TMT and PRM Based Quantitative Proteomics to Explore the Protective Role and Mechanism of Iristectorin B in Stroke.

Stroke is a serious disease caused by the rupture or blockage of the cerebrovascular system. Its pathogenesis is complex and involves multiple mechanisms. Iristectorin B is a natural isoflavone that has certain anti stroke effects. In this study, an in vitro stroke injury model of glyoxylate deprivation was established using PC12 cells, which was used to evaluate the anti-stroke activity of Iristectorin B in ejecta stem. The results showed that Iristectorin B, a natural isoflavone derived from Dried Shoot, significantly reduced the damage to PC12 cells caused by oxygen glucose deprivation/reoxygenation, decreased apoptosis, enhanced cell survival and reduced Ca2+, LDH and ROS levels. The results showed that Iristectorin B had a significant protective effect on Na2S2O4-injured PC12 cells, and the mechanism may be related to the protective effect of neurons in the brain. After protein extraction and various analyses were performed, a series of cutting-edge technologies were organically combined to study the quantitative proteome of each group. Differential proteins were then analyzed. According to the protein screening principle, ferroptosis-related proteins were most closely associated with stroke. The differential proteins associated with ferroptosis screened were SLC3A2, TFR1 and HMOX1, with HMOX1 being the most significantly elevated and reduced via dosing. Iristectorin B may act as a protective agent against stroke by regulating ferroptosis, and SLC3A2, TFR1 and HMOX1 may serve as potential diagnostic biomarkers for stroke, providing additional evidence to support the importance of ferroptosis in stroke.

The protection impact of tectoridin on PC12 cell preventing OGD/R-caused damage through PI3K/AKT signaling channel.

The present work examined the effect exerted by tectoridin preventing oxygen glucose deprivation/reoxygenation (OGD/R) damage within PC12 cell. We incubated PC12 cells with Na2S2O4 (10 mM) for 2 h, and tectoridin at different concentrations was then added; based on methyl-thiazolyl-tetrazolium (MTT) and lactate dehydrogenase (LDH) tests, the protection impact was tested. 2',7'-dicholorofluorescein diacetate (DCFH-DA), Fluo-3AM, and 5, 5', 6, 6' -tetrachloro-1, 1', 3, 3' -tetraethyl-imidacarbocyanine iodide (JC-1) staining, and Western blotting were used for determining reactive oxygen species (ROS) level, intracellular Ca2+ content, mitochondrial membrane potential (MMP) and the related proteins contents. As a result, tectoridin could improve the cell viability and inhibit the release of LDH. In-depth studies demonstrated that tectoridin limited the overproduction of ROS and intracellular Ca2+ content and increased MMP, which showed a close association with ROS-mediated mitochondrial function. Moreover, tectoridin hindered apoptosis based on the up-regulation of the expressions of p-AKT, Bcl-2/Bax and p-mTOR. Furthermore, the level of Nrf2 was also improved by treatment of tectoridin. In addition, the expression of Bcl-2/Bax, p-Akt, p-mTOR, Nrf2, HO-1, NQO1 and GCLM were reduced by LY294002 and the protective role of tectoridin was limited by LY294002. The results unambiguously suggested that tectoridin reduced OGD/R-caused damage to PC12 cells and might ensure neuroprotection by stimulating the PI3K/AKT signaling channel.

Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy: A Double-Blind, Placebo-Controlled, Phase 2 Randomized Clinical Trial.

Importance: Safe and effective prophylactic therapies for radiation-induced dermatitis (RID) remain an unmet need. Objective: To determine if epigallocatechin-3-gallate (EGCG) solution reduces the incidence of RID in patients undergoing radiotherapy after breast cancer surgery. Design, Setting, and Participants: This phase 2 double-blind, placebo-controlled randomized clinical trial enrolled 180 patients with breast cancer receiving postoperative radiotherapy at Shandong Cancer Hospital and Institute in Shandong, China, between November 2014 and June 2019. Data analysis was performed from September 2019 to January 2020. Interventions: Participants were randomly assigned (2:1) to receive either EGCG solution (660 µmol/L) or placebo (0.9% NaCl saline) sprayed to the whole radiation field from day 1 of the radiation until 2 weeks after radiation completion. Main Outcomes and Measures: The primary end point was incidence of grade 2 or worse RID, defined by the Radiation Therapy Oncology Group scale. The secondary end points included RID index (RIDI), symptom index, changes in the skin temperature measured by infrared thermal images, and safety. Results: A total of 180 eligible patients were enrolled, of whom 165 (EGCG, n = 111; placebo, n = 54) were evaluable for efficacy (median [range] age, 46 [26-67] years). The occurrence of grade 2 or worse RID was significantly lower (50.5%; 95% CI, 41.2%-59.8%) in the EGCG group than in the placebo group (72.2%; 95% CI, 60.3%-84.1%) (P = .008). The mean RIDI in the EGCG group was significantly lower than that in the placebo group. Furthermore, symptom indexes were significantly lower in patients receiving EGCG. Four patients (3.6%) had adverse events related to the EGCG treatment, including grade 1 pricking skin sensation (3 [2.7%]) and pruritus (1 [0.9%]). Conclusions and Relevance: In this randomized clinical trial, prophylactic use of EGCG solution significantly reduced the incidence and severity of RID in patients receiving adjuvant radiotherapy for breast cancer. It has the potential to become a new choice of skin care for patients receiving radiotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02580279.

Dual-energy computed tomography could reliably differentiate metastatic from non-metastatic lymph nodes of less than 0.5 cm in patients with papillary thyroid carcinoma.

BACKGROUND: Dual-energy computed tomography (DECT) has been widely applied to detect lymph node (LN) and lymph node metastasis (LNM) in various cancers, including papillary thyroid carcinoma (PTC). This study aimed to quantitatively evaluate metastatic cervical lymph nodes (LNs) <0.5 cm in patients with PTC using DECT, which has not been done in previous studies. METHODS: Preoperative DECT data of patients with pathologically confirmed PTC were retrospectively collected and analyzed between May 2016 and June 2018. A total of 359 LNs from 52 patients were included. Diameter, iodine concentration (IC), normalized iodine concentration (NIC), and the slope of the energy spectrum curve (λHU) of LNs in the arterial and the venous phases were compared between metastatic and non-metastatic LNs. The optimal parameters were obtained from the receiver operating characteristic (ROC) curves. The generalized estimation equation (GEE) model was used to evaluate independent diagnostic factors for LNM. RESULTS: A total of 139 metastatic and 220 non-metastatic LNs were analyzed. There were statistical differences of quantitative parameters between the two groups (P value 0.000-0.007). The optimal parameter for diagnosing LNM was IC in the arterial phase, and its area under the curve (AUC), sensitivity, and specificity were 0.775, 71.9%, and 73.6%, respectively. When the three parameters of diameter, IC in the arterial phase, and NIC in the venous phase were combined, the prediction efficiency was better, and the AUC was 0.819. The GEE results showed that LNs located in level VIa [odds ratio (OR) 2.030, 95% confidence interval (CI): 1.134-3.634, P=0.017], VIb (OR 2.836, 95% CI: 1.597-5.038, P=0.000), diameter (OR 2.023, 95% CI: 1.158-3.532, P=0.013), IC in the arterial phase (OR 4.444, 95% CI: 2.808-7.035, P=0.000), and IC in the venous phase (OR 5.387, 95% CI: 3.449-8.413, P=0.000) were independent risk factors for LNM in patients with PTC. CONCLUSIONS: DECT had good diagnostic performance in the differentiation of cervical metastatic LNs <0.5 cm in patients with PTC.

CircHIF1A regulated by FUS accelerates triple-negative breast cancer progression by modulating NFIB expression and translocation.

Emerging evidence has demonstrated that circular RNAs (circRNAs) play critical roles in the development and progression of human cancer. However, the biological functions and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) remain to be investigated. In our present study, we found that the novel circRNA circHIF1A was significantly overexpressed in breast cancer tissues and that it was associated with metastasis, poor prognosis, and the TNBC subtype. Gain- and loss-of-function experiments were conducted to investigate the biological roles of circHIF1A in TNBC. Overexpression of circHIF1A significantly promoted TNBC growth and metastasis in vitro and in vivo, while knockdown of circHIF1A exerted the opposite effects. Mechanistically, circHIF1A modulated the expression and translocation of NFIB through posttranscriptional and posttranslational modifications, resulting in the activation of the AKT/STAT3 signaling pathway and inhibition of P21. The RNA binding protein FUS could regulate the biogenesis of circHIF1A by interacting with the flanking intron, and FUS was transcriptionally regulated by NFIB, thus forming the circHIF1A/NFIB/FUS positive feedback loop. Moreover, circHIF1A could be packaged into exosomes and was upregulated in the plasma of breast cancer patients. Our findings indicated that circHIF1A played a critical role in the growth and metastasis of TNBC via a positive feedback loop and that circHIF1A could be a promising biomarker for breast cancer diagnosis and a potential therapeutic target for TNBC treatment.

Evaluation of bone marrow infiltration in multiple myeloma using whole-body diffusion-weighted imaging and T1-weighted water-fat separation Dixon.

BACKGROUND: Multiple myeloma (MM) is a blood cancer caused by the unlimited proliferation of intramedullary plasma cells. The presence of focal lesions (FLs) is presumed to be a more relevant factor for patient outcomes and risk distribution than diffuse bone marrow signal abnormalities. Signal changes in these FLs also have a good correlation with prognosis. As the cell density increased, a lower apparent diffusion coefficient (ADC) value was found with the diffusion-weighted imaging (DWI) sequence. Therefore, whole-body magnetic resonance imaging (MRI) with DWI sequences is sensitive to cell density and viability and may be vital for disease detection and therapy response assessments. However, the correlation between the DWI signal and the degree of bone destruction and the proportion of bone marrow plasma cells (BMPC) was still unclear in patients with MM. Water-fat separation MRI is used mainly for evaluating liver and bone marrow fat quantification, and fat quantification in other diseases. Meanwhile, it is also possible to assess the extent of bone marrow invasion in medullary lesions. This study aimed to investigate the correlation between ADC values from whole-body DWI and water/fat MRI signals from T1-weighted water-fat separation in evaluating bone marrow infiltration in patients with MM. METHODS: The study included 35 patients with MM who underwent whole-body DWI and T1-weighted water-fat separation Dixon examinations before therapy. The ADC values, normalized fat signal intensity (nMfat), normalized water molecular signal intensity (nMwater), and normalized fat fraction (nFF) of the thoracolumbar spine was measured in FLs and the normal-appearing bone marrow (NABM). The differences in values were compared using the independent-samples t-test. The correlation between ADC values and water-fat MRI signals was estimated using the Pearson or Spearman correlation test. The correlation between the MRI above parameters and proportions of BMPC was also explored. RESULTS: Statistically significant differences were found between the mean ADC values in FLs and NABM (0.72 vs. 0.33 mm2/s, P<0.0001). Significantly elevated nMwater values and decreased nMfat and nFF values were observed in FLs; no correlations were found in NABM (P>0.05). The ADC value highly correlated with nMfat and nFF values and moderately with the nMwater value in FLs (r=-0.899, -0.834, 0.642, respectively, P<0.0001). Correlations were also observed between the proportion of BMPC and MRI parameters in MM (r=0.984, 0.716, -0.938, and -0.905, respectively, P<0.05). CONCLUSIONS: The ADC value combined with water-fat separation parameters could be used for evaluating thoracolumbar bone marrow infiltration in MM. All parameters correlated with the proportion of BMPC, which helped assess the early response in MM therapy.

Alkaloids extracted from Uncaria rhynchophylla demonstrate neuroprotective effects in MPTP-induced experimental parkinsonism by regulating the PI3K/Akt/mTOR signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Alkaloids isolated from Uncaria rhynchophylla (Miq.) Miq. ex Havil. (Rubiaceae), alkaloids (URA) have been used to treat diseases related to the central nervous system, such as Parkinson's disease. Nevertheless, the potential mechanisms underlying their neuroprotective effects are not well-understood. AIM OF THE STUDY: We investigated the neuroprotective effects of URAs in a mouse model of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) and the possible involvement of a molecular signaling pathway. MATERIALS AND METHODS: Two typical experiments for animal behavior despair, the spontaneous motor activity and the rotarod experiments, were employed to evaluate the efficacy of URAs in mice with PD symptoms. Dopamine (DA) neurons and their metabolism were evaluated using high-performance liquid chromatography-tandem mass spectrometry. The mechanism of action of the alkaloids was investigated by analyzing their effects on the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway using western blotting. RESULTS: URA treatment effectively improved the behaviors of the mice during the "spontaneous motor activity and latency to fall off the rotarod test". Moreover, URAs demonstrated a protective role in dopaminergic neurons by increasing the expression of the dopamine transporter and tyrosine hydroxylase, which were supposed to be reduced by MPTP, inhibiting dopamine turnover, and changing dopamine and relevant metabolites. In addition to its association with the increase in the Bcl-2/Bad ratio, URA treatment also attenuated the cleaved caspase-3 level and enhanced the phosphorylation of Akt and mTOR. CONCLUSION: These findings provide evidence that URA can effectively protect neurons from the neurotoxicity caused by MPTP in mouse models of PD by up-regulating the PI3K/Akt/mTOR signaling pathway.

Protection by rhynchophylline against MPTP/MPP+-induced neurotoxicity via regulating PI3K/Akt pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Isolated from Uncaria rhynchophylla (U. rhynchophylla), rhynchophylline (Rhy) has been applied for treating diseases related to central nervous system such as Parkinson's disease. Nevertheless, the molecular mechanism of the neuroprotective effect has not been well interpreted. AIM OF THE STUDY: To investigate the effects of Rhy on MPTP/MPP + -induced neurotoxicity in C57BL/6 mice or PC12 cells and study the mechanisms involved. MATERIALS AND METHODS: The neuroprotective effect of Rhy on MPTP-induced neurotoxicity was evaluated by spontaneous motor activity test, as well as a test of rota-rod on a rat model of Parkinson's disease. The numbers of TH-positive neurons in the substantia nigra pars compacta (SNpc) was assessed by immunohistological. CCK-8, lactate dehydrogenase (LDH), reactive oxygen species (ROS), the concentration of intracellular calcium ([Ca2+]i) and flow cytometry analysis were performed to evaluate the pharmacological property of Rhy on 1-methyl-4-phenylpyridinium (MPP+) induced neurotoxicity in PC12 cells. Besides, LY294002, a PI3K inhibitor was employed to determine the underlying molecular signaling pathway revealing the effect of Rhy by western-blot analysis. RESULTS: The results showed that Rhy exhibited a protective effect against the MPTP-induced decrease in tyrosine hydroxylase (TH)-positive fibers in the substantia nigra at 30 mg/kg, demonstrated by the immunohistological and behavioral outcomes. Furthermore, it has been indicated that cell viability was improved and the MPP+-induced apoptosis was inhibited after the treatment of Rhy at 20 µM, which were severally analyzed by the CCK-8 and the Annexin V/propidium iodide staining method. In addition, Rhy treatment attenuated MPP+-induced up-regulation of LDH, ([Ca2+]i), and the levels of ROS. Besides, it can be revealed from the Western blot assay that LY294002, as a selective Phosphatidylinositol 3-Kinase (PI3K) inhibitor, effectively inhibited the Akt phosphorylation caused by Rhy, which suggested that Rhy showed its protective property through the activated the PI3K/Akt signaling pathway. Moreover, the Rhy-induced decreases of Bax and caspase-3 as the proapoptotic markers and the increase of Bcl-2 as the antiapoptotic marker, were blocked by LY294002 in the MPP+-treated PC12 cells. CONCLUSIONS: Rhy exerts a neuroprotective effect is partly mediated by activating the PI3K/Akt signaling pathway.

Rapid screening and evaluation of XOD inhibitors and O2 •- scavenger from total flavonoids of Ginkgo biloba leaves by LC-MS and multimode microplate reader.

Superoxide anion radical scavenger and xanthine oxidase inhibitor play an important role in the treatment of several relevant human diseases. In the present study, ultrafiltration liquid chromatography-mass spectrometry coupled to microplate reader was applied to screen and identify superoxide anion radical scavengers and xanthine oxidase inhibitors from total flavonoids of Ginkgo biloba leaves. As a result, four compounds (quercetin, apigenin, kaempferol and isorhamnetin) were screened as xanthine oxidase inhibitors by ultrafiltration LC-MS, and the 50% scavenging concentration values of the screened flavonoids were lower than those for allopurinol. Lineweaver-Burk plot results indicated that kaempferol was a competitive xanthine oxidase inhibitor; the other flavonoids were all anticompetitive inhibitors. Four flavonoids-rutin, quercetin, kaempferol and isorhamnetin-were screened as superoxide anion radical scavengers by LC-MS. The results demonstrate that the method for screening and evaluation of superoxide anion radical scavenger and xanthine oxidase inhibitor from a complex mixture system is feasible and efficient.

Sec-O-glucosylhamaudol suppressed inflammatory reaction induced by LPS in RAW264.7 cells through inhibition of NF-κB and MAPKs signaling.

As a major bioactive compound from the Saposhnikovia divaricata (Turcz.) Schischk, sec-O-glucosylhamaudol (SOG), has been reported to have anti-nociceptive activity and high 5-lipoxygenase (5-LOX) activity. Nevertheless, the mechanism of the potential anti-inflammatory effects of SOG is unclear. The anti-inflammatory impacts of SOG in RAW 264.7 cell lines stimulated by LPS were explored in the present study. It was found that SOG dose-dependently reduced the emergence of inflammation cytokines, such as IL-6 and TNF-α in Raw264.7 murine macrophages stimulated by LPS. Real-time PCR assay demonstrated the SOG dose-dependently inhibited transcription of these cytokines as well. In addition, it was also found that NF-κB activation and MAPKs phosphorylation including p38, JNK and ERK1/2 induced by LPS were suppressed by SOG. Due to its anti-inflammatory activity, our results suggest that SOG might have therapeutic effects on inflammatory disease, such as acute lung injury or rheumatoid arthritis.

Middle cerebral artery thrombus susceptibility-weighted imaging mapping predicts prognosis.

BACKGROUND: Susceptibility weighted imaging and mapping (SWIM) of magnetic resonance imaging (MRI) is used to evaluate cerebral arterial thrombosis. The aim of this research was to assess susceptibility, length, and clot burden score (CBS) of thrombus in the middle cerebral artery (MCA) and their relationship with cerebral infarction and early clinical prognosis in patients with acute or subacute cerebral infarction. METHODS: In total, 56 patients with acute or subacute cerebral infarction (with the time from onset to admission less than 72 h) and only unilateral MCA occlusion were included in the current study. All the patients had the corresponding susceptibility vessel sign (SVS) on susceptibility-weighted imaging (SWI). Parameters including susceptibility, length, and CBS of thrombus were obtained from SWI and SWIM. The differences in susceptibility of different portions of the thrombus were compared with each other by one-way ANOVA test. The relationship between susceptibility and stroke onset time was further analyzed by Spearman correlation analysis, in addition to the relationships between susceptibility, length, CBS, diffusion-weighted imaging-Alberta stroke program early CT score (DWI-ASPECTS), and admission and discharge National Institutes of Health Stroke Scale (NIHSS). RESULTS: The susceptibility among different portions and different segments of thrombus showed no statistical difference. The susceptibility and length were weakly yet negatively correlated with DWI-ASPECTS (rs=-0.382, -0.457; P=0.004, 0.000). The susceptibility was weakly yet positively correlated with admission NIHSS and discharged NIHSS (rs=0.403, 0.430; P=0.002, 0.001). CBS was weakly yet positively correlated with DWI-ASPECTS (rs=0.349; P=0.008) and weakly yet negatively correlated with admission and discharged NIHSS (rs=-0.375, -0.335; P=0.004, 0.012). CONCLUSIONS: The susceptibility remained consistent regardless of location, length, and onset time, which indicates that the thrombus composition was similar when detected on SWI less than 72 h from the onset. Susceptibility and CBS may help to predict clinical severity and short-term clinical prognosis to some extent.

Total glucosides of paeony (TGP) extracted from Radix Paeoniae Alba exerts neuroprotective effects in MPTP-induced experimental parkinsonism by regulating the cAMP/PKA/CREB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: The totally-amounted glucosides of paeony (TGP), which are made up of paeoniflorin, albiflorin, oxypaeoniflorin as well as benzoylpaeoniflorin, constitute the Baishao' actively-working component extracted from Radix Paeonia alba employed in conventional oriental medicine aiming to treat cerebrovascular disorders, such as Parkinson's disease. However, its pharmacologic mechanism is not clear. AIM OF THE STUDY: The initial investigation was made on TGP's neuroprotective effects on PD of the mouse model based on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) as well as the identification of potential involvement of a molecular signaling pathway. MATERIALS AND METHODS: The evaluation of the behavioral damage as well as neurotoxicity in mice was made through MPTP. Spontaneous motor activity test, as well as a test of Rota-rod on mice was employed for the measurement of bradykinesia symptom. Additionally, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS-MS) works as the determiner of the main monoamine neurotransmitters dopamine (DA) along with its metabolites 3, 4-dihydroxyphenylacetic acid (DOPAC) as well as homovanillic acid (HVA) based on mouse hippocampus connected with the anti-Parkinson's disease like effect of TGP. Besides, the measurement of the effects of TGP treatment on the expressions level of TH, DAT, a-synuclein, p-CREBS133 as well as apoptosis influence was made with the help of western-blot assay with apoptosis-related markers such as Bax and Bcl-2. RESULTS: The results showed that TGP treatment lessened the behavior-based loss shown "in the spontaneous motor activity as well as the potential of falling to rotarod test". In addition, we found that pretreatment with TGP markedly improved motor coordination, striatal dopamine and its metabolite levels. Furthermore, pretreatment of TGP conducted the protection for dopaminergic neurons with the prevented MPTP-induced reductions within the tyrosine hydroxylase (TH), substantia nigra dopaminergic transporter (DAT), as well as increasing α-synuclein protein levels with transformed dopamine catabolism as well as inhibited dopamine turnover. Besides, TGP treatment helped reversed apoptosis signaling molecules Bcl-2/Bax' reduction; meanwhile improving p-CREBS133 the factor of growth signaling in the substantia nigra' decrease. CONCLUSION: These results suggested that TGP can enhance dopaminergic neuron's cell survival in the SNpc in virtue of the activated cAMP/PKA/CREB factor of growth on inhibiting the pathway of second messenger apoptosis as well. In conclusion, the current findings indicate TGP is expected to be a new cure for PD.

Improving breast cancer therapy using doxorubicin loaded solid lipid nanoparticles: Synthesis of a novel arginine-glycine-aspartic tripeptide conjugated, pH sensitive lipid and evaluation of the nanomedicine in vitro and in vivo.

Breast cancer is the leading cause of cancer mortality in women worldwide. To overcome the toxic side effects and multidrug resistance (MDR) during doxorubicin (DOX) chemotherapy, an arginine-glycine-aspartic (RGD) tripeptide modified, pH-sensitive solid lipid nanoparticles (SLNs) is employed in this study. In this study, a RGD conjugated, pH sensitive lipid was synthesized using glycerin monostearate (GMS) and adipic acid dihydrazide (HZ) as lipid materials and named RGD-HZ-GMS. RGD-HZ-GMS was applied to encapsulate DOX to construct a RGD modified, DOX loaded SLNs (RGD-DOX-SLNs). To evaluate the anticancer effect of RGD-DOX-SLNs, breast cancer cell line (MCF-7 cells) and DOX resistant cell line (MCF-7/ADR cells) were used. in vivo tumor suspension and toxicity effects were evaluated on mice bearing MCF-7/ADR cells breast cancer model. RGD-DOX-SLNs had a uniformly spherical shape. The mean particle size and zeta potential of the RGD-DOX-SLNs was 96.3 nm and 35.6 mV, respectively. RGD-DOX-SLNs showed 5.58 fold higher area under the plasma concentration - time curve (AUC) compared with DOX solution. Terminal half life (T1/2) and peak concentration (Cmax) of RGD-DOX-SLNs was 10.85 h and 39.12 ± 2.71 L/kg/h. in vitro and in vivo antitumor results indicate that RGD-DOX-SLNs might be a promising novel lipid carrier which could improve breast cancer therapy.

Comparison and Correlation of Magnetic Resonance Imaging and Clinical Severity in Nonhuman Immunodeficiency Virus Patients with Cryptococcal Infection of Central Nervous System.

BACKGROUND: The incidence of cryptococcal meningitis among immunocompetent patients increases, especially in China and imaging plays an important role. The current study was to find the correlation between magnetic resonance imaging (MRI) manifestation and clinical severity in nonhuman immunodeficiency virus patients with cryptococcal infection of central nervous system (CNS). METHODS: A total of 65 patients with CNS cryptococcal infection from August 2014 to October 2016 were retrospectively included in this study. All the patients had MRI data and clinical data. The patients were divided into two groups according to whether the patients were confirmed with identifiable underlying disease. Comparison and correlation of MRI and clinical data in both groups were investigated using independent sample t- test, Chi-square test, Mann-Whitney test and Spearman rank correlation analysis. RESULTS: In all 65 patients, 41 cases (41/65, 63.1%; Group 1) had normal immunity and 24 cases (24/65, 36.9%; Group 2) had at least one identifiable underlying disease. Fever, higher percentage of neutrophil (NEUT) in white blood cell (WBC), and increased cell number of cerebral spinal fluid (CSF) were much common in patients with underlying disease (Group 1 vs. Group 2: Fever: 21/41 vs. 21/24, χ2 = 8.715, P = 0.003; NEUT in WBC: 73.15% vs. 79.60%, Z = -2.370, P = 0.018; cell number of CSF: 19 vs. 200, Z = -4.298, P < 0.001; respectively). Compared to the patients with normal immunity, the lesions are more common in the basal ganglia among patients with identifiable underlying disease (Group 1 vs. Group 2: 20/41 vs. 20/24, χ2 = 7.636, P = 0.006). The number of the involved brain areas in patients with identifiable underlying disease were well correlated with the number of cells and pressure of CSF (r = -0.472, P = 0.031; r = 0.779, P = 0.039; respectively). CONCLUSIONS: With the increased number of the involved brain areas in patients with identifiable underlying disease, the body has lower immunity against the organism which might result in higher intracranial pressure and more severe clinical status.

Ginsenoside Rg2 protects PC12 cells against ß-amyloid25-35-induced apoptosis via the phosphoinositide 3-kinase/Akt pathway.

Alzheimer's disease (AD) is one of the most debilitating neurodegenerative diseases in an aging population. Excessive accumulation of ß-amyloid (Aß) has been proposed as a pivotal event in the pathogenesis of AD. Ginsenoside Rg2 has been reported to exert neuroprotective effects. However, the underlying mechanism for its neuroprotection is not well-understood. In this study, we investigated the protective effects of ginsenoside Rg2 on Aß25-35-induced neurotoxicity in PC12 cells and identified a potential molecular signaling pathway involved. The results showed that pretreatment of PC12 cells with ginsenoside Rg2 followed by Aß25-35 increased cell viability in a concentration-dependent manner compared to cells that were not pretreated. In addition, ginsenoside Rg2 pretreatment attenuated Aß25-35-induced increases in the release of lactate dehydrogenase, the intracellular calcium concentration, and levels of reactive oxygen species. Pretreatment with ginsenoside Rg2 increased the Bcl-2/Bax ratio. Moreover, ginsenoside Rg2 attenuated the cleavage of caspase-3 induced by Aß25-35 thereby improving cell survival. Ginsenoside Rg2 significantly enhanced the phosphorylation of Akt in PC12 cells. Additionally, pretreatment with the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, completely abolished the protective effects of ginsenoside Rg2 against Aß25-35-induced neuronal cell apoptosis. These findings unambiguously suggested that the protective effect of ginsenoside Rg2 against Aß25-35-induced apoptosis in PC12 cells was associated with enhancement of the PI3K/Akt signaling pathway.

Neuroprotection by Paeoniflorin in the MPTP mouse model of Parkinson's disease.

Paeoniflorin (PF) is a major bioactive ingredient in Radix Paeonia alba roots that has low toxicity and has been shown to have neuroprotective effects. Our in vitro experiments suggested that PF affords a significant neuroprotective effect against MPP+-induced damage and apoptosis in PC12 cells through Bcl-2/Bax/caspase-3 pathway. The objectives of the present study were to explore the potential neuroprotective effect of PF in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease (PD). Our results demonstrated that PF treatment ameliorated the behavioral deficits of "in spontaneous motor activity and latency to fall of the rotarod test", and reduced dopaminergic cell loss that were induced by MPTP in a dose-dependent manner in an in vivo model of PD. In addition, we found that treatment of PF protected dopaminergic neurons by preventing MPTP-induced decreases in striatal and substantia nigra dopaminergic transporter (DAT) and tyrosine hydroxylase (TH) protein levels, and by changing dopamine catabolism and inhibiting dopamine turnover. Furthermore, it was also associated with up-regulation of the Bcl-2/BAD ratio, and inhibition of the activation of caspase-9 and caspase-3. These results showed that PF promoted dopamine neuron survival in vivo due to the MAO-B inhibition, and the PI3K/Akt signaling pathway may have mediated the protection of PF against MPTP, suggesting that PF treatment might represent a neuroprotective treatment for PD.

miR-375 inhibits cancer stem cell phenotype and tamoxifen resistance by degrading HOXB3 in human ER-positive breast cancer.

Cancer stem cell (CSC) formation and epithelial-mesenchymal transition (EMT) are pivotal events in tumor cell invasion and metastasis. They have been shown to occur in resistance to tamoxifen. Moreover, microRNAs (miRNAs) have been associated with CSCs, EMT as well as tamoxifen resistance. Studying molecular mechanism of CSCs, EMT as well as tamoxifen resistance will help us to further understand the pathogenesis and progression of the disease and offer new targets for effective therapies. In the present study, we showed that miR-375 inhibits CSC traits in breast cancer MCF-7 cells. Bioinformatics analysis and experimental validation identified HOXB3 as a direct target of miR-375. Overexpressing miR-375 degraded HOXB3 mRNA in MCF-7 cells. Moreover, overexpression of HOXB3 induced formation of CSC phenotypes, EMT and tamoxifen-resistance as well as enhanced ability of migration and invasion in MCF-7 cells. Most ER-positive breast cancer-related deaths occur, because of resistance to standard therapies and metastasis, restoring miR-375 or targeting HOXB3 might serve as potential therapeutic approaches for the treatment of tamoxifen-resistant breast cancer.

MicroRNA-223 Increases the Sensitivity of Triple-Negative Breast Cancer Stem Cells to TRAIL-Induced Apoptosis by Targeting HAX-1.

Drug resistance remains a significant challenge in the treatment of triple-negative breast cancer (TNBC). Recent studies have demonstrated that this drug resistance is associated with a group of cells known as cancer stem cells (CSCs), which are believed to determine the sensitivity of tumor cells to cancer treatment. MicroRNAs (miRNAs) are small, non-coding RNAs that play significant roles in normal and cancer cells. MiR-223 reportedly acts as a tumor suppressor in a range of cancers. However, the role of miR-223 in TNBC, especially in triple-negative breast cancer stem cells (TNBCSCs), remains unknown. Here, we found that miR-223 expression was down-regulated in CD44+CD24-/low TNBCSCs compared with non-CSCs. Furthermore, we found that miR-223 overexpression resensitized TNBCSCs to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. The HAX-1 gene, which is located in the mitochondria and functions as an anti-apoptotic protein, was found to be directly regulated by miR-223 in MDA-MB-231 cells. We demonstrated that miR-223 overexpression promoted TRAIL-induced apoptosis through the mitochondria/ROS pathway. In conclusion, our results suggest that miR-223 increases the sensitivity of TNBCSCs to TRAIL-induced apoptosis by targeting HAX-1. Our findings have improved our understanding of the role of miR-223 in TNBC and may contribute to TNBC treatment.

The contribution of CT and MRI in staging, treatment planning and prognosis prediction of malignant tumors of external auditory canal.

Carcinomas of external auditory canal (EAC) are rare. Radiological imaging particular in computed tomography (CT) and magnetic resonance imaging (MRI) plays an important role in the staging, treatment planning and follow up of the patients with malignant EAC tumor. This article aims to review the role of CT and MRI in the describing different tumor growth pattern, tumor staging, treatment planning, follow up and predicting the prognosis of malignant tumors of EAC.

Epigallocatechin-3-gallate ameliorates radiation-induced acute skin damage in breast cancer patients undergoing adjuvant radiotherapy.

There are few effective treatment options for radiation-induced dermatitis in breast cancer patients. We conducted a single-arm trial to tested the hypothesis that topical epigallocatechin-3-gallate (EGCG) is effective against radiation-induced dermatitis in breast cancer patients undergoing radiotherapy. Forty-nine patients participated in this study. The patients underwent mastectomy followed by adjuvant radiotherapy. Topical EGCG was applied daily, starting when grade I dermatitis appeared and ending two weeks after radiotherapy. The maximum dermatitis observed during the EGCG treatment was as follows: Grade 1 toxicity, 71.4% (35 patients); grade 2 toxicity, 28.6% (14 patients); there were no patients with grade 3 or 4 toxicity. The majority of the radiation-induced dermatitis was observed 1 week after the end of radiotherapy. EGCG reduced the pain in 85.7% of patients, burning-feeling in 89.8%, itching in 87.8%, pulling in 71.4%, and tenderness in 79.6%. These findings suggest topical EGCG may be an effective treatment for radiation-induced dermatitis and has acceptable toxicity.