, hedyotis diffusa can reduce human gastric cancer MNK-45 cells mitochondrial membrane potential, induce apoptosis and up-regulate Cyt c, caspase3 and caspase9 gene expressions.

Core-Shell-Satellite Nanomaces as Remotely Controlled Self-Fueling Fenton Reagents for Imaging-Guided Triple-Negative Breast Cancer-Specific Therapy.

Triple-negative breast cancer (TNBC) is highly aggressive and insensitive to conventional targeted therapies, resulting in poor therapeutic outcomes. Recent studies have shown that abnormal iron metabolism is observed in TNBC, suggesting an opportunity for TNBC treatment via the iron-dependent Fenton reaction. Nevertheless, the efficiency of current Fenton reagents is largely restricted by the lack of specificity and low intracellular H2 O2 level of cancer cells. Herein, core-shell-satellite nanomaces (Au @ MSN@IONP) are fabricated, as near-infrared (NIR) light-triggered self-fueling Fenton reagents for the amplified Fenton reaction inside TNBC cells. Specifically, the Au nanorod core can convert NIR light energy into heat to induce massive production of intracellular H2 O2 , thereby the surface-decorated iron oxide nanoparticles (IONP) are being fueled for robust Fenton reaction. By exploiting the vulnerability of iron efflux in TNBC cells, such a self-fueling Fenton reaction leads to highly specific anti-TNBC efficacy with minimal cytotoxicity to normal cells. The PI3K/Akt/FoxO axis, intimately involved in the redox regulation and survival of TNBC, is demonstrated to be inhibited after the treatment. Consequently, precise in vivo orthotopic TNBC ablation is achieved under the guidance of IONP-enhanced magnetic resonance imaging. The results demonstrate the proof-of-concept of NIR-light-triggered self-fueling Fenton reagents against TNBC with low ferroportin levels.

Effect of Hyperbaric Oxygen on Tissue Damage and Expression of Adhesion Molecules and C3 in a Rat Model of Renal Ischemia-Reperfusion Injury After Kidney Transplantation.

BACKGROUND The aim of this study was to investigate the protective effect and mechanism of hyperbaric oxygen (HBO) in a rat model of renal ischemia-reperfusion injury following kidney transplantation. MATERIAL AND METHODS Sprague Dawley rats were randomly divided into 3 groups (n=18): sham group, kidney transplantation group, and HBO treatment group. Six rats in each group were sacrificed at 1, 3, and 5 hours after reperfusion, and serum and renal tissue were then collected. The serum creatinine levels and histopathological changes of the renal tissue were detected. ICAM-1, VCAM-1, and C3 expression levels were also detected by immunohistochemical staining or real-time polymerase chain reaction. RESULTS Renal function was damaged in the kidney transplantation group and the HBO treatment group compared with sham group (P<0.05). Renal histopathological changes, including tubular cell swelling, tubular dilatation, and hyaline casts, were remarkably reduced in the HBO treatment group compared to the kidney transplantation group. In the immunohistochemical examination, the expression levels of ICAM-1, VCAM-1, and C3 were obviously increased in the kidney transplantation group and the HBO treatment group; moreover, the levels in the HBO treatment group were significantly lower than in the kidney transplantation group (P<0.05). In addition, the ICAM-1 and C3 mRNA levels were increased in the kidney transplantation group and HBO treatment group, but the levels of in the HBO treatment group them were significantly decreased compared to the kidney transplantation group that at 3 and 5 hours after reperfusion (P<0.05). CONCLUSIONS HBO treatment exerted a protective effect on renal function through inhibition of adhesion molecule overexpression and complement system activation in a rat model of renal ischemia-reperfusion injury after kidney transplantation.

Ferrimagnetic Vortex Nanoring-Mediated Mild Magnetic Hyperthermia Imparts Potent Immunological Effect for Treating Cancer Metastasis.

Cancer metastasis is a serious concern and a major reason for treatment failure. Herein, we have reported the development of an effective and safe nanotherapeutic strategy that can eradicate primary tumors, inhibit metastasizing to lung, and control the metastasis and growth of distant tumors. Briefly, ferrimagnetic vortex-domain iron oxide nanoring (FVIO)-mediated mild magnetic hyperthermia caused calreticulin (CRT) expression on the 4T1 breast cancer cells. The CRT expression transmitted an "eat-me" signal and promoted phagocytic uptake of cancer cells by the immune system to induce an efficient immunogenic cell death, further leading to the macrophage polarization. This mild thermotherapy promoted 88% increase of CD8+ cytotoxic T lymphocyte infiltration in distant tumors and triggered immunotherapy by effectively sensitizing tumors to the PD-L1 checkpoint blockade. The percentage of CD8+ cytotoxic T lymphocytes can be further increased from 55.4% to 64.5% after combining with PD-L1 blockade. Moreover, the combination treatment also inhibited the immunosuppressive response of the tumor, evidenced by significant down-regulation of myeloid-derived suppressor cells (MDSCs). Our results revealed that the FVIO-mediated mild magnetic hyperthermia can activate the host immune systems and efficiently cooperate with PD-L1 blockade to inhibit the potential metastatic spreading as well as the growth of distant tumors.

Inverse Association Between Serum Vitamin B12 Concentration and Obesity Among Adults in the United States.

Introduction: Several studies have suggested that vitamin B12 deficiency is more common in obese individuals. We evaluated the cross-sectional associations of serum vitamin B12 concentrations with obesity in a nationally representative sample of adults in the United States. Methods: We included 9,075 participants aged ≥20 years in the National Health and Nutrition Examination Survey 2011-2014. Serum vitamin B12 concentrations were measured by electrochemiluminescence immunoassay. Obesity was defined as BMI ≥30 kg/m2. We used logistic regression with sample weights to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). Results: Serum vitamin B12 concentrations were lower among obese adults compared with non-obese adults. After adjustment for age, gender, race/ethnicity, socioeconomic status, dietary and lifestyle factors, use of medications that could affect the serum vitamin B12 levels, dietary supplement use and fasting time, the multivariable-adjusted ORs (95% CIs) of obesity were 1.00 (reference), 0.95 (0.79, 1.14), 0.86 (0.74, 0.99), and 0.71 (0.60, 0.84) (p for trend <0.001) for increasing quartiles of serum vitamin B12 concentrations. Conclusions: In a large nationally representative sample of U.S. adults, higher serum vitamin B12 levels were inversely associated with obesity. Further investigation is needed to understand the underlying mechanisms.

Synergistic triple-combination therapy with hyaluronic acid-shelled PPy/CPT nanoparticles results in tumor regression and prevents tumor recurrence and metastasis in 4T1 breast cancer.

Breast cancer is characterized by high aggression, poor prognosis, and high recurrence rate. Early detection and specific targeted treatment with less toxicity are the ultimate goals for breast cancer therapy. To improve antitumor therapeutic effects, we developed a novel polypyrrole nanoparticle using the near infrared dye IRDye800CW with camptothecin (CPT)-conjugated hyaluronic acid (HA) shell (PPy@CPT-HA-IRDye800CW) and performed a photothermal therapy (PTT), along with chemotherapy, guided by fluorescence and photoacoustic dual-modality imaging, in combination with immunotherapy. Irradiation with near infrared (NIR) light offered a strong PTT effect and promoted CPT drug release in tumors. Moreover, we found that chemo-photothermal therapy with PPy@CPT-HA-IRDye800CW NPs, in combination with immune checkpoint inhibitor anti-PD-L1 immunotherapy, synergistically enhanced the anti-tumor immune response, thereby eliminating primary breast cancer and preventing tumor metastases and recurrences in 4T1 tumor-bearing mice. This approach may provide important clues for the clinical management of breast cancer and other malignant tumors.

The efficacy and safety of inositol supplementation in preterm infants to prevent retinopathy of prematurity: a systematic review and meta-analysis.

BACKGROUND: Inositol supplementation has been linked to beneficial effects on reducing the incidence of retinopathy of prematurity (ROP); however, it's controversial. The meta-analysis aimed to check out the efficacy and safety of inositol supplementation in preterm infants for preventing ROP. METHODS: We conducted searches through PubMed, EMBASE, Medline, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, ClinicalTrials.gov website and conference proceedings. Randomized controlled trials comparing inositol supplementation with placebo were included. Two independent reviewers performed screening, review, and extraction. Statistical analysis was performed using R Project. RESULTS: Six studies (1194 infants) were proved eligible. In comparison with placebo, inositol supplementation revealed no effect on the incidence of severe ROP (relative risk [RR] = 0.49, 95% confidence interval [CI], 0.18-1.32; heterogeneity, P = .02; I2 = 66%; low quality of evidence [QOE]), mortality (RR = 1.25, 95% CI, 0.82-1.90; heterogeneity, P = .07; I2 = 51%; low QOE), all stages of ROP (RR = 0.98, 95% CI, 0.87-1.11; heterogeneity, P = .41; I2 = 0%; moderate QOE) and other adverse events. Sensitivity analysis showed an increased mortality in the inositol group (RR = 1.55, 95% CI, 1.14-2.11; heterogeneity, P = .30; I2 = 18%) after removing the study Hallman 1986, and meta-regression showed a significant association between publication year and efficacy of inositol compared with placebo (ß = 0.1241; 95% CI, 0.0417-0.0026; z = 2.9527; p = .0032). CONCLUSIONS: Based on current evidence, inositol supplementation showed no significant effect on preventing severe ROP, and exploratory sensitivity analysis showed a trend toward an increase on mortality.