Nrf3 alleviates oxidative stress and promotes the survival of colon cancer cells by activating AKT/BCL-2 signal pathway.

Oxidative stress is closely linked to tumor initiation and development, conferring a survival advantage to cancer cells. Therefore, understanding cancer cells' antioxidant molecular mechanisms is crucial to cancer therapy. In this study, we discovered that H2O2-induced oxidative stress increased Nrf3 expression in colon cancer cells. Overexpression of Nrf3 decreased H2O2-mediated cytotoxicity and apoptosis. Furthermore, Nrf3 reduced reactive oxygen species levels and malondialdehyde concentrations after H2O2 treatment. Mechanistically, H2O2-mediated cell apoptosis involves multiple signaling proteins, including Akt, bcl-2, JNK, and p38. An increase in Nrf3 expression in colon cancer cells treated with H2O2 partly reversed Akt/Bcl-2 inhibition, whereas it decreased activation of p38 and JNK. In addition, we found that increasing Nrf3 decreased stress-associated chemical-induced cell death, resulting in drug resistance. According to these results, Nrf3 is critical for drug resistance and oxidant adaptation.

Nrf3 promotes the proliferation and migration of triple­negative breast cancer by activating PI3K/AKT/mTOR and epithelial­mesenchymal transition.

Nuclear factor erythroid 2-related factor 3 (Nrf3) is increasingly implicated in multiple types of cancer; however, its function in triple-negative breast cancer (TNBC) remains unclear. This study aimed to examine the role of Nrf3 in TNBC. Compared with adjacent normal tissues, TNBC tissues expressed higher levels of Nrf3, and its expression was negatively correlated with survival time. Additionally, Nrf3 knockdown reduced the proliferation and migration of TNBC cells, whereas overexpression of Nrf3 had the opposite effects in vitro and in vivo. Moreover, functional enrichment of TNBC cells overexpressing Nrf3 allowed for the identification of numerous genes and pathways that were altered following Nrf3 overexpression. Further study showed that overexpression of Nrf3 activated the PI3K/AKT/mTOR signaling pathway and regulated the expression of proteins associated with epithelial-mesenchymal transition. Nrf3 was found to directly bind to p110α promoter regions, as evidenced by luciferase reporter and chromatin immunoprecipitation assays. Furthermore, PI3K inhibitors partially decreased the proliferation and migration of the Nrf3 overexpressing TNBC cells. In conclusion, Nrf3 enhances cellular proliferation and migration by activating PI3K/AKT/mTOR signaling pathways, highlighting a novel therapeutic target for TNBC.

HIV-1 remission and possible cure in a woman after haplo-cord blood transplant.

Previously, two men were cured of HIV-1 through CCR5Δ32 homozygous (CCR5Δ32/Δ32) allogeneic adult stem cell transplant. We report the first remission and possible HIV-1 cure in a mixed-race woman who received a CCR5Δ32/Δ32 haplo-cord transplant (cord blood cells combined with haploidentical stem cells from an adult) to treat acute myeloid leukemia (AML). Peripheral blood chimerism was 100% CCR5Δ32/Δ32 cord blood by week 14 post-transplant and persisted through 4.8 years of follow-up. Immune reconstitution was associated with (1) loss of detectable replication-competent HIV-1 reservoirs, (2) loss of HIV-1-specific immune responses, (3) in vitro resistance to X4 and R5 laboratory variants, including pre-transplant autologous latent reservoir isolates, and (4) 18 months of HIV-1 control with aviremia, off antiretroviral therapy, starting at 37 months post-transplant. CCR5Δ32/Δ32 haplo-cord transplant achieved remission and a possible HIV-1 cure for a person of diverse ancestry, living with HIV-1, who required a stem cell transplant for acute leukemia.

Hesperetin Induces Autophagy and Delayed Apoptosis by Modulating the AMPK/Akt/mTOR Pathway in Human Leukemia Cells In Vitro.

BACKGROUND: Hesperetin has been reported to have anticancer properties. However, the molecular mechanisms underlying its action on leukemia cells remain unclear. This in vitro study evaluated the possible mechanisms of hesperetin in leukemia cells (HL-60 and U937). METHODS: Cell viability was evaluated using a cell counting kit-8 (CCK-8) assay. Apoptosis and autophagy assays were conducted through annexin V/PI staining and acidic vesicular organelle (AVO) staining. Cell cycle analysis was conducted through propidium iodide (PI) and flow cytometry. The expression of proteins related to apoptosis and autophagy, including cleaved-PARP-1, Bcl-2, Bax, LC3-I/II, Beclin-1, Atg5, p62, phospho-AMPK, AMPK, phospho-mTOR, mTOR, phospho-Akt, and Akt, in human leukemia cells were evaluated using Western blotting. RESULTS: Hesperetin dose-dependently inhibited leukemia cell viability. However, we found a low degree of apoptosis and cell cycle arrest induced by hesperetin in U937 cells. These findings imply the presence of additional mechanisms modulating hesperetin-induced cell death. Next, we evaluated autophagy, the possible mechanism modulating cell death or survival, to clarify the underlying mechanism of hesperetin-induced cell death. Hesperetin also dose-dependently increased the ratio of LC3II/I, Atg5, and Beclin 1 and decreased p62. Moreover, 3-methyladenine (3-MA) and bafilomycin A1 (Baf-A1) inhibited hesperetin-induced autophagy. We suggest that hesperetin can protect cancer cells during the transient period and may extend survival. Furthermore, a decrease in p-mTOR and p-Akt expression and an increase in p-AMPK expression were observed. Collectively, these findings suggest that hesperetin induces autophagy by modulating the AMPK/Akt/mTOR pathway. CONCLUSION: Hesperetin promoted cell death in the human leukemic cell line U937 by inducing a low degree of slight apoptosis, cell cycle arrest, and autophagy. It is therefore a potential adjuvant to antileukemia therapy and may be combined with other chemotherapeutic drugs to reduce chemoresistance and side effects.

Synergistic Combination of Luteolin and Asiatic Acid on Cervical Cancer In Vitro and In Vivo.

Cervical cancer is an important issue globally because it is the second most common gynecological malignant tumor and conventional treatment effects have been shown to be limited. Lut and AsA are plant-derived natural flavonoid and triterpenoid products that have exhibited anticancer activities and can modulate various signaling pathways. Thus, the aim of the present study was to evaluate whether Lut combined with AsA could enhance the anticancer effect to inhibit cervical cancer cell proliferation and examine the underlying molecular mechanisms in vitro and in vivo. The results of a CCK-8 assay showed that Lut combined with AsA more effectively inhibited the proliferation of CaSki and HeLa cells than Lut or AsA treatment alone. Lut combined with AsA caused apoptosis induction and sub-G1-phase arrest in CaSki and HeLa cells, as confirmed by flow cytometry, mitoROS analysis, antioxidant activity measurement and western blot assay. In addition, Lut combined with AsA significantly inhibited the cell migration ability of CaSki and HeLa cells in a wound-healing assay. Furthermore, Lut combined with AsA induced apoptosis and inhibited migration through downregulated PI3K/AKT (PI3K, AKT and p70S6K), JNK/p38 MAPK and FAK (integrin ß1, paxillin and FAK) signaling and upregulated ERK signaling. In an in vivo study, Lut combined with AsA markedly inhibited cervical cancer cell-derived xenograft tumor growth. Collectively, the present study showed that Lut combined with AsA may be used as an anticancer agent to improve the prognosis of cervical cancer. Indeed, with additional research to develop standardized dosages, Lut and AsA combination therapy could also be applied in clinical medicine.

PIM1-Induced Cytoplasmic Expression of RBMY Mediates Hepatocellular Carcinoma Metastasis.

BACKGROUND & AIMS: Metastasis indicates a grave prognosis in patients with hepatocellular carcinoma (HCC). Our previous studies showed that RNA binding motif protein Y-linked (RBMY) is potentially a biomarker for poor survival in HCC patients, but its role in metastasis is largely unclear. METHODS: A total of 308 male patients with primary HCC were enrolled. RBMY expression was traced longitudinally by immunostaining from the manifestation of a primary HCC tumor to the formation of a distant metastasis, and its upstream regulators were screened with a protein microarray. A series of metastasis assays in mouse models and HCC cell lines were performed to explore new functional insights into RBMY. RESULTS: Cytoplasmic expression of RBMY was associated with rapid distant metastasis (approximately 1 year after resection) and had a predictive power of 82.4% for HCC metastasis. RBMY conferred high migratory and invasive potential upon phosphorylation by the provirus integration in Moloney 1 (PIM1) kinase. Binding of PIM1 to RBMY caused mutual stabilization and massive translocation of RBMY from nuclei to mitochondria, thereby preventing mitochondrial apoptosis and augmenting mitochondrial generation of adenosine triphosphate/reactive oxygen species to enhance cell motility. Depletion of RBMY suppressed Snail1/zinc finger E-box binding homeobox transcription factor 1-mediated epithelial-mesenchymal transition and dynamin-related protein 1-dependent mitochondrial fission. Inactivation and knockout of PIM1 down-regulated the expression of RBMY. In nude mice, cytoplasmic RBMY promoted liver-to-lung metastasis by increasing epithelial-mesenchymal transition, mitochondrial proliferation, and mitochondrial fission, whereas nuclear-restricted RBMY impeded the mitochondrial switch and failed to induce lung metastasis. CONCLUSIONS: This study showed the regulation of HCC metastasis by PIM1-driven cytoplasmic expression of RBMY and suggested a novel therapeutic target for attenuating metastasis.

Accidental discovery of appendiceal carcinoma during gynecological surgery: A case report.

BACKGROUND: Malignant tumors of the appendix are extremely rare, constituting about 1% of all gastrointestinal tumors. Generally, pathology identifies these tumors during or after appendectomy because they are difficult to detect at the preoperative stage. This case report aims to introduce the definitive diagnosis and treatment of mucinous adenocarcinoma of the appendix. CASE SUMMARY: A 49-year-old female patient came to our hospital with right lower abdominal pain, nausea, and vomiting for three days. There was no change in the menstrual cycle. Gynecological ultrasound showed a cystic, solid mass in the right adnexa. Abdominal enhanced computed tomography showed a thick appendix. Cancer was found on exploration of the appendix during gynecological surgery. The right colon was removed. After surgery, the patient received chemotherapy and is recovering well. CONCLUSION: Appendiceal carcinoma is frequently found during or after surgery, and both preoperative examination and early evaluation of clinical manifestations are extremely important.

Special epithelioid trophoblastic tumor: A case report.

BACKGROUND: Epithelioid trophoblastic tumor (ETT) is a special type of gestational trophoblastic tumor. However, its pathogenesis has been incompletely elucidated. ETT rarely occurs in the ovaries and fallopian tubes, unlike placental site trophoblastic tumor, requiring a histopathological biopsy and immunohistochemistry for further diagnosis. CASE SUMMARY: A 29-year-old woman with irregular vaginal bleeding and elevated serum chorionic gonadotropin (ß-hCG) levels presented similar symptoms to ectopic pregnancy. Transvaginal ultrasound revealed abnormal echoes of the left adnexa. Postoperatively, the pathology of the left ovary and fallopian tube was reported as ETT. The patient was followed up with regular hCG measurements and ultrasounds. The blood hCG values showed an upward trend 3 mo after the operation and then chemotherapy was prescribed. The current health status is normal. CONCLUSION: For women of childbearing age with elevated serum ß-hCG levels, practitioners should consider ETT and be alert to the poor prognosis of the disease. After surgery, the patient's condition should be closely observed to prevent recurrence and metastasis. Postoperative chemotherapy is only helpful for treating the disease to a certain extent.

The Post-Traumatic Growth of Primary Caregivers of Patients after Liver Transplantation.

Liver transplantation is a very important surgery. In many cases, it involves two loved ones (receiver and donor in the same family) and causes stress and feelings of burden in family caregivers. The purpose of this study was to investigate post-traumatic growth in primary caregivers of liver transplant patients. A cross-sectional research design was adopted to recruit 84 participants. The Perceived Stress Scale, Short-Form Coping Strategies Scale, and Post-traumatic Growth Scale were used. The results revealed that the total score of perceived stress of the main caregivers of liver transplantation was 27.27 ± 6.63; problem-oriented coping and emotion-oriented coping were used as the main coping strategies, and the traumatic growth score was 42.01 ± 13.84. All three variables were significant predictors of post-traumatic growth (F = 13.71, p < 0.05), explaining 38% of the total variance. This study can help nurses understand the post-traumatic growth status and related factors of the main caregivers of liver transplant patients. It can also help caregivers understand their own perceived pressure and then take relevant care measures to reduce the degree of physical and mental load and achieve a balanced state.

Genetic variants of NTCP gene and hepatitis B vaccine failure in Taiwanese children of hepatitis B e antigen positive mothers.

BACKGROUND AND AIMS: Hepatitis B virus (HBV) vaccine failure remains a hurdle to the global elimination of HBV infections in the vaccination era. We aimed to elucidate the relationships between HBV entry receptor sodium taurocholate co-transporting polypeptide (NTCP) and vaccine failure in children born to highly infectious mothers. METHODS: The genetic variants rs7154439, rs4646285, rs4646287, and rs2296651 were genotyped in 170 children with chronic HBV infections and 138 control children of mothers positive for hepatitis B e antigen (HBeAg). All children received hepatitis B immunoglobulin and complete HBV vaccination. Total RNAs from 82 adult non-tumor liver tissues were quantified for NTCP, type I interferons and interferon-induced transmembrane protein 3 (IFITM3) levels. RESULTS: A higher rate of the GA/AA genotype (28.3% vs. 15.3%, p = 0.006) of the genetic variant rs4646287 in intron 1 of the NTCP gene was detected in control children compared to the carrier children. The rs4646287 G > A genotype was associated with younger ages at which spontaneous HBeAg seroconversion occurred (10.8 ± 8.4 vs. 14.6 ± 8.7 years, p = 0.003) in chronic HBV-infected children. Unique correlation patterns of NTCP and innate immunity-related genes (type I interferons and IFITM3) were found in HBV-infected liver tissues with the rs4646287 G > A genotype. CONCLUSION: The rs4646287 G > A genotype of the NTCP gene may be associated with lower risk for HBV vaccine failure in children born to highly infectious mothers. The protective effect of rs4646287 G > A was also present in carrier children, evidenced by earlier spontaneous HBeAg seroconversion.

Anticancer Effects and Molecular Mechanisms of Apigenin in Cervical Cancer Cells.

Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects in various cancers, but its effects are not widely accepted by clinical practitioners. The present study investigated the anticancer effects and molecular mechanisms of apigenin in cervical cancer in vitro and in vivo. HeLa and C33A cells were treated with different concentrations of apigenin. The effects of apigenin on cell viability, cell cycle distribution, migration potential, phosphorylation of PI3K/AKT, the integrin ß1-FAK signaling pathway, and epithelial-to-mesenchymal transition (EMT)-related protein levels were investigated. Mechanisms identified from the in vitro study were further validated in a cervical tumor xenograft mouse model. Apigenin effectively inhibited the growth of cervical cancer cells and cervical tumors in xenograft mice. Furthermore, the apigenin down-regulated FAK signaling (FAK, paxillin, and integrin ß1) and PI3K/AKT signaling (PI3K, AKT, and mTOR), inactivated or activated various signaling targets, such as Bcl-2, Bax, p21cip1, CDK1, CDC25c, cyclin B1, fibronectin, N-cadherin, vimentin, laminin, and E-cadherin, promoted mitochondrial-mediated apoptosis, induced G2/M-phase cell cycle arrest, and reduced EMT to inhibit HeLa and C33A cancer cell migration, producing anticancer effects in cervical cancer. Thus, apigenin may act as a chemotherapeutic agent for cervical cancer treatment.

Clinical manifestations and genetic analysis of a family with neurofibromatosis type 2.

BACKGROUND: Neurofibromatosis type 2 (NF2) is an autosomal dominantly inherited disease with slow, yet potentially life-threatening progression. OBJECTIVE: We describe the clinical manifestations and genetic profile of a family with NF2. METHODS: We enrolled a 16-member family with NF2. We collected clinical examinations and imaging information. Genetic analysis was conducted through multiplex ligation-dependent probe amplification (MLPA). The SALSA MLPA probemix P044-B2 NF2 kit was used to detect genetic variations in genomic upstream and 17 exons of the NF2 gene. RESULTS: The most common clinical manifestation was hearing impairment (37.5%), followed by tinnitus (18.8%). Four participants had vestibular schwannoma: 2 were bilateral and 2 unilateral, and tumor size ranged from 86.3 to 5064 mm3. A weak correlation between hearing impairment and tumor size was observed. Genetic analysis revealed that the DNA dosages of exons 9, 10, and 11 of the NF2 gene in 3 diseased family members (participants #3, #5, and #11) were higher than those in the controls. However, we could not detect an indicative abnormal DNA dosage of NF2 in participant #6 despite such a dosage being considered a diagnostic indicator of NF2. CONCLUSIONS: Hearing impairment was the most common clinical manifestation in this family. The NF2 gene is a gene of interest that warrants familial genetic screening.

Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo.

Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.