PKA inhibition kills L-asparaginase-resistant leukemic cells from relapsed acute lymphoblastic leukemia patients.

Despite the success in treating newly diagnosed pediatric acute lymphoblastic leukemia (aLL), the long-term cure rate for the 20% of children who relapse is poor, making relapsed aLL the primary cause of cancer death in children. By unbiased genome-wide retroviral RNAi screening and knockdown studies, we previously discovered opioid receptor mu 1 (OPRM1) as a new aLL cell resistance biomarker for the aLL chemotherapeutic drug, L-asparaginase, i.e., OPRM1 loss triggers L-asparaginase resistance. Indeed, aLL cell OPRM1 level is inversely proportional to L-asparaginase IC50: the lower the OPRM1 level, the higher the L-asparaginase IC50, indicating that aLL cells expressing reduced OPRM1 levels show resistance to L-asparaginase. In the current study, we utilized OPRM1-expressing and -knockdown aLL cells as well as relapsed patient aLL cells to identify candidate targeted therapy for L-asparaginase-resistant aLL. In OPRM1-expressing cells, L-asparaginase induces apoptosis via a cascade of events that include OPRM1-mediated decline in [cAMP]i, downregulation of PKA-mediated BAD S118 phosphorylation that can be reversed by 8-CPT-cAMP, cyt C release from the mitochondria, and subsequent caspase activation and PARP1 cleavage. The critical role of PKA inhibition due to a decrease in [cAMP]i in this apoptotic process is evident in the killing of OPRM1-knockdown and low OPRM1-expressing relapsed patient aLL cells by the PKA inhibitors, H89 and 14-22 amide. These findings demonstrate for the first time that PKA can be targeted to kill aLL cells resistant to L-asparaginase due to OPRM1 loss, and that H89 and 14-22 amide may be utilized to destroy L-asparaginase-resistant patient aLL cells.

Gasless endoscopic transaxillary subcutaneous mastectomy and immediate reconstruction with implants (GETSMIRI) for breast cancer: Lei's five-step method.

Background: Endoscopic nipple-sparing mastectomy (E-NSM) is a promising procedure in the treatment of breast cancer, but the limitations of endoscopic tools and intrinsic technical complexity of the technique hinder its applicability. Here, we introduce a novel surgery, gasless endoscopic transaxillary subcutaneous mastectomy and immediate reconstruction with implants (GETSMIRI), for breast cancer. and early effects. Methods: A retrospective analysis of the clinical data of 11 female patients, aged 50 (27-78) years, admitted to our hospital from January to December 2022, who underwent gasless endoscopic transaxillary subcutaneous mastectomy and immediate reconstruction with implants (GETSMIRI), was conducted. This study was designed to assess patient satisfaction before and after breast reconstruction, early complications, and breast function. Results: The tumors were all solitary, with a mean maximum diameter of 1.0 (0-2.0) cm and a mean distance of 2.3 (2-4) cm from the nipple, the mean intraoperative bleeding volume was 47.5 mL, and the mean hospital stay was 1.5 d. Postoperatively, 1 patient developed depigmentation of the nipple due to mild ischemia. There were no incisional complications, subcutaneous emphysema, infection, areola necrosis, skin flap necrosis, or removal of the prosthesis and/or patch. No tumor recurrence or metastasis was observed during the follow-up period. The difference between breast satisfaction and psychosocial health scores was not statistically significant (P = 0.680; P = 0.612). Conclusion: GETSMIRI, immediate implantable breast reconstruction, is less invasive than other such procedures, and short-term follow-up results show good postoperative satisfaction, making it an alternative surgical method.

m6A modified BACE1-AS contributes to liver metastasis and stemness-like properties in colorectal cancer through TUFT1 dependent activation of Wnt signaling.

BACKGROUND: Liver metastasis is one of the most important reasons for high mortality of colorectal cancer (CRC). Growing evidence illustrates that lncRNAs play a critical role in CRC liver metastasis. Here we described a novel function and mechanisms of BACE1-AS promoting CRC liver metastasis. METHODS: qRT-PCR and in situ hybridization were performed to examine the BACE1-AS level in CRC. IGF2BP2 binding to m6A motifs in BACE1-AS was determined by RIP assay and S1m-tagged immunoprecipitation. Transwell assay and liver metastasis mice model experiments were performed to examine the metastasis capabilities of BACE1-AS knockout cells. Stemness-like properties was examined by tumor sphere assay and the expression of stemness biomarkers. Microarray data were acquired to analyze the signaling pathways involved in BACE1-AS promoting CRC metastasis. RESULTS: BACE1-AS is the most up-regulated in metastatic CRC associated with unfavorable prognosis. Sequence blast revealed two m6A motifs in BACE1-AS. IGF2BP2 binding to these two m6A motifs is required for BACE1-AS boost in metastatic CRC. m6A modified BACE1-AS drives CRC cells migration and invasion and liver metastasis both in vitro and in vivo. Moreover, BACE1-AS maintains the stemness-like properties of CRC cells. Mechanically, BACE1-AS promoted TUFT1 expression by ceRNA network through miR-214-3p. CRC patients with such ceRNA network suffer poorer prognosis than ceRNA-negative patients. Depletion of TUFT1 mimics BACE1-AS loss. BACE1-AS activated Wnt signaling pathway in a TUFT1 dependent manner. BACE1-AS/miR-214-3p/TUFT1/Wnt signaling regulatory axis is essential for CRC liver metastasis. Pharmacologic inhibition of Wnt signaling pathway repressed liver metastasis and stemness-like features in BACE1-AS over-expressed CRC cells. CONCLUSION: Our study demonstrated BACE1-AS as a novel target of IGF2BP2 through m6A modification. m6A modified BACE1-AS promotes CRC liver metastasis through TUFT1 dependent activation of Wnt signaling pathway. Thus, targeting BACE1-AS and its downstream Wnt signaling pathways may provide a new opportunity for metastatic CRC intervention and treatment.

The macrophage polarization by miRNAs and its potential role in the treatment of tumor and inflammation (Review).

The characteristics of monocyte/macrophage lineage are diversity and plasticity, mainly manifested by M1 and M2 subtypes in the body tissues, and playing different roles in the immunity. In the polarization process of macrophages, the classic molecular mechanism is related to sequential transcription factors. Whether in tumor or inflammatory local microenvironment, the pathological factors of the local microenvironment often affect the polarization of M1 and M2 macrophages, and participate in the occurrence and development of these pathological processes. In recent years, a growing number of research results demonstrated that non­coding RNA (ncRNA) also participates in the polarization process of macrophages, in addition to traditional cytokines and transcriptional regulation signal pathway molecules. Among numerous ncRNAs, microRNAs (miRNAs) have attracted more attention from scholars both domestically and internationally, and significant progress has been made in basic and clinical research. Therefore, for improved understanding of the molecular mechanism of miRNAs in macrophage polarization and analysis of the potential value of this regulatory pathway in tumor and inflammatory intervention therapy, a comprehensive review of the progress of relevant literature research was conducted and some viewpoints and perspectives were proposed.

EGCG attenuates METH self-administration and reinstatement of METH seeking in mice.

Methamphetamine (METH) use disorder is a chronic, relapsing disorder and involves frequent failures of self-control of drug seeking and taking. Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic compounds of green tea, which has shown great therapeutic effectiveness in neurological disorders. However, it is still unknown whether and how EGCG affects METH seeking behaviour. Here, we show nanostructured EGCG/ascorbic acid nanoparticles (EGCG/AA NPs) dose-dependently reduced METH self-administration (SA) under fixed-ratio 1 (FR1) and progressive ratio (PR) reinforcement schedules in mice and shifted METH dose-response curves downward. Furthermore, EGCG/AA NPs decreased drug- and cue-induced METH seeking. In addition, we found that METH SA led to a decrease in inhibitory postsynaptic currents (IPSCs) and increase in the AMPAR/NMDAR ratio and excitation/inhibition (E/I) ratio in ex vivo midbrain slices from ventral tegmental area (VTA) dopamine neurons. EGCG/AA NPs enhanced Gamma-aminobutyric acid (GABA)ergic inhibition and normalized the E/I ratio. EGCG restored the balance between excitation and inhibition in VTA dopamine neurons, which may contribute to the attenuation of METH SA. These findings indicate that EGCG is a promising pharmacotherapy for METH use disorder.

Cope with copper: From copper linked mechanisms to copper-based clinical cancer therapies.

Recent studies have established a strong link between copper and cancer biology, as copper is necessary for cancer growth and metastasis. Beyond the conventional concept of copper serving as a catalytic cofactor of metalloenzymes, emerging evidence demonstrates copper as a regulator for signaling transduction and gene expression, which are vital for tumorigenesis and cancer progression. Interestingly, strong redox-active properties make copper both beneficial and detrimental to cancer cells. Cuproplasia is copper-dependent cell growth and proliferation, whereas cuproptosis is copper-dependent cell death. Both mechanisms act in cancer cells, suggesting that copper depletion and copper supplementation may be viable approaches for developing novel anticancer therapies. In this review, we summarized the current understanding of copper's biological role and related molecular mechanisms in cancer proliferation, angiogenesis, metastasis, autophagy, immunosuppressive microenvironment development, and copper-mediated cancer cell death. We also highlighted copper-based strategies for cancer treatment. The current challenges of copper in cancer biology and therapy and their potential solutions were also discussed. Further investigation in this field will yield a more comprehensive molecular explanation for the causal relationship between copper and cancers. It will reveal a series of key regulators governing copper-dependent signaling pathways, thereby providing potential targets for developing copper-related anticancer drugs.

An unconventional cancer-promoting function of methamphetamine in hepatocellular carcinoma.

For the past decade, the prevalence and mortality of methamphetamine (METH) use have doubled, suggesting that METH use could be the next substance use crisis worldwide. Ingested METH is transformed into other products in the liver, a major metabolic organ. Studies have revealed that METH causes deleterious inflammatory response, oxidative stress, and extensive DNA damage. These pathological damages are driving factors of hepatocellular carcinoma (HCC). Nonetheless, the potential role of METH in HCC and the underlying mechanisms remain unknown. Herein, we found a higher HCC incidence in METH abusers. METH promoted cellular proliferation, migration, and invasion in two human-derived HCC cells. Consistently, METH uptake promoted HCC progression in a xenograft mouse model. Mechanistically, METH exposure induced ROS production, which activated the Ras/MEK/ERK signaling pathway. Clearance of ROS by NAC suppressed METH-induced activation of Ras/ERK1/2 pathways, leading to arrest of HCC xenograft formation in nude mice. To the best of our knowledge, this is the first study to substantiate that METH promotes HCC progression and inhibition of ROS may reverse this process.

miR-let-7c-3p targeting on Egr-1 contributes to the committed differentiation of leukemia cells into monocyte/macrophages.

In preliminary experiments, it was found that the expression of early growth response-1 (Egr-1) was upregulated during the committed differentiation of leukemia cells into monocytes/macrophages. The cross-analysis of gene chip detection and database prediction indicated that Egr-1 was associated with upstream microRNA (miR)-let-7c-3p, thus the present study focused on the role of the miR-let-7c-3p/Egr-1 signaling axis in the committed differentiation of leukemia cells into monocytes/macrophages. Phorbol 12-myristate 13-acetate (PMA) was used to induce the directed differentiation of human K562 leukemia cells into monocytes/macrophages and the differentiation of K562 leukemia cells was determined by cell morphology observation and expression of differentiation antigens CD11b and CD14 by flow cytometry. The expression levels of Egr-1 and miR-let-7c-3p were detected by reverse transcription-quantitative PCR and the protein expression of Egr-1 was detected by western blotting. The effect of Egr-1 on the differentiation of K562 cells was detected by short interfering (si)RNA interference assay. A dual-luciferase reporter assay was used to detect target binding of miR-let-7c-3p on the 3'UTR of Egr-1. Cell transfection of miR-let-7c-3p mimics and inhibitors was used to modulate the expression of miR-let-7c-3p, as indicated by RT-qPCR assays. Western blotting was also used to examine the effect of miR-let-7c-3p on Egr-1 expression. The PMA-induced differentiation of K562 cells was transfected with miR-let-7c-3p and the expression of differentiation antigen was detected by flow cytometry. A differentiation model of K562 leukemia cells into monocytes/macrophages was induced by PMA, which was indicated by morphological observations and upregulation of CD11b and CD14 antigens. The gene or protein expression of Egr-1 was significantly higher compared with that of the control group, while the expression of miR-let-7c-3p was significantly lower compared with that of the control group. siRNA interference experiments showed that the expression of cell differentiation antigen CD14 in the 100 µg/ml PMA + si-Egr-1 group was significantly lower compared with that in the 100 µg/ml PMA + si-ctrl group. The dual luciferase reporter gene results showed that the luciferase activity of the co-transfected mimic and Egr-1 WT groups was significantly lower than that of the NC control group, while the luciferase activity of the co-transfected mimic and Egr-1 MUT groups was comparable to that of the NC control group. Therefore, the dual-luciferase reporter gene assay confirmed that miR-let-7c-3p can target Egr-1. Western blotting showed that the expression of Egr-1 following transfection with miR-let-7c-3p inhibitor was significantly higher compared with that of the negative control and the expression of Egr-1 after transfection with miR-let-7c-3p mimic was significantly lower than that of the negative control. Following exposure to PMA, the expressions of CD11b and CD14 in the miR-let-7c-3p inhibitor group were significantly higher than those in the miR-let-7c-3p NC group, as indicated by CD11b and CD14 respectively. In conclusion, miR-let-7c-3p could bind to the 3'UTR of Egr-1 and negatively regulated Egr-1 expression. The miR-let-7c-3p/Egr-1 signaling axis was closely associated with the committed differentiation of K562 cells from leukemia cells to monocytes/macrophages.

CDK5RAP2 loss-of-function causes premature cell senescence via the GSK3ß/ß-catenin-WIP1 pathway.

Developmental disorders characterized by small body size have been linked to CDK5RAP2 loss-of-function mutations, but the mechanisms underlying which remain obscure. Here, we demonstrate that knocking down CDK5RAP2 in human fibroblasts triggers premature cell senescence that is recapitulated in Cdk5rap2an/an mouse embryonic fibroblasts and embryos, which exhibit reduced body weight and size, and increased senescence-associated (SA)-ß-gal staining compared to Cdk5rap2+/+ and Cdk5rap2+/an embryos. Interestingly, CDK5RAP2-knockdown human fibroblasts show increased p53 Ser15 phosphorylation that does not correlate with activation of p53 kinases, but rather correlates with decreased level of the p53 phosphatase, WIP1. Ectopic WIP1 expression reverses the senescent phenotype in CDK5RAP2-knockdown cells, indicating that senescence in these cells is linked to WIP1 downregulation. CDK5RAP2 interacts with GSK3ß, causing increased inhibitory GSK3ß Ser9 phosphorylation and inhibiting the activity of GSK3ß, which phosphorylates ß-catenin, tagging ß-catenin for degradation. Thus, loss of CDK5RAP2 decreases GSK3ß Ser9 phosphorylation and increases GSK3ß activity, reducing nuclear ß-catenin, which affects the expression of NF-κB target genes such as WIP1. Consequently, loss of CDK5RAP2 or ß-catenin causes WIP1 downregulation. Inhibition of GSK3ß activity restores ß-catenin and WIP1 levels in CDK5RAP2-knockdown cells, reducing p53 Ser15 phosphorylation and preventing senescence in these cells. Conversely, inhibition of WIP1 activity increases p53 Ser15 phosphorylation and senescence in CDK5RAP2-depleted cells lacking GSK3ß activity. These findings indicate that loss of CDK5RAP2 promotes premature cell senescence through GSK3ß/ß-catenin downregulation of WIP1. Premature cell senescence may contribute to reduced body size associated with CDK5RAP2 loss-of-function.

Muscle atrophy induced by overexpression of ALAS2 is related to muscle mitochondrial dysfunction.

BACKGROUND: ALAS2 (delta-aminolevulinate synthase 2) is one of the two isoenzymes catalyzing the synthesis of delta-aminolevulinic acid (ALA), which is the first precursor of heme synthesis. ALAS2-overexpressing transgenic mice (Tg mice) showed syndrome of porphyria, a series of diseases related to the heme anabolism deficiency. Tg mice showed an obvious decrease in muscle size. Muscle atrophy results from a decrease in protein synthesis and an increase in protein degradation, which ultimately leads to a decrease in myofiber size due to loss of contractile proteins, organelles, nuclei, and cytoplasm. METHODS: The forelimb muscle grip strength of age-matched ALAS-2 transgenic mice (Tg mice) and wild-type mice (WT mice) were measured with an automated grip strength meter. The activities of serum LDH and CK-MB were measured by Modular DPP. The histology of skeletal muscle (quadriceps femoris and gastrocnemius) was observed by hematoxylin and eosin (HE) staining, immunohistochemistry, and transmission electron microscope. Real-time PCR was used to detect mtDNA content and UCP3 mRNA expression. Evans blue dye staining was used to detect the membrane damage of the muscle fiber. Single skeletal muscle fiber diameter was measured by single-fiber analyses. Muscle adenosine triphosphate (ATP) levels were detected by a luminometric assay with an ATP assay kit. RESULTS: Compared with WT mice, the strength of forelimb muscle and mass of gastrocnemius were decreased in Tg mice. The activities of serum CK-MB and LDH, the number of central nuclei fibers, and Evans blue positive fibers were more than those in WT mice, while the diameter of single fibers was smaller, which were associated with suppressed expression levels of MHC, myoD1, dystrophin, atrogin1, and MuRF1. Re-expression of eMyHC was only showed in the quadriceps of Tg mice, but not in WT mice. Muscle mitochondria in Tg mice showed dysfunction with descented ATP production and mtDNA content, downregulated UCP3 mRNA expression, and swelling of mitochondria. CONCLUSION: ALAS2 overexpressing-transgenic mice (Tg mice) showed muscle dystrophy, which was associated with decreased atrogin-1 and MuRF-1, and closely related to mitochondrial dysfunction.

Centromeric chromatin integrity is compromised by loss of Cdk5rap2, a transcriptional activator of CENP-A.

Centromeres are chromosomal loci where kinetochores assemble to ensure faithful chromosome segregation during mitosis. CENP-A defines the loci by serving as an epigenetic marker that recruits other centromere components for a functional structure. However, the mechanism that controls CENP-A regulation of centromeric chromatin integrity remains to be explored. Separate studies have shown that loss of CENP-A or the Cdk5 regulatory subunit associated protein 2 (Cdk5rap2), a key player in mitotic progression, triggers the occurrence of lagging chromosomes. This prompted us to investigate a potential link between CENP-A and Cdk5rap2 in the maintenance of centromeric chromatin integrity. Here, we demonstrate that loss of Cdk5rap2 causes reduced CENP-A expression while exogenous Cdk5rap2 expression in cells depleted of endogenous Cdk5rap2 restores CENP-A expression. Indeed, we show that Cdk5rap2 is a nuclear protein that acts as a positive transcriptional regulator of CENP-A. Cdk5rap2 interacts with the CENP-A promoter and upregulates CENP-A transcription. Accordingly, loss of Cdk5rap2 causes reduced level of centromeric CENP-A. Exogenous CENP-A expression partially inhibits the occurrence of lagging chromosomes in Cdk5rap2 knockdown cells, indicating that lagging chromosomes induced by loss of Cdk5rap2 is due, in part, to loss of CENP-A. Aside from manifesting lagging chromosomes, cells depleted of Cdk5rap2, and thus CENP-A, show increased micronuclei and chromatin bridge formation. Altogether, our findings indicate that Cdk5rap2 serves to maintain centromeric chromatin integrity partly through CENP-A.

Evidence and perspectives of cell senescence in neurodegenerative diseases.

Increased life expectancies have significantly increased the number of individuals suffering from geriatric neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The financial cost for current and future patients with these diseases is overwhelming, resulting in substantial economic and societal costs. Unfortunately, most recent high-profile clinical trials for neurodegenerative diseases have failed to obtain efficacious results, indicating that novel approaches are desperately needed to treat these pathologies. Cell senescence, characterized by permanent cell cycle arrest, resistance to apoptosis, mitochondrial alterations, and secretion of senescence-associated secretory phenotype (SASP) components, has been extensively studied in mitotic cells such as fibroblasts, which is considered a hallmark of aging. Furthermore, multiple cell types in the senescent state in the brain, including neurons, microglia, astrocytes, and neural stem cells, have recently been observed in the context of neurodegenerative diseases, suggesting that these senescent cells may play an essential role in the pathological processes of neurodegenerative diseases. Therefore, this review begins by outlining key aspects of cell senescence constitution followed by examining the evidence implicating senescent cells in neurodegenerative diseases. In the final section, we review how cell senescence may be targeted as novel therapeutics to treat pathologies associated with neurodegenerative diseases.

Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis.

BACKGROUND: Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. METHODS: ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. RESULTS: We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. CONCLUSION: In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

Stem Cell Therapies in Alzheimer's Disease: Applications for Disease Modeling.

Alzheimer's disease (AD) is a neurodegenerative disease with complex pathologic and biologic characteristics. Extracellular ß-amyloid deposits, such as senile plaques, and intracellular aggregation of hyperphosphorylated tau, such as neurofibrillary tangles, remain the main neuropathological criteria for the diagnosis of AD. There is currently no effective treatment of the disease, and many clinical trials have failed to prove any benefits of new therapeutics. More recently, there has been increasing interest in harnessing the potential of stem cell technologies for drug discovery, disease modeling, and cell therapies, which have been used to study an array of human conditions, including AD. The recently developed and optimized induced pluripotent stem cell (iPSC) technology is a critical platform for screening anti-AD drugs and understanding mutations that modify AD. Neural stem cell (NSC) transplantation has been investigated as a new therapeutic approach to treat neurodegenerative diseases. Mesenchymal stem cells (MSCs) also exhibit considerable potential to treat neurodegenerative diseases by secreting growth factors and exosomes, attenuating neuroinflammation. This review highlights recent progress in stem cell research and the translational applications and challenges of iPSCs, NSCs, and MSCs as treatment strategies for AD. Even though these treatments are still in relative infancy, these developing stem cell technologies hold considerable promise to combat AD and other neurodegenerative disorders. SIGNIFICANCE STATEMENT: Alzheimer's disease (AD) is a neurodegenerative disease that results in learning and memory defects. Although some drugs have been approved for AD treatment, fewer than 20% of patients with AD benefit from these drugs. Therapies based on stem cells, including induced pluripotent stem cells, neural stem cells, and mesenchymal stem cells, provide promising therapeutic strategies for AD.

The Neuroprotective and Neurodegeneration Effects of Heme Oxygenase-1 in Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by complex pathological and biological features. Notably, extracellular amyloid-ß deposits as senile plaques and intracellular aggregation of hyperphosphorylated tau as neurofibrillary tangles remain the primary premortem criterion for the diagnosis of AD. Currently, there exist no disease-modifying therapies for AD, and many clinical trials have failed to show its benefits for patients. Heme oxygenase 1 (HO-1) is a 32 kDa enzyme, which catalyzes the degradation of cellular heme to free ferrous iron, biliverdin, and carbon monoxide under stressful conditions. Several studies highlight the crucial pathological roles of HO-1 in the molecular processes of AD. The beneficial roles of HO-1 overexpression in AD brains are widely accepted due to its ability to convert pro-oxidant heme to biliverdin and bilirubin (antioxidants), which promote restoration of a suitable tissue redox microenvironment. However, the intracellular oxidative stress might be amplified by metabolites of HO-1 and exacerbate the progression of AD under certain circumstances. Several lines of evidence have demonstrated that upregulated HO-1 is linked to tauopathies, neuronal damage, and synapse aberrations in AD. Here, we review the aspects of the molecular mechanisms by which HO-1 regulates AD and the latest information on the pathobiology of AD. We further highlight the neuroprotective and neurodystrophic actions of HO-1 and the feasibility of HO-1 as a therapeutic target for AD.

Heme Oxygenase 1 Inhibits Adult Neural Stem Cells Proliferation and Survival via Modulation of Wnt/ß-Catenin Signaling.

BACKGROUND: Adult hippocampal neurogenesis is critical for renewing hippocampal neural circuits and maintaining hippocampal cognitive function and is closely associated with age-related neurodegenerative diseases. Heme oxygenase 1 (HO-1) is a stress protein that catalyzes the degradation of heme into free iron, biliverdin, and carbon monoxide. Elevated HO-1 level constitutes a pathological feature of Alzheimer's disease, Parkinson's disease, and many other age-related neurodegenerative diseases. OBJECTIVE: Here we research the precise role of HO-1 in adult hippocampal neurogenesis. METHODS: To explore the effect of HO-1 overexpression on adult neural stem cells (aNSCs) and elucidate its mechanisms, Tg(HO-1) was constructed. The transgenic mice and aNSCs were subjected to neurosphereing assay, clonal analysis, and BrdU labelling to detect the proliferation and self-renewal ability. LiCl, MG132, CHX, and IGF-1 treatment were used to research the signaling pathways which regulated by HO-1. RESULTS: HO-1 overexpression decreased proliferation ability and induced apoptosis of aNSCs in subgranular zoon (SGZ) in vivo and in vitro. Furthermore, HO-1 overexpression inactivated canonical WNT/ß-catenin pathway. Re-activate canonical WNT/ß-catenin pathway rescued aNSCs proliferation and survival upon HO-1 overexpression. More importantly, phosphorylation of AKTS473 and GSK3ßS9 was found to be significantly decreased in HO-1 overexpressed aNSCs. Re-activation of AKT signaling proved that HO-1 inhibited Wnt/ß-catenin signaling pathway via AKT/GSK3ß signaling pathway. CONCLUSION: These results demonstrated a critical role of HO-1 in regulating aNSCs survival and proliferation by inhibiting Wnt/ß-catenin pathway through repression of AKT/GSK3ß, which provide a novel insight into the role of HO-1 in Alzheimer's disease pathogenesis.

Adipose-derived stem cells: Sources, potency, and implications for regenerative therapies.

Adipose-derived stem cells (ASCs) are a subset of mesenchymal stem cells (MSCs) that can be obtained easily from adipose tissues and possess many of the same regenerative properties as other MSCs. ASCs easily adhere to plastic culture flasks, expand in vitro, and have the capacity to differentiate into multiple cell lineages, offering the potential to repair, maintain, or enhance various tissues. Since human adipose tissue is ubiquitous and easily obtained in large quantities using a minimally invasive procedure, the use of autologous ASCs is promising for both regenerative medicine and organs damaged by injury and disease, leading to a rapidly increasing field of research. ASCs are effective for the treatment of severe symptoms such as atrophy, fibrosis, retraction, and ulcers induced by radiation therapy. Moreover, ASCs have been shown to be effective for pathological wound healing such as aberrant scar formation. Additionally, ASCs have been shown to be effective in treating severe refractory acute graft-versus-host disease and hematological and immunological disorders such as idiopathic thrombocytopenic purpura and refractory pure red cell aplasia, indicating that ASCs may have immunomodulatory function. Although many experimental procedures have been proposed, standardized harvesting protocols and processing techniques do not yet exist. Therefore, in this review we focus on the current landscape of ASC isolation, identification, location, and differentiation ability, and summarize the recent progress in ASC applications, the latest preclinical and clinical research, and future approaches for the use of ASCs.

HAP1 loss confers l-asparaginase resistance in ALL by downregulating the calpain-1-Bid-caspase-3/12 pathway.

l-Asparaginase (l-ASNase) is a strategic component of treatment protocols for acute lymphoblastic leukemia (ALL). It causes asparagine deficit, resulting in protein synthesis inhibition and subsequent leukemic cell death and ALL remission. However, patients often relapse because of the development of resistance, but the underlying mechanism of ALL cell resistance to l-asparaginase remains unknown. Through unbiased genome-wide RNA interference screening, we identified huntingtin associated protein 1 (HAP1) as an ALL biomarker for l-asparaginase resistance. Knocking down HAP1 induces l-asparaginase resistance. HAP1 interacts with huntingtin and the intracellular Ca2+ channel, inositol 1,4,5-triphosphate receptor to form a ternary complex that mediates endoplasmic reticulum (ER) Ca2+ release upon stimulation with inositol 1,4,5-triphosphate3 Loss of HAP1 prevents the formation of the ternary complex and thus l-asparaginase-mediated ER Ca2+ release. HAP1 loss also inhibits external Ca2+ entry, blocking an excessive rise in [Ca2+]i, and reduces activation of the Ca2+-dependent calpain-1, Bid, and caspase-3 and caspase-12, leading to reduced number of apoptotic cells. These findings indicate that HAP1 loss prevents l-asparaginase-induced apoptosis through downregulation of the Ca2+-mediated calpain-1-Bid-caspase-3/12 apoptotic pathway. Treatment with BAPTA-AM [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester)] reverses the l-asparaginase apoptotic effect in control cells, supporting a link between l-asparaginase-induced [Ca2+]i increase and apoptotic cell death. Consistent with these findings, ALL patient leukemic cells with lower HAP1 levels showed resistance to l-asparaginase, indicating the clinical relevance of HAP1 loss in the development of l-asparaginase resistance, and pointing to HAP1 as a functional l-asparaginase resistance biomarker that may be used for the design of effective treatment of l-asparaginase-resistant ALL.

Trends in clinical features and survival of oral cavity cancer: fifty years of experience with 3,362 consecutive cases from a single institution.

BACKGROUND: Global data demonstrate minimal improvement in the survival rate for oral cavity cancer (OCC) patients. We wished to know whether or not clinical features and survival rate have changed over time for OCC patients receiving initial treatment and follow-up at a large cancer center in China. METHODS: Clinical features and survival data were collected on patients diagnosed during the successive decades of 1960-1969 (n=253), 1970-1979 (n=497), 1980-1989 (n= 659), 1990-1999 (n=793), and 2000-2009 (n=1,160) at the Sun Yat-sen University Cancer Center. RESULTS: Over time, the overall 5-year survival rate for OCC patients was 52.0%. According to tumor localization, this rate was 71.4% for lip cancer, 56.3% for oral tongue cancer, and 42.7% for other parts of the oral cavity. From the 1960s to the 2000s, the 5-year survival rate steadily improved from 47.8% to 55.6% (P<0.001). Survival steadily decreased with age and was higher for women than for men in the 3 most recent decades. The survival rate for male patients was constant over time, while the rate for female patients improved dramatically. Obvious trends in clinical features over time included the following: increasing age of patients, increasing proportions of localized disease at diagnosis, decreasing proportions of diagnoses of lip cancer, decreasing proportions of diagnoses of squamous cell carcinoma, and decreasing proportions of non-surgical treatment approaches. CONCLUSION: The survival rate has steadily improved for OCC patients at this cancer center.

Heme Oxygenase 1 Induces Tau Oligomer Formation and Synapse Aberrations in Hippocampal Neurons.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by behavioral changes and cognitive decline. Recent evidence suggests that it is the soluble forms of tau oligomers (Tau-O) and Aß oligomers (oAß) rather than the well-studied insoluble protein aggregates that possess the neurotoxicity, infectivity, and amplification underlying disease progression. Heme oxygenase 1 (HO-1), an inducible enzyme upregulated in the cortex and hippocampus of AD brains, was reported to damage neural structures and disrupt brain function, suggesting possible contributions to Tau-O-mediated neurodegeneration. In this study, we focused on the effects of HO-1 on Tau-O formation. In hippocampus of HO-1-overexpressing transgenic mice and neural 2a (N2a) cells, Tau-O was co-localized with HO-1 as visualized by immunofluorescence staining. Furthermore, primary cultured hippocampal neurons from HO-1 transgenic mice showed elevated Tau-O and concomitant reductions in spine density and length as well as dendritic length, diameter, and arborization. Blocking Tau-O formation by isoprenaline reversed these HO-1-induced morphological changes. These results indicated that HO-1 contributes to Tau-O formation and ensuing synaptic damage. Thus, HO-1 is a promising target for AD drug development.