A systematic review of qualitative research on the self-management experience of breast cancer patients.

OBJECTIVE: To integrate the qualitative research on the self-management experience of breast cancer patients and conduct a systematic review of their self-management experience. METHODS: Using a computer to search a series of databases such as CNKI, Wanfang, VIP, and China Biomedical Database, systematically collect and integrate qualitative research on the self-management experience of breast cancer patients, and the search time is limited to January 2010 to December 2022. The qualitative research quality evaluation standard of the Joanna Briggs Institute Centre for Evidence-Based Health Care in Australia was used as the evaluation standard of this project to complete the accurate evaluation of the literature; Meta-analysis was used to complete the effective integration of the results. RESULTS: 17 pieces of literature were included in this project, and 37 research results with strong integrity were extracted accordingly. On this basis, 7 different categories were summarised, and three integrated results were obtained: the experience of maintaining self-management, symptom recognition, and self-management. CONCLUSION: In the different stages of self-management of breast cancer patients, medical staff should give targeted guidance to help patients obtain a good prognosis.

NVP-CGM097, an HDM2 Inhibitor, Antagonizes ATP-Binding Cassette Subfamily B Member 1-Mediated Drug Resistance.

Multidrug resistance (MDR) is a major challenge in the treatment of tumors. It refers to cancer cells become resistant to not only the therapeutic drug, but also cross-resistant to multiple drugs with distinct structures and mechanisms of action when they are exposed to a drug for a period of time. An essential mechanism of MDR is the aberrant expression and function of ATP-binding cassette (ABC) transporters. Therefore, blocking the function of ABC transporters has the therapeutic potential in reversing MDR. The hdm2 oncogene product, HDM2 (also known as MDM2), is an important negative regulator of the p53 tumor suppressor. NVP-CGM097 is an HDM2 inhibitor that can inhibit the proliferation of tumor cells and is currently under clinical trials. In this study, we evaluate whether NVP-CGM097 could reverse ABCB1-mediated MDR. The results of reversal experiment showed that NVP-CGM097 remarkably reversed ABCB1-mediated MDR but not ABCG2-mediated MDR. The results of Western blot and immunofluorescence suggested that the level of expression and subcellular localization of ABCB1 protein were not significantly altered by NVP-CGM097. Mechanism studies indicated that NVP-CGM097 could reverse ABCB1-mediated MDR by directly blocking the ABCB1-mediated drug efflux and raising the accumulation of chemotherapeutic drugs in cancer cells. ATPase analysis showed that low concentration NVP-CGM097 activates ABCB1 ATPase activity while high concentration NVP-CGM097 inhibited ABCB1-associated ATPase. Docking study indicated that NVP-CGM097 tended to bind to the inhibitory site, which led to slight but critical conformational changes in the transporter and reduced the ATPase activity. Overall, our study demonstrates that NVP-CGM097 can be used in conjunction with chemotherapeutic drugs to counteract MDR and improve the antitumor responses.

Yanghe Huayan decoction inhibits the capability of trans-endothelium and angiogenesis of HER2+ breast cancer via pAkt signaling.

Background: Yanghe Huayan Decoction (YHD), a traditional Chinese medicine, is one of the most common complementary medicine currently used in the treatment of breast cancer (BC). It has been recently linked to suppress precancerous lesion and tumor development. The current study sought to explore the role of YHD on trans-endothelium and angiogenesis of BC. Methods: HER2+ BC cells were treated with YHD, Trastuzumab, or the combination in vitro and in vivo to compare the effects of them on trans-endothelium and angiogenesis features. The present study also investigated the potential molecular mechanism of YHD in inhibiting angiogenesis of BC. Results: YHD significantly suppressed the invasion and angiogenesis of BC cells via elevated pAkt signaling. Administration of YHD in vivo also strikingly repressed angiogenesis in tumor grafts. Conclusion: YHD could partially inhibit and reverse tumorigenesis of BC. It also could inhibit Akt activation and angiogenesis in vitro and in vivo Its effect was superior to trastuzumab. Thus it was suitable for prevention and treatment of BC.

PTEN and SHIP: Impact on lymphatic metastasis in breast cancer.

Lymph node metastasis is the most common form of metastasis in breast cancer and a crucial indicator influencing breast cancer treatment results. The biological process of lymph node metastasis involves deficiency and mutation of tumor suppressor genes. PTEN and SHIP are critical indicators used to detect occurrence, development, invasion, and metastasis of breast cancer. Loss of expressions of PTEN and SHIP may contribute to lymphatic metastasis of breast cancer, so they can be used as objective indicators for judging the biological behavior of breast cancer. In this study, we perform a comprehensive analysis to investigate the effect of PTEN and SHIP gene expression on regulating lymph node metastasis in breast cancer.

Androgenic regulation of beta-defensins in the mouse epididymis.

BACKGROUND: The majority of beta-defensin family members are exclusively expressed in the epididymis, and some members have been shown to play essential roles in sperm maturation and fertility in rats, mice and humans. Therefore, beta-defensins are hypothesized to be potential targets for contraception and infertility diagnosis and treatment. Clarifying the regulatory mechanisms for the expression of these genes is necessary. Androgen/androgen receptor (AR) signaling plays an important regulatory role in epididymal structure and function. However, very little is known about the androgenic regulation on the production and secretion of the epididymal beta-defensins. METHODS: The expression of beta-defensins was detected by quantitative RT-PCR. The androgen dependence of beta-defensins was determined by bilateral orchiectomy and androgen supplementation. The androgen response elements (AREs) in the promoters of beta-defensins were identified using the MatInspector software. The binding of AR to AREs was assayed by ChIP-PCR/qPCR. RESULTS: We demonstrated that 23 mouse caput epididymal beta-defensins were differentially regulated by androgen/androgen receptor. Six genes, Defb18, 19, 20, 39, 41, and 42, showed full regulation by androgens. Ten genes, Defb15, 30, 34, 37, 40, 45, 51, 52, 22 and Spag11a, were partially regulated by androgens. Defb15, 18, 19, 20, 30, 34, 37, 39, 41, 42, 22 and Spag11a were associated with androgen receptor binding sites in their promoter or intronic regions, indicating direct regulation of AR. Six genes, Defb1, 12, 13, 29, 35, and spag11b/c, exhibited an androgen-independent expression pattern. One gene, Defb25, was highly dependent on testicular factors rather on androgens. CONCLUSIONS: The present study provides novel insights into the mechanisms of androgen regulation on epididymal beta-defensins, enabling a better understanding of the function of beta-defensins in sperm maturation and fertility.

Immobilization contributes to exaggerated neuropeptide signaling, inflammatory changes, and nociceptive sensitization after fracture in rats.

UNLABELLED: A tibia fracture cast immobilized for 4 weeks can induce exaggerated substance P and calcitonin gene-related peptide signaling and neuropeptide-dependent nociceptive and inflammatory changes in the hind limbs of rats similar to those seen in complex regional pain syndrome (CRPS). Four weeks of hind limb cast immobilization can also induce nociceptive and vascular changes resembling CRPS. To test our hypothesis that immobilization alone could cause exaggerated neuropeptide signaling and inflammatory changes, we tested 5 cohorts of rats: 1) controls; 2) tibia fracture and hind limb casted; 3) hind limb casted, no fracture; 4) tibia fracture with intramedullary pinning, no cast; and 5) tibia fracture with intramedullary pinning and hind limb casting. After 4 weeks, the casts were removed and hind limb allodynia, unweighting, warmth, edema, sciatic nerve neuropeptide content, cutaneous and spinal cord inflammatory mediator levels, and spinal c-Fos activation were measured. After fracture with casting, there was allodynia, unweighting, warmth, edema, increased sciatic nerve substance P and calcitonin gene-related peptide, increased skin neurokinin 1 receptors and keratinocyte proliferation, increased inflammatory mediator expression in the hind paw skin (tumor necrosis factor-α, interleukin [IL]-1ß, IL-6, nerve growth factor) and cord (IL-1ß, nerve growth factor), and increased spinal c-Fos activation. These same changes were observed after cast immobilization alone, except that spinal IL-1ß levels were not increased. Treating cast-only rats with a neurokinin 1 receptor antagonist inhibited development of nociceptive and inflammatory changes. Four weeks after fracture with pinning, all nociceptive and vascular changes had resolved and there were no increases in neuropeptide signaling or inflammatory mediator expression. PERSPECTIVE: Collectively, these data indicate that immobilization alone increased neuropeptide signaling and caused nociceptive and inflammatory changes similar to those observed after tibia fracture and casting, and that early mobilization after fracture with pinning inhibited these changes. Early limb mobilization after fracture may prevent the development of CRPS.

Epigenetic regulation of spinal CXCR2 signaling in incisional hypersensitivity in mice.

BACKGROUND: The regulation of gene expression in nociceptive pathways contributes to the induction and maintenance of pain sensitization. Histone acetylation is a key epigenetic mechanism controlling chromatin structure and gene expression. Chemokine CC motif receptor 2 (CXCR2) is a proinflammatory receptor implicated in neuropathic and inflammatory pain and is known to be regulated by histone acetylation in some settings. The authors sought to investigate the role of histone acetylation on spinal CXCR2 signaling after incision. METHODS: Groups of 5-8 mice underwent hind paw incision. Suberoylanilide hydroxamic acid and anacardic acid were used to inhibit histone deacetylase and histone acetyltransferase, respectively. Behavioral measures of thermal and mechanical sensitization as well as hyperalgesic priming were used. Both message RNA quantification and chromatin immunoprecipitation analysis were used to study the regulation of CXCR2 and ligand expression. Finally, the selective CXCR2 antagonist SB225002 was administered intrathecally to reveal the function of spinal CXCR2 receptors after hind paw incision. RESULTS: Suberoylanilide hydroxamic acid significantly exacerbated mechanical sensitization after incision. Conversely, anacardic acid reduced incisional sensitization and also attenuated incision-induced hyperalgesic priming. Overall, acetylated histone H3 at lysine 9 was increased in spinal cord tissues after incision, and enhanced association of acetylated histone H3 at lysine 9 with the promoter regions of CXCR2 and keratinocyte-derived chemokine (CXCL1) was observed as well. Blocking CXCR2 reversed mechanical hypersensitivity after hind paw incision. CONCLUSIONS: Histone modification is an important epigenetic mechanism regulating incision-induced nociceptive sensitization. The spinal CXCR2 signaling pathway is one epigenetically regulated pathway controlling early and latent sensitization after incision.

miR-203 regulates nociceptive sensitization after incision by controlling phospholipase A2 activating protein expression.

BACKGROUND: After incision keratinocytes in the epidermis become activated to produce a range of pain-related mediators. microRNA 203 (miR-203) is known to be involved in keratinocyte growth, differentiation, and skin inflammation. We hypothesized that one or more of these mediators might be under the control of miR-203. METHODS: The expression of miR-203 and its target gene, phospholipase A2 activating protein (PLAA), were examined after hind paw incision in mice. We investigated the local effect of intraplantar PLAA peptide injection in normal mice and the effects of a selective secretory phospholipase A2 inhibitor (HK064) on PLAA or incision-induced mechanical allodynia. Last, we investigated the role of substance P signaling in regulating miR-203 and PLAA expression in vitro and in vivo. RESULTS: Levels of miR-203 were strongly down-regulated in keratinocytes after incision. Informatics-based approaches identified PLAA as a likely candidate for regulation by miR-203. PLAA caused mechanical allodynia and conditioned place aversion but not thermal sensitization. HK064 reduced mechanical allodynia after incision and after intraplantar injection of PLAA. Using preprotachykinin gene knockout mice or with neurokinin-1 selective antagonist LY303870 treatment, we observed that substance P-mediated signaling was also required for miR-203 and PLAA regulation after incision. Finally, using the rat epidermal keratinocyte cell line, we observed that a miR-203 mimic molecule could block the substance P-induced increase in PLAA expression observed under control conditions. CONCLUSIONS: miR-203 may regulate expression of the novel nociceptive mediator PLAA after incision. Furthermore, the regulation of miR-203 and PLAA levels is reliant upon intact substance P signaling.

AU-rich-element-dependent translation repression requires the cooperation of tristetraprolin and RCK/P54.

AU-rich elements (AREs), residing in the 3' untranslated region (UTR) of many labile mRNAs, are important cis-acting elements that modulate the stability of these mRNAs by collaborating with trans-acting factors such as tristetraprolin (TTP). AREs also regulate translation, but the underlying mechanism is not fully understood. Here we examined the function and mechanism of TTP in ARE-mRNA translation. Through a luciferase-based reporter system, we used knockdown, overexpression, and tethering assays in 293T cells to demonstrate that TTP represses ARE reporter mRNA translation. Polyribosome fractionation experiments showed that TTP shifts target mRNAs to lighter fractions. In murine RAW264.7 macrophages, knocking down TTP produces significantly more tumor necrosis factor alpha (TNF-α) than the control, while the corresponding mRNA level has a marginal change. Furthermore, knockdown of TTP increases the rate of biosynthesis of TNF-α, suggesting that TTP can exert effects at translational levels. Finally, we demonstrate that the general translational repressor RCK may cooperate with TTP to regulate ARE-mRNA translation. Collectively, our studies reveal a novel function of TTP in repressing ARE-mRNA translation and that RCK is a functional partner of TTP in promoting TTP-mediated translational repression.

Two functional microRNA-126s repress a novel target gene p21-activated kinase 1 to regulate vascular integrity in zebrafish.

RATIONALE: MicroRNAs (miRNAs) are key regulators of vascular development and diseases. The function and underlying mechanism of endothelial miRNAs have not been fully defined. OBJECTIVE: To investigate the role of endothelial miR-126 in zebrafish vascular development. METHODS AND RESULTS: Two homologs of miR-126, miR-126a (namely miR-126 in previous literature) and miR-126b, with only 1 nucleotide difference in their mature sequences, were identified in zebrafish genome. In vitro analysis showed that both precursors could sufficiently produce mature functional miRNAs. Expression analyses by Northern blot and quantitative RT-PCR showed that both miR-126s accumulated significantly 12 hours after fertilization and were specifically expressed in endothelial cells of zebrafish. Inhibition of miR-126a or miR-126b with specific morpholinos caused cranial hemorrhage, and simultaneous inhibition of both miR-126s resulted in a pronounced hemorrhage in higher percentage of embryos. Bioinformatics prediction showed that the targets of miR-126a/b partially overlapped but essentially differed. p21-activated kinase1 (pak1) was identified as a novel target of miR-126a/b, and pak1 3' untranslated region was differently regulated by these 2 miRNAs. Quantitative RT-PCR, in situ hybridization, and Western blot analyses showed that the level of pak1 was reduced when miR-126a/b were overexpressed. Notably, pak1 expression in endothelial cells was increased when miR-126a/b were knocked down. Furthermore, overexpression of the active form of human pak1 caused cranial hemorrhage, and knockdown pak1 effectively rescued the hemorrhage caused by inhibiting miR-126a/b. CONCLUSIONS: Two functional endothelial cell-specific miRNAs, miR-126a and miR-126b, synergistically regulate zebrafish vascular integrity, and pak1 is a critical target of miR-126a/b in vascular development.

[Intervention of rukangyin on the lymphangiogenesis in breast cancer metastasis nude spontaneous mouse model].

OBJECTIVE: To observe the effects of rukangyin (RKY) on the lymphangiogenesis and lymph node metastasis of breast cancer transplantation tumor mice, thus exploring its anti-tumor metastasis mechanisms. METHODS: Human breast cancer cell line MDA-MB-435S were in situ implanted into the mammary fat pad of 30 female nude mice to establish breast cancer transplantation tumor spontaneous metastasis model. They were randomly divided into six groups, i.e., the model control group, the 5-FU control group, the small, medium, large dose RKY groups, and the medium dose RKY +5-FU group, 5 in each. Normal saline was given to mice in the model control group at the daily dose of 0.4 mL/kg by gastrogavage. 5-FU was given to mice in the 5-FU control group at the daily dose of 30 mg/kg by peritoneal injection. RKY was given to mice in the small, medium, large dose RKY groups at the daily dose of 18, 45, and 90 g/kg by gastrogavage. 5-FU 30 mg/kg (by peritoneal injection) + RKY 45 g/( kg x d) (by gastrogavage) was given to mice in the medium dose RKY +5-FU group. All medication was carried out once daily for 6 successive weeks. The tumor volume, the tumor inhibition ratio, and the inhibition ratio of axillary lymph node metastasis were detected after medication. The lymphatic microvessel density (LMVD) and expressions of vascular endothelial growth factor-C (VEGF-C) and vascular endothelial growth factor receptor-3 (VEGFR-3) of the breast cancer tissues were detected using immunohistochemical assay. RESULTS: Compared with the model control group, the tumor volume was markedly reduced in the small, medium, large dose RKY groups, and the medium dose RKY +5-FU group, the expressions of VEGF-C and VEGFR-3 were significantly down-regulated and LMVD were obviously lowered, showing statistical difference (P < 0.05, P < 0.01). The inhibition rates of tumor and axillary lymph node metastasis were highest and the LMVD was the lowest in the medium dose RKY +5-FU group, showing statistical difference when compared with other medication groups (P < 0.05, P < 0.01). CONCLUSION: RKY might inhibit the lymph node metastasis of breast cancer possibly through intervening the expressions of VEGF-C and VEGFR-3, and suppressing lymphangiogenesis.

Fracture induces keratinocyte activation, proliferation, and expression of pro-nociceptive inflammatory mediators.

Tibia fracture in rats results in chronic vascular and nociceptive changes in the injured limb resembling complex regional pain syndrome (CRPS) and up-regulates expression of interleukin 1ß (IL-1ß), interleukin IL-6 (IL-6), tumor necrosis factor-α (TNF-α), and nerve growth factor-ß (NGF-ß) in the hindpaw skin. When fractured rats are treated with cytokine or NGF inhibitors nociceptive sensitization is blocked. Because there is no leukocyte infiltration in the hindpaw skin we postulated that resident skin cells produce the inflammatory mediators causing nociceptive sensitization after fracture. To test this hypothesis rats underwent distal tibia fracture and hindlimb casting for 4 weeks, then the hindpaw skin was harvested and immunostained for keratin, cytokines and NGF. BrdU staining was used to evaluate cell proliferation. Hindpaw nociceptive thresholds, edema, and temperature were tested before and up to 96h after intraplantar injections of IL-6 and TNF-α. Tibia fracture caused keratinocyte activation, proliferation, and up-regulated IL-1ß, IL-6, TNF-α and NGF-ß protein expression in the hindpaw keratinocytes. Local injections of IL-6 and TNF-α induced hindpaw mechanical allodynia lasting for several days and modest increases in temperature and edema. These data indicate that activated keratinocytes proliferate and express IL-1ß, IL-6, TNF-α, and NGF-ß after fracture and that excess amounts of inflammatory mediators in the skin cause sustained nociceptive sensitization. This is the first study demonstrating in vivo keratinocyte expression of IL-6, TNF-α and NGF-ß in a CRPS model and we postulate that the keratinocyte is the primary cellular source for the inflammatory signals mediating cutaneous nociceptive sensitization in early CRPS.

Attenuation of microRNA-1 derepresses the cytoskeleton regulatory protein twinfilin-1 to provoke cardiac hypertrophy.

MicroRNAs are involved in several aspects of cardiac hypertrophy, including cardiac growth, conduction, and fibrosis. However, their effects on the regulation of the cardiomyocyte cytoskeleton in this pathological process are not known. Here, with microRNA microarray and small RNA library sequencing, we show that microRNA-1 (miR-1) is the most abundant microRNA in the human heart. By applying bioinformatic target prediction, a cytoskeleton regulatory protein twinfilin-1 was identified as a potential target of miR-1. Overexpression of miR-1 not only reduced the luciferase activity of the reporter containing the 3' untranslated region of twinfilin-1 mRNA, but also suppressed the endogenous protein expression of twinfilin-1, indicating that twinfilin-1 is a direct target of miR-1. miR-1 was substantially downregulated in the rat hypertrophic left ventricle and phenylephrine-induced hypertrophic cardiomyocytes, and accordingly, the protein level of twinfilin-1 was increased. Furthermore, overexpression of miR-1 in hypertrophic cardiomyocytes reduced the cell size and attenuated the expression of hypertrophic markers, whereas silencing of miR-1 in cardiomyocytes resulted in the hypertrophic phenotype. In accordance, twinfilin-1 overexpression promoted cardiomyocyte hypertrophy. Taken together, our results demonstrate that the cytoskeleton regulatory protein twinfilin-1 is a novel target of miR-1, and that reduction of miR-1 by hypertrophic stimuli induces the upregulation of twinfilin-1, which in turn evokes hypertrophy through the regulation of cardiac cytoskeleton.

[Effect of glutamate on distortion product otoacoustic emission and auditory brainstem response in guinea pigs].

OBJECTIVE: To investigate the changes of the potentials and structure of the guinea pig cochlear during whole cochlear perfusion with glutamate. METHODS: Cochlear microphonics (CM), compound action potential (CAP), distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) were measured to indicate the cochlear functional properties during whole cochlear perfusion. The morphology of the cochlear was monitored by transmission electron microscopy. RESULTS: There were no significant DPOAE changes before and after glutamate perfusion. CM I/O function maintained a nonlinear characteristic during infusion. After glutamate perfusion, ABR latencies were delayed. There was significant difference in CAP threshold before and after glutamate perfusion. The average CAP threshold was elevated 35 dB. The OHCs appeared normal, but IHCs and afferent dendrites showed cytoplasmic blebs after glutamate infusion. CONCLUSIONS: Glutamate is thought to be a primary amino acid neurotransmitter at the synapses formed by cochlear hair cells and spiral ganglion neurons. However, the excessive glutamate is neurotoxic for cells, and it can destroy the IHCs and spiral ganglion neurons. The present method can also be built up as an animal model of auditory neuropathy.