Vitexin Regulates Angiogenesis and Osteogenesis in Ovariectomy-Induced Osteoporosis of Rats via the VDR/PI3K/AKT/eNOS Signaling Pathway.

It is extremely important to promote angiogenesis-dependent osteogenesis and ameliorate bone loss for the prevention and treatment of osteoporosis (OP) development. Vitexin, as one of the major active components in pigeonpea leave, promoted the proliferation of osteoblast and HUVECs in hypoxia. The present study aimed to investigate the effect of vitexin on alleviating osteoporosis in ovariectomized (OVX) rats and further explore its underlying mechanisms. Herein, the OVX rat model was established and treated with vitexin (10 mg kg-1) for 3 months. After being sacrificed, we performed hematoxylin-eosin (H&E) staining and micro-computed tomography (micro-CT) to assess bone mass, which found that trabecular bone was damaged in the OVX rat model. Vitexin could repair bone injury and promote osteoblast biochemical indicators and angiogenesis indicators. Furthermore, EAhy926 cells were used to further explore the effect of vitexin on improving hypoxia-induced endothelial injury in vitro. Vitexin had a protective effect on hypoxia-treated EAhy926 cells and up-regulated vitamin D receptor (VDR) signaling and promoted phosphorylation of phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), and endothelial NO synthase (eNOS), which enhanced endothelial cell migration and tube formation. VDR small-interfering RNA (siRNA) transfection significantly decreased both VDR and p-eNOS proteins, and VDR siRNA transfection + vitexin could not further increase VDR and downstream proteins. Overall, this study presented that vitexin regulates angiogenesis and osteogenesis in ovariectomy-induced osteoporosis of rats via the VDR/eNOS signaling pathway.

Establishment of a lysosome-related prognostic signature in breast cancer to predict immune infiltration and therapy response.

Background: Lysosomes are instrumental in intracellular degradation and recycling, with their functional alterations holding significance in tumor growth. Nevertheless, the precise role of lysosome-related genes (LRGs) in breast cancer (BC) remains elucidated. This study aimed to establish a prognostic model for BC based on LRGs. Methods: Employing The Cancer Genome Atlas (TCGA) BC cohort as a training dataset, this study identified differentially expressed lysosome-related genes (DLRGs) through intersecting LRGs with differential expression genes (DEGs) between tumor and normal samples. A prognostic model of BC was subsequently developed using Cox regression analysis and validated within two Gene Expression Omnibus (GEO) external validation sets. Further analyses explored functional pathways, the immune microenvironment, immunotherapeutic responses, and sensitivity to chemotherapeutic drugs in different risk groups. Additionally, the mRNA and protein expression levels of genes within the risk model were examined by utilizing the Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) databases. Clinical tissue specimens obtained from patients were gathered to validate the expression of the model genes via Real-Time Polymerase Chain Reaction (RT-PCR). Results: We developed a risk model of BC based on five specific genes (ATP6AP1, SLC7A5, EPDR1, SDC1, and PIGR). The model was validated for overall survival (OS) in two GEO validation sets (p=0.00034 for GSE20685 and p=0.0095 for GSE58812). In addition, the nomogram incorporating clinical factors showed better predictive performance. Compared to the low-risk group, the high-risk group had a higher level of certain immune cell infiltration, including regulatory T cells (Tregs) and type 2 T helper cells (Th2). The high-risk patients appeared to respond less well to general immunotherapy and chemotherapeutic drugs, according to the Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenotype Score (IPS), and drug sensitivity scores. The RT-PCR results validated the expression trends of some prognostic-related genes in agreement with the previous differential expression analysis. Conclusion: Our innovative lysosome-associated signature can predict the prognosis for BC patients, offering insights for guiding subsequent immunotherapeutic and chemotherapeutic interventions. Furthermore, it has the potential to provide a scientific foundation for identifying prospective therapeutic targets.

Prognostic Value of Negative Emotions on the Incidence of Breast Cancer: A Systematic Review and Meta-Analysis of 129,621 Patients with Breast Cancer.

Breast cancer (BC) is one of the common malignant tumors in women and affects 1.6 million new cases globally each year. Investigators have recently found that negative emotions (NEs) and their impacts have greatly influenced the incidence and risk of BC. The present study aims to provide an association between NEs and the incidence of BC with possible risk factors. A total of 9343 studies were screened; nine studies met all inclusion criteria that were considered for the meta-analysis. The qualitative studies were measured by the Newcastle-Ottawa Scale; the observational studies were included with relative risks (RR) and corresponding 95% confidence intervals (CI). Besides the NEs and BC, the possible risk factors were evaluated. We analyzed data from 129,621 women diagnosed with NEs of which 2080 women were diagnosed with BC and their follow-up year ranges were from 4-24 years. NEs were significantly (p < 0.0001) associated with a higher incidence of BC with RR = 1.59, 95% CI:1.15-2.19, with other high-risk factors including, geographical distribution, emotion types, standard diagnosis of NEs, and follow-up duration. This study suggests that NEs significantly increase the risk for the incidence of BC, which can be supportive of the prognosis of the disease.

Perillaldehyde inhibits bone metastasis and receptor activator of nuclear factor-κB ligand (RANKL) signaling-induced osteoclastogenesis in prostate cancer cell lines.

Perillaldehyde (PAH), one of the active ingredients of the traditional Chinese medicine (TCM) plant Perilla frutescens, is widely used and exerts crucial anti-cancer activities. The aim of current study is to illustrate the potential mechanisms of PAH-mediated regulation of bone metastasis and osteoclastogenesis in prostate cancer (PCa) cell lines. Effects of PAH on proliferation, invasion and migration of PC-3 cells were assessed with the Cell Counting Kit-8 (CCK-8) assay and Transwell assays, respectively. Effects of PAH on stem cell characteristics of PC-3 cells were evaluated by cell-matrix adhesion assay, colony formation assay, spheroid formation assay, as well as western blot . The anti-metastasis and anti-osteoclastogenesis activity of PAH in RAW264.7 cells was examined by osteoclast differentiation assay and western blot. The protein levels of CD133 and CD44 in PC-3 cells and the activity of nuclear factor kappa B (NF-κB) signaling pathway in RAW264.7 cells were measured by western blot. PAH suppressed proliferation, invasion and migration of PC-3 cells, prevented stem cell characteristics including cell-matrix adhesion, colony formation, spheroid formation as well as CD133 and CD44 expression. PAH inhibited bone metastasis and osteoclastogenesis via repressing the activation of NF-κB pathway as well as (RANKL) - and cancer cell-induced osteoclastogenesis in PCa cells. These findings suggested the potential therapeutic effects of PAH on the metastasis of patients with PCa.

Modified Grisotti flap technique in centrally located breast cancer: case report.

Traditionally, breast cancer patients with centrally located mass always receive mastectomy or the combination of central excision and primary closure. With the development of modern oncoplastic breast-conserving techniques, these patients can conserve their breast, and achieve satisfactory cosmetic outcome as well as clear margin. A variety of techniques are available to deal with centrally located breast cancers (CLBCs). Among these techniques, Grisotti flap technique is special, because it is easy to handle, and only causes minor injury by using a local rotational dermoglandular flap to fill the defection of central part. However, in our clinical practice, we find a lot of women in south China have special properties. Such as short distance from inframammary liner to the nipple, long distance from midclavicular to the nipple, and large breast diameter. Simply apply the Grisotti flap technique to those patients is not very suitable that drive us to modify this technique to suit our patients. We adopt the idea that use pedicled skin flap with skin island to replace the central defection to modify Grisotti flap technique. And applied this technique to two patients. We find modified Grisotti flap technique for Paget's disease or CLBC had good cosmetic results as well as safety in suitable patients. In the future, we can use superior pedicle with skin island for ptotic breasts, and lateral pedicle is suitable for patients without large and ptotic breasts.

Tailoring assembly behavior of starches to control insulin release from layer-by-layer assembled colloidal particles.

Self-assembly behavior of charged-starches significantly influenced core-shell structures of layer-by-layer assembled particles. In this study, insulin (IN)-loaded nanoparticles with structured shell features were fabricated to investigate how the interactions of carboxymethyl starch (CMS) with spermine-modified starch (SS) influenced IN release properties of the particles (IN/CMS/SS/CMS) within the gastrointestinal tract (GIT). Results indicated that the assembly action of CMS and SS could be controlled by simply tailoring the ratio of CMS/SS content. An intermediate CMS/SS ratio (1:4) was required to construct nanoparticles with compact shell structure and desirable IN release properties in the colon (74.23%). However, a higher CMS/SS ratio (1:2) yielded particles with loose shell structure and an excessive IN release in the upper GIT (58.89%), and a lower CMS/SS ratio (1:8) rather resulted in particles with higher compactness shell structure along with limited IN release in the colon (29.01%). The interactions between CMS and SS should be the key factor influencing core-shell structures and in turn the IN-release properties of the carrier. The shell structure and release properties of layer-by-layer assembled particles could be tailored by controlling the interactions between starches.

The role of surgical intervention for isolated breast cancer liver metastasis: Results of case-control study with comparison to medical treatment.

BACKGROUND: Combined with systemic therapy, the surgical intervention for breast cancer liver metastases (BCLM) is increasingly accepted but lacks convincing evidence. The aim of this study was to evaluate the disease control efficacy of hepatic surgery in isolated BCLM patients. METHODS: Between 2012 and 2017, metastatic breast cancer patients with isolated liver metastasis and regular follow-up were identified. Cohort design was conducted to compare the progression-free survival (PFS) between the surgical and nonsurgical BCLM patients. Univariate analysis and multivariate Cox regression survival analyses were performed to identify significant prognostic factors. RESULT: In all, 148 isolated BCLM patients were enrolled and 95 participants received hepatic surgery for metastatic lesions. With median follow-up of 36.47 months, there was no significant difference between hepatic surgical group and nonsurgical group for PFS (median PFS: 11.17 months vs 10.10 m, P = .092). Based on the multivariate analysis, the disease-free interval (DFI) was an independent prognostic factor for isolated BCLM patients. Among the surgical group, BCLM patients who had ideal response after first salvage systemic treatment experienced the best long-term survival (median PFS: 14.20 months). CONCLUSION: For isolated BCLM patients with ideal response in first-line medical treatment, surgical intervention (hepatectomy, radiofrequency ablation) combining with systemic treatment could bring improved progression-free survival compared to sole systemic treatment, indicating that hepatic surgery may be considered as a therapeutic choice for selected isolated BCLM patients in clinical practice.

Understanding the nutritional functions of thermally-processed whole grain highland barley in vitro and in vivo.

The objective of this study was to investigate the nutritional functions of highland barley subjected to heat-moisture treatment (HMT) and dry heat treatment (DHT) in vitro and in vivo. In vitro test indicated HMT and DHT play part in the reduced glycemic potency of highland barley. Meanwhile, in vivo results showed that thermally-processed highland barley (THB) supplementation significantly decreased the body weight and serum glucose, improved oxidation resistance and altered the composition of gut microbiota. Bifidobacteria, Fusicatenibacter and Desulfovibrio were identified as types of bacteria that might related to the relatively higher content of dietary fiber in THB. The Spearman's correlation analysis revealed that Fusicatenibacter and Desulfovibrio were positively correlated with T-AOC levels. In addition, the putative metagenomes implicated that THB might regulate the metabolic pathways of gut microbiota. Overall, our findings provide important information for the rational design of highland barley-based health-promoting foods with nutritional functions.

Synergistic Effect Between Full-Term Pregnancy/Breastfeeding And Familial Susceptibility On Breast Cancer Risk.

BACKGROUND: Breast cancer is the most common cancer in women worldwide, and reproductive factors and family history of malignancy are considered as high risk factors. The present study aimed to evaluate the synergistic effect of reproductive factors and family history on breast cancer. METHOD: A total of 1215 breast cancer patients and 1215 control participants from two medical centers were enrolled, and reproductive factor history and family cancer history information was collected. Multivariate logistic regression analyses were performed to estimate the adjusted odds ratio (OR), and synergy index (SI) was used to assess the combined effect of potential factors. RESULTS: Compared to the controls, a negative association between full-term pregnancy/breastfeeding and breast cancer was observed regardless of the status of family cancer history (OR: 0.675, 95% CI: 0.560-0.814 and OR: 0.631, 95% CI: 0.503-0.789 respectively) after adjustment of other confounders, while the risk effect of abortion was unproven. The synergistic effect of history of full-term pregnancy and family history of malignancy was indicated in the combined analyses with SI as 9.429 (95% CI:1.248-71.245). CONCLUSION: Full-term pregnancy/breastfeeding were protective factors against breast cancer and synergistic additive effect was demonstrated between no full-term pregnancy/breastfeeding and a family history of malignancy on the risk of breast cancer.

[Analysis of professor Lin Yi's experience for metastasis breast cancer by data mining].

Data mining method based on the traditional Chinese medicine(TCM) inheritance system(V2.5) was adopted to analyze professor Lin Yi's experience for metastasis breast cancer(MBC) by analysing the high frequency medicine, drug categories，drug properties，the key symptoms and key drugs of different metastasis regions and different syndromes, drug symptom analysis in the effective prescriptions for treating MBC by Lin from January 2013 to December 2017. A total of 89 MBC patients, 5 syndromes and 117 prescriptions were involved. The first 10 most frequently used were Atractylodis Macrocephalae Rhizoma, Poria, Dioscoreae Rhizoma, Coicis Semen, Crataegi Fructus, Hordei Fructus Germinatus, Galli Gigerii Endothelium Corneum, Hedyotis Diffusa, Codonopsis Radix, Astragali Radix. The warm and placid property was higher, the most herbs had Gan taste, the first two channel tropisms were spleen and the stomach. Drug symptom analysis in 5 different metastasis regions and 6 different syndromes were also been done. The conclusion showed that professor Lin's experience as: recognizing the basis of diseases,differentiating the syndrome, combinating disease and syndrome, cautiously grasping pathogenesis,combinating tonification and purgation together, regulating balance, treating the symptoms and origin, regulating spleen and stomach, caring for the postnatal throughout, prefering ancient prescription,rational compatibility, using medicine gently.

Traditional Chinese Medicine Extract from Huaier Increases the Expression of Duffy Antigen Receptor for Chemokines and Reduces the Expression of Its Ligands.

AIMS: The aim of the present study is to investigate whether the aqueous extract from Huaier, a traditional Chinese medicine (TCM), can affect the expression of Duffy antigen receptor for chemokines (DARC) and its ligands. Moreover, we compare the status of DARC in primary and metastatic breast cancer tissues from the same patient. METHODS: Immunohistochemistry was used to detect the expression of DARC in primary and metastatic focuses in 30 patients with breast cancer. The effect of Huaier aqueous extract on the expression of DARC and its ligands was investigated by quantitative real-time polymerase chain reaction, Western blotting, and enzyme-linked immunosorbent assay. RESULTS: The expression score of DARC in primary focuses was significantly higher than that in metastatic focuses, while changes of ER, PR, and HER2 receptors were not significantly different between primary and metastatic focuses. Huaier aqueous extract promoted the expression of DARC and reduced the secretion of CC chemokine ligand 2 (CCL-2), CXC chemokine ligand 8 (CXCL-8, IL-8), matrix metalloproteinase 2 (MMP-2), and CXC chemokine ligand 1 (CXCL-1). CONCLUSION: The present study demonstrates that difference in expression level of DARC between primary and metastatic focuses of breast cancer was significant, while differences in expression of ER, PR, and HER2 between primary and metastatic focuses were not significant. DARC may play a negative role in the metastasis of breast cancer. Traditional Chinese medicine extract from Huaier can increase DARC expression and reduce the expression of its ligands such as CCL-2, IL-8, MMP-2, and CXCL-1.

Development and validation of a nomogram for predicting survival on the base of modified lymph node ratio in breast cancer patients.

BACKGROUND: Axillary lymph node status is one of the most important prognostic factors in breast cancer and previous studies indicated that lymph node ratio (LNR) could better predict the outcome than the counting of positive lymph nodes. In the current study, we evaluated the prognostic effect of modified LNR in breast cancer patients. METHODS: A total of 3339 breast cancer patients undergoing axillary lymph nodes dissection were enrolled and respectively analyzed. Seventy five percent of participants were randomly selected as training cohort and the remaining 25% were as validation cohort. Univariate and multivariate analyses were performed and the prognostic impact of mLNR was compared with pN staging. A prognostic nomogram was established and externally validated in the validation cohort. RESULT: In multivariate analysis, both the mLNR and pN staging were independent prognostic factors for breast cancer patients, and the mLNR manifested superior discrimination power than the pN stages regardless of the total number of lymph nodes retrieved and the lymph node status. The nomogram was built including the identified independent prognostic factors and the calibration curves indicated optimal agreement between nomogram prediction and actual observation. The Concordance index (C-index) of the nomogram was statistically higher than that of the TNM system (0.747 vs. 0.711 in training cohort, 0.789 vs. 0.760 in validation cohort, both p < 0.05). CONCLUSION: Modified LNR is an important prognostic parameter and can predict survival more accurately than pN staging. The novel nomogram could provide individual prediction for breast cancer patients and help clinicians in treatment option making and prognosis evaluation.

The inflammasome: an emerging therapeutic oncotarget for cancer prevention.

Deregulated inflammation is considered to be one of the hallmarks of cancer initiation and development regulation. Emerging evidence indicates that the inflammasome plays a central role in regulating immune cells and cytokines related to cancer. The inflammasome is a multimeric complex consisting of Nod-like receptors (NLRs) and responds to a variety of endogenous (damage-associated molecular patterns) and exogenous (pathogen-associated molecular patterns) stimuli. Several lines of evidence suggests that in cancer the inflammasome is positively associated with characteristics such as elevated levels of IL-1ß and IL-18, activation of NF-κB signaling, enhanced mitochondrial oxidative stress, and activation of autophagic process. A number of NLRs, such as NLRP3 and NLRC4 are also highlighted in carcinogenesis and closely correlate to chemoresponse and prognosis. Although conflicting evidence suggested the duplex role of inflammasome in cancer development, the phenomenon might be attributed to NLRs difference, cell and tissue type, cancer stage, and specific experimental conditions. Given the promising role of inflammasome in mediating cancer development, precise elucidation of its signaling network and pathological significance may lead to novel therapeutic options for malignancy therapy and prevention.

Targeting AMPK Signaling Pathway to Overcome Drug Resistance for Cancer Therapy.

Mulitdrug resistance (MDR) is one of critical factorslimiting the efficacy of cancer chemoor radiotherapy. Emerging evidence has indicated that MDR is a complex process regulated by multiple factors, among which stress response molecules are considered as central players. AMP-activated protein kinase (AMPK) is a major regulator balancing energy supply and ultimately protects cells from harmful stresses via coordinating multiple metabolic pathways Notably, AMPK activation was recently shown to mediate the metabolism reprogramming in drug resistant cancer cells including promoting Warburg effects and mitochondrial biogenesis. Furthermore, AMPK activity has also been shown to regulate the self-renewal ability of cancer stem cells that are often refractory to chemotherapy. In addition, AMPK phosphorylation was critical in mediating autophagy induction, a process demonstrated to be effective in chemosensitivity modulation via degrading cellular components to satisfy nutrients requirement under stressful condition. Meanwhile, drug discovery targeting AMPK has been developed to validate the pathological significance of AMPK in cancer prevention and treatment. Although conflicting evidence focusing on the AMPK modulation for cancer treatment is still remained, this might be attributed to differences in AMPK isotypes in specific tissues, off-targets effects, the degree and duration of drug administration and experimental setting of stress conditions. This review will focus on AMPK mediated resistance to cancer therapy and discuss its potential therapeutic implication and targeting drug development.

Caveolin-1 mediates chemoresistance in breast cancer stem cells via ß-catenin/ABCG2 signaling pathway.

Accumulating evidence has suggested that cancer stem cells (CSCs) are at the root of drug resistance, and recent studies have indicated that caveolin-1, a membrane transporter protein, is involved in the regulation of cancer chemoresistance and stem cell signaling. However, the current understanding of the role of caveolin-1 in breast cancer development remains controversial. Herein, we demonstrate that caveolin-1 expression was upregulated after breast cancer chemotherapy in vitro and in vivo, accompanied by co-overexpression of ß-catenin and ATP-binding cassette subfamily G member 2 (ABCG2) signaling. Additionally, breast CSCs were enriched for caveolin-1 expression. Caveolin-1 silencing sensitized breast CSCs by limiting their self-renewal ability but promoting the differentiation process. ß-catenin silencing prevented the enhanced chemoresistance of CSCs induced by caveolin-1 overexpression, indicating that ß-catenin is an essential molecule responsible for caveolin-1-mediated action. Further mechanistic investigation revealed that caveolin-1 silencing could downregulate the ß-catenin/ABCG2 pathway through glycogen synthase kinase 3 beta activation and Akt inhibition, resulting in increased ß-catenin phosphorylation and proteasomal degradation. Clinical investigation also revealed a close correlation between caveolin-1 and ß-catenin/ABCG2 signaling in breast cancer samples. Notably, caveolin-1 was highly elevated in triple-negative breast cancer, and caveolin-1 silencing significantly impaired the tumorigenicity and chemoresistance of breast CSCs in in vivo models. Overall, our study not only highlights the role of caveolin-1 in mediating the chemoresistance of breast CSCs via ß-catenin/ABCG2 regulation but also provides novel approaches for future therapies targeting CSCs.