A comparative study of transperineal software-assisted magnetic resonance/ultrasound fusion biopsy and transrectal cognitive fusion biopsy of the prostate.

BACKGROUND: The advantages and disadvantages of transperineal and transrectal biopsies remain controversial in the era of prostate targeted biopsy. In this study, we compared the cancer detection and complication rates of transperineal magnetic resonance/ultrasound (MR/US) fusion biopsy and transrectal cognitive fusion biopsy of the prostate. METHODS: This was a comparative study of two prospectively collected cohorts. Men with clinically suspected prostate cancer and prostate imaging reporting and data system (PI-RADS) score ≥ 3 lesions on multi-parametric magnetic resonance imaging (mpMRI) were enrolled. They underwent either transperineal software fusion biopsy or transrectal cognitive fusion biopsy and systematic biopsy. The detection rates of any prostate cancer and clinically significant prostate cancer (csPC, defined as Gleason score ≥ 3 + 4) and the complication rates between both groups were analysed. RESULTS: Ninety-two and 85 patients underwent transperineal software fusion and transrectal cognitive fusion biopsies, respectively. The detection rate for any prostate cancer was similar between both groups (60.8% vs. 56.4%, p = 0.659). In terms of csPC detection, transperineal fusion biopsy outperformed transrectal fusion biopsy (52.2% vs. 36.5%, p = 0.036). In multivariate regression analysis, age, PI-RADS score > 3, and transperineal route were significant predictors of csPC. Meanwhile, transperineal biopsy resulted in a higher rate of urinary retention than transrectal biopsy (18.5% vs. 4.7%, p = 0.009). No serious infectious complications were noted, although a patient developed sepsis after transrectal biopsy. CONCLUSIONS: Transperineal software fusion biopsy provided a higher csPC detection rate than transrectal cognitive fusion biopsy and carried minimal risk for infectious complications in patients with MRI-visible prostate lesions.

Schizophyllum commune Reduces Expression of the SARS-CoV-2 Receptors ACE2 and TMPRSS2.

The current global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of COVID-19 has infected hundreds of millions of people, killed millions, and continues to pose a threat. It has become one of the largest epidemics in human history, causing enormous damage to people's lives and economies in the whole world. However, there are still many uncertainties and continued attention to the impact of SARS-CoV-2 on human health. The entry of SARS-CoV-2 into host cells is facilitated by the binding of the spike protein on the virus surface to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). Furthermore, transmembrane protease serine 2 (TMPRSS2) is a host surface protease that cleaves and proteolytically activates its S protein, which is necessary for viral infection. Thus, SARS-CoV-2 uses the ACE2 receptor for cell entry and initiates the S protein using the protease TMPRSS2. Schizophyllum commune (SC) is one of the most widely distributed fungi, often found on the rotten wood of trees that has been found to have various health benefits, including anticancer, antimicrobial activity, antiparasitic, and immunomodulatory function. In this article, SC significantly diminished the expression ACE2 and TMPRSS2 protein in vitro and in vivo without cell damage. In addition, adenosine from SC was also proven in this experiment to reduce the ACE2 and TMPRSS2 expression. Thus, our findings suggest that SC and adenosine exhibit potential for the repression of SARS-CoV-2 infection via the ACE2 and TMPRSS2 axis.

Combining prostate health index and multiparametric magnetic resonance imaging in estimating the histological diameter of prostate cancer.

BACKGROUND: Although multiparametric magnetic resonance imaging (mpMRI) is widely used to assess the volume of prostate cancer, it often underestimates the histological tumor boundary. The aim of this study was to evaluate the feasibility of combining prostate health index (PHI) and mpMRI to estimate the histological tumor diameter and determine the safety margin during treatment of prostate cancer. METHODS: We retrospectively enrolled 72 prostate cancer patients who underwent radical prostatectomy and had received PHI tests and mpMRI before surgery. We compared the discrepancy between histological and radiological tumor diameter stratified by Prostate Imaging-Reporting and Data System (PI-RADS) score, and then assessed the influence of PHI on the discrepancy between low PI-RADS (2 or 3) and high PI-RADS (4 or 5) groups. RESULTS: The mean radiological and histological tumor diameters were 1.60 cm and 2.13 cm, respectively. The median discrepancy between radiological and histological tumor diameter of PI-RADS 4 or 5 lesions was significantly greater than that of PI-RADS 2 or 3 lesions (0.50 cm, IQR (0.00-0.90) vs. 0.00 cm, IQR (-0.10-0.20), p = 0.02). In the low PI-RADS group, the upper limit of the discrepancy was 0.2 cm; so the safety margin could be set at 0.1 cm. In the high PI-RADS group, the upper limits of the discrepancy were 1.2, 1.6, and 2.2 cm in men with PHI < 30, 30-60, and > 60; so the safety margin could be set at 0.6, 0.8, and 1.1 cm, respectively. CONCLUSIONS: Radiological tumor diameter on mpMRI often underestimated the histological tumor diameter, especially for PI-RADS 4 or 5 lesions. Combining mpMRI and PHI may help to better estimate the histological tumor diameter.

Osajin displays potential antiprostate cancer efficacy via impairment of fatty acid synthase and androgen receptor expression.

BACKGROUND: Currently, antiprostate cancer (PCa) drugs, including androgen deprivation therapy (ADT), are initially effective; however, most patients with PCa who receive ADT eventually progress to deadly aggressiveness. There is an urgent need to seek alternative strategies to cure this lethal disease. Activation of lipogenesis has been demonstrated to lead to PCa progression. Therefore, targeting the aberrant lipogenic activity could be developed therapeutically in PCa. The aim of this study is to investigate the molecular basis and efficacy of osajin, a bioactive prenylated isoflavonoid, in PCa. METHODS: PCa cells, LNCaP (androgen-sensitive) and C4-2 (androgen-insensitive/castration-resistant), were used in this study. Proliferation, migration, and invasion analyses were conducted by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, a wound healing assay, and the transwell method. Lipogenesis was determined by a Fatty Acid Quantification Kit and oil red O staining. Apoptosis was assessed by annexin V-fluorescein isothiocyanate/propidium iodide staining, caspase enzymatic activity, and Western blot analyses. RESULTS: Osajin inhibited fatty acid synthase (FASN) expression, a key enzyme for lipogenesis, in PCa cells. By inhibiting FASN, osajin decreased the fatty-acid levels and lipid accumulation. Significantly, osajin downregulated androgen receptor (AR) and prostate-specific antigen (PSA) in PCa cells. Moreover, osajin suppressed PCa cell growth, migration, and invasion. Through activation of the caspase-dependent pathway, osajin induced apoptosis in PCa cells. CONCLUSIONS: These data provide a novel molecular basis of osajin in PCa cells, and cotargeting lipogenesis and the AR axis via impairment of FASN and AR expression by osajin could be applied as a new and promising approach for the treatment of malignant PCa.

Chinese Herbal Medicine Ganoderma tsugae Displays Potential Anti-Cancer Efficacy on Metastatic Prostate Cancer Cells.

Resistance to the current therapies is the main clinical challenge in the treatment of lethal metastatic prostate cancer (mPCa). Developing novel therapeutic approaches with effective regimes and minimal side effects for this fatal disease remain a priority in prostate cancer study. In the present study, we demonstrated that a traditional Chinese medicine, quality-assured Ganoderma tsugae ethanol extract (GTEE), significantly suppressed cell growth and metastatic capability and caused cell cycle arrest through decreasing expression of cyclins in mPCa cells, PC-3 and DU145 cells. GTEE also induced caspase-dependent apoptosis in mPCa cells. We further showed the potent therapeutic efficacy of GTEE by inhibiting subcutaneous PC-3 tumor growth in a xenograft model. The in vitro and in vivo efficacies on mPCa cells were due to blockade of the PI3K/Akt and MAPK/ERK signaling pathways associated with cancer cell growth, survival and apoptosis. These preclinical data provide the molecular basis for a new potential therapeutic approach toward the treatment of lethal prostate cancer progression.

Ganoderma tsugae Inhibits the SREBP-1/AR Axis Leading to Suppression of Cell Growth and Activation of Apoptosis in Prostate Cancer Cells.

Recent research suggests that the activation of lipid biosynthesis (lipogenesis) is linked with prostate cancer (PCa) malignancy. Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcriptional regulator controlling lipogenesis. Moreover, androgen receptor (AR) has been well defined to play an important role in lethal PCa aggressiveness from androgen-responsive to castration-resistant status. In this study, we showed that the quality-assured Ganoderma tsugae ethanol extract (GTEE), a Chinese natural and herbal product, significantly inhibited expression of SREBP-1 and its downstream genes associated with lipogenesis in PCa cells. Through inhibiting SREBP-1, GTEE reduced the levels of intracellular fatty acids and lipids in PCa cells. Importantly, GTEE also downregulated the expression of AR and prostate-specific antigen (PSA) in both androgen-responsive and castration-resistant PCa cells. By blocking the SREBP-1/AR axis, GTEE suppressed cell growth and progressive behaviors, as well as activating the caspase-dependent apoptotic pathway in PCa cells. These data provide a new molecular basis of GTEE for the development of a potential therapeutic approach to treat PCa malignancy.

Pten Mutations Alter Brain Growth Trajectory and Allocation of Cell Types through Elevated ß-Catenin Signaling.

Abnormal patterns of head and brain growth are a replicated finding in a subset of individuals with autism spectrum disorder (ASD). It is not known whether risk factors associated with ASD and abnormal brain growth (both overgrowth and undergrowth) converge on common biological pathways and cellular mechanisms in the developing brain. Heterozygous mutations in PTEN (PTEN(+/-)), which encodes a negative regulator of the PI3K-Akt-mTOR pathway, are a risk factor for ASD and macrocephaly. Here we use the developing cerebral cortex of Pten(+/-) mice to investigate the trajectory of brain overgrowth and underlying cellular mechanisms. We find that overgrowth is detectable from birth to adulthood, is driven by hyperplasia, and coincides with excess neurons at birth and excess glia in adulthood. ß-Catenin signaling is elevated in the developing Pten(+/-) cortex, and a heterozygous mutation in Ctnnb1 (encoding ß-catenin), itself a candidate gene for ASD and microcephaly, can suppress Pten(+/-) cortical overgrowth. Thus, a balance of Pten and ß-catenin signaling regulates normal brain growth trajectory by controlling cell number, and imbalance in this relationship can result in abnormal brain growth. SIGNIFICANCE STATEMENT: We report that Pten haploinsufficiency leads to a dynamic trajectory of brain overgrowth during development and altered scaling of neuronal and glial cell populations. ß-catenin signaling is elevated in the developing cerebral cortex of Pten haploinsufficient mice, and a heterozygous mutation in ß-catenin, itself a candidate gene for ASD and microcephaly, suppresses Pten(+/-) cortical overgrowth. This leads to the new insight that Pten and ß-catenin signaling act in a common pathway to regulate normal brain growth trajectory by controlling cell number, and disruption of this pathway can result in abnormal brain growth.

ADAM9 drives the immunosuppressive microenvironment by cholesterol biosynthesis-mediated activation of IL6-STAT3 signaling for lung tumor progression.

Chronic inflammation associated with lung cancers contributes to immunosuppressive tumor microenvironments, reducing CD8+ T-cell function and leading to poor patient outcomes. A disintegrin and metalloprotease domain 9 (ADAM9) promotes cancer progression. Here, we aim to elucidate the role of ADAM9 in the immunosuppressive tumor microenvironment. A bioinformatic analysis of TIMER2.0 was used to investigate the correlation of ADAM9 and to infiltrate immune cells in the human lung cancer database and mouse lung tumor samples. Flow cytometry, immunohistochemistry, and RNA sequencing (RNA-seq) were performed to investigate the ADAM9-mediated immunosuppressive microenvironment. The coculture system of lung cancer cells with immune cells, cytokine array assays, and proteomic approach was used to investigate the mechanism. By analyzing the human LUAD database and the mouse lung cancer models, we showed that ADAM9 was associated with the immunosuppressive microenvironment. Additionally, ADAM9 released IL6 protein from cancer cells to inhibit IL12p40 secretion from dendritic cells, therefore leading to dendritic cell dysfunction and further affecting T-cell functions. Proteomic analysis indicated that ADAM9 promoted cholesterol biosynthesis and increased IL6-STAT3 signaling. Mechanistically, ADAM9 reduced the protein stability of LDLR, resulting in reduced cholesterol uptake and induced cholesterol biosynthesis. Moreover, LDLR reduction enhanced IL6-STAT3 activation. We reveal that ADAM9 has a novel biological function that drives the immunosuppressive tumor microenvironment by linking lung cancer's metabolic and signaling axes. Thus, by targeting ADAM9 an innovative and promising therapeutic opportunity was indicated for regulating the immunosuppression of lung cancer.

Associations of Matrix Metalloproteinase-8 Genotypes to Renal Cell Carcinoma in Taiwan.

BACKGROUND/AIM: Renal cell carcinoma (RCC) presents a formidable clinical challenge due to its aggressive behavior and limited therapeutic options. Matrix metalloproteinase-8 (MMP-8) has recently emerged as a potential biomarker and therapeutic target for various cancers. However, the genetic involvement of MMP-8 in RCC has remained largely obscure. This study aimed to elucidate the role of MMP-8 genotypes in RCC susceptibility. MATERIALS AND METHODS: The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed to scrutinize the genotypes of MMP-8 C-799T (rs11225395), Val436Ala (rs34009635), and Lys460Thr (rs35866072) among 118 RCC patients and 590 controls. Furthermore, potential associations between MMP-8 genotypes and age, sex, smoking, alcohol consumption, hypertension, diabetes, and family history status in relation to RCC risk were assessed. RESULTS: No significant disparities in the distribution of MMP-8 rs11225395, rs34009635, and rs35866072 genotypes were observed between the RCC case and control cohorts (p>0.05). Individuals with CT and TT genotypes at MMP-8 rs11225395 exhibited 0.86- and 0.80-fold RCC risks, respectively (OR=0.57-1.31 and 0.42-1.55, p=0.5585 and 0.6228, respectively). Intriguingly, hypertensive individuals carrying the MMP-8 rs11225395 CT or TT genotype demonstrated an elevated risk for RCC compared to those with wild-type CC genotype (p=0.0440). No interactions of MMP-8 genotypes with age, sex, smoking, alcohol consumption, or diabetes status were evident (all p>0.05). No significant association was discerned for MMP-8 rs34009635 or rs35866072 genotypes. CONCLUSION: MMP-8 genotypes appear to have a modest influence on individual susceptibility to RCC. Hypertensive patients with the CT or TT MMP-8 rs11225395 genotype may have an elevated risk of RCC.

Elucidation of scandenolone as anti-cancer activity through impairment of the metabolic and signaling vulnerabilities in prostate cancer.

Prostate cancer (PCa) is the most prevalent men's cancer in America and Western countries. No effective therapies are currently available for PCa aggressiveness, including castration-resistant progression (CRPC). This study aims at evaluation of the prospective efficacy and the molecular mechanism of scandenolone (SCA), a natural isoflavone, in PCa progression. SCA suppressed cell viability and progression and induced apoptosis in PCa cells. SCA inhibited the expression of lipogenesis and cholesterogenesis related key genes. Through inhibition of these metabolic genes, SCA decreased the levels of fatty acids, lipid droplets and cholesterols in PCa cells. Moreover, SCA enhanced the expression of antioxidant factors, including Nrf2, HO-1, catalase and SOD-1, and reduced the ROS levels in PCa cells. Substantially, SCA displayed the potential efficacy on CRPC tumors. This paper offers a new insight into the underlying molecular basis of SCA in PCa cells. By coordinated impairment of the metabolic and signaling vulnerabilities, including lipogenesis, cholesterogenesis, ROS and the AR/PSA axis, SCA could be applied as a novel and promising remedy to cure malignant PCa.

Association of Matrix Metalloproteinase-2 Genotypes With Prostate Cancer Risk.

BACKGROUND/AIM: Prostate cancer is one of the most commonly diagnosed malignancies among males, especially in Western populations. Matrix metalloproteinase-2 (MMP-2) plays a critical role in extracellular regulation and metastasis. However, its genotypes have seldom been examined among patients with prostate cancer (PCa). Therefore, the purpose of the study was to evaluate the association of genotypes at MMP-2 promoter -1306 (rs243865) and -735 (rs2285053) with PCa risk in a Taiwanese cohort. MATERIALS AND METHODS: The profiles of MMP-2 rs243865 and rs2285053 genotypes were examined among 218 PCa patients and 436 healthy controls by polymerase chain reaction-restriction fragment length polymorphism methodologies. RESULTS: The percentages of wild-type CC, and variant CT and TT genotypes on MMP-2 rs243865 were 88.5, 10.6, and 0.9% in the PCa case group and 85.6, 13.5, and 0.9% in the control group, respectively (p for trend=0.5544). The allelic frequency distribution showed that the variant T allele at MMP-2 rs24386 5 was not associated with PCa risk (p=0.3250). As for MMP-2 rs2285053, the results were also non-significant. In addition, there was no association between the genotypes of MMP-2 rs243865 or rs2285053 with age or smoking status on PCa risk. CONCLUSION: rs11568818 and rs11568819 at MMP-2 promoter region played minor roles in determining individual PCa risk.

Learning Curve of Transperineal MRI/US Fusion Prostate Biopsy: 4-Year Experience.

This study aimed to evaluate the learning curve of transperineal magnetic resonance imaging (MRI)/ultrasound (US) fusion biopsy in a team composed of a single surgeon, a single radiologist, and a single pathologist. We prospectively enrolled 206 patients undergoing MRI/US fusion prostate biopsy and divided them into four cohorts by the year of biopsy. We analyzed temporal changes in clinically significant prostate cancer (csPC) detection rate, percentage of positive cores on biopsy, and Gleason upgrading rate after radical prostatectomy. The csPC detection rate by MRI/US fusion targeted biopsy (TB) increased significantly (from 35.3% to 60.0%, p = 0.01). With increased experience, the csPC detection rates for small (≤1 cm) and anterior target lesions gradually increased (from 41.2% to 51.6%, p = 0.5; from 54.5% to 88.2%, p = 0.8, respectively). The percentage of positive cores on TB increased significantly (from 18.4% to 44.2%, p = 0.001). The Gleason upgrading rate gradually decreased (from 22.2% to 11.1%, p = 0.4). In conclusion, with accumulated experience and teamwork, the csPC detection rate by TB significantly increased. Multidisciplinary team meetings and a free-hand biopsy technique were the key factors for overcoming the learning curve.

Lateral mammillary body neurons in mouse brain are disproportionately vulnerable in Alzheimer's disease.

The neural circuits governing the induction and progression of neurodegeneration and memory impairment in Alzheimer's disease (AD) are incompletely understood. The mammillary body (MB), a subcortical node of the medial limbic circuit, is one of the first brain regions to exhibit amyloid deposition in the 5xFAD mouse model of AD. Amyloid burden in the MB correlates with pathological diagnosis of AD in human postmortem brain tissue. Whether and how MB neuronal circuitry contributes to neurodegeneration and memory deficits in AD are unknown. Using 5xFAD mice and postmortem MB samples from individuals with varying degrees of AD pathology, we identified two neuronal cell types in the MB harboring distinct electrophysiological properties and long-range projections: lateral neurons and medial neurons. lateral MB neurons harbored aberrant hyperactivity and exhibited early neurodegeneration in 5xFAD mice compared with lateral MB neurons in wild-type littermates. Inducing hyperactivity in lateral MB neurons in wild-type mice impaired performance on memory tasks, whereas attenuating aberrant hyperactivity in lateral MB neurons ameliorated memory deficits in 5xFAD mice. Our findings suggest that neurodegeneration may be a result of genetically distinct, projection-specific cellular dysfunction and that dysregulated lateral MB neurons may be causally linked to memory deficits in AD.

Association of Matrix Metalloproteinase-7 Genotypes With Prostate Cancer Risk.

BACKGROUND/AIM: Prostate cancer is one of the most commonly diagnosed malignancies among males worldwide. It has been shown that MMP-7 gene is closely correlated with prostate carcinogenesis. However, the role of the MMP-7 genotypes has been seldom examined among prostate cancer patients. Therefore, the purpose of the study was to evaluate the contribution of MMP-7 promoter genotypes A-181G (rs11568818) and C-153T (rs11568819) to prostate cancer risk in Taiwan. MATERIALS AND METHODS: Two hundred and eighteen prostate cancer patients and 436 sex- and age-matched healthy controls were genotyped for MMP-7 rs11568818 and rs11568819 by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing methodologies. RESULTS: The percentages of wild-type AA, and variant AG and GG genotypes on MMP-7 rs11568818 were 85.3, 13.5, and 1.2% among the prostate cancer cases and 87.6, 10.1, and 2.3% among the healthy controls, respectively (p for trend=0.2557). Interestingly, no MMP-7 rs11568819 genotypes were identified among Taiwanese. The allelic frequency distribution also showed that the variant G allele of MMP-7 rs11568818 seemed not to be a determinant of prostate cancer risk (p=0.7977). There was no joint effect between the genotypes of MMP-7 rs11568818 and age and smoking status on prostate cancer risk. CONCLUSION: rs11568818 and rs11568819 at MMP-7 promoter region, played no role in determining personal susceptibility to prostate cancer in Taiwan.

Impacts of Matrix Metalloproteinase 9 Genotypes on Renal Cell Carcinoma.

BACKGROUND/AIM: The expression of matrix metalloproteinase 9 (MMP9) is elevated in various renal diseases, including renal cell carcinoma. However, the role of MMP9 genotype in this context remains unclear. This study aimed to investigate the association between MMP9 promoter rs3918242 genotypes and the risk of renal cell carcinoma. MATERIALS AND METHODS: The MMP9 rs3918242 genotypes of 118 patients with renal cell carcinoma and 590 healthy subjects were determined using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The results indicated that individuals carrying the CT or TT genotype of MMP9 rs3918242 did not exhibit an increased risk of renal cell carcinoma compared to wild-type CC carriers (odds ratio=1.20 and 2.68, 95% confidence interval=0.75-1.92 and 0.89-8.03; p=0.5270 and 0.1420, respectively). However, individuals with the CT and TT genotypes had a higher prevalence of renal cell carcinoma than those with the CC genotype when they also had hypertension (p=0.0010), diabetes (p=0.0010), or a family history of cancer (p<0.00001). No correlation was observed between MMP9 rs3918242 genotypic distribution and age (60 years or younger vs. older than 60 years) or sex (both p>0.05). Additionally, no correlation was found between MMP9 rs3918242 genotype and the risk of renal cell carcinoma in individuals with smoking or alcohol consumption habits. CONCLUSION: Carrying the T allele for MMP9 rs3918242 may predict a higher risk of renal cell carcinoma among individuals diagnosed with hypertension, diabetes, or with a family history of cancer.

Alpinumisoflavone Exhibits the Therapeutic Effect on Prostate Cancer Cells by Repressing AR and Co-Targeting FASN- and HMGCR-Mediated Lipid and Cholesterol Biosynthesis.

Prostate cancer (PCa) is the most common cancer in men, and this has been mainly noticed in Western and Asian countries. The aggregations of PCa and castration-resistant PCa (CRPC) progression are the crucial causes in the mortality of patients without the effective treatment. To seek new remedies for the lethal PCa diseases is currently an urgent need. In this study, we endeavored to investigate the therapeutic efficacy of alpinumisoflavone (AIF), a natural product, in PCa. LNCaP (androgen- sensitive) and C4-2 (CRPC) PCa cells were used. An MTT-based method, soft agar colony forming assay, biological progression approaches were applied to determine cell viability, migration, and invasion. A fatty acid quantification kit, a cholesterol detection kit and oil red O staining were conducted to analyze the intracellular levels of lipids and cholesterols. Apoptosis assays were also performed. AIF reduced cell viability, migration, and invasion in PCa cells. The expression of androgen receptor (AR), fatty acid synthase (FASN), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was substantially inhibited by AIF treatment in PCa cells. Furthermore, by inhibiting FASN and HMGCR expression, AIF decreased the amounts of intracellular fatty acids, cholesterols, and lipid droplets in PCa cells. Significantly, through coordinated targeting FASN- and HMGCR-regulated biosynthesis and the AR axis, AIF activated the caspase-associated apoptosis in PCa cells. These results collectively demonstrated for the first time the potential of AIF as a novel and attractive remedy and provided an alternative opportunity to cure PCa malignancy.

Intramuscular delivery of neural crest stem cell spheroids enhances neuromuscular regeneration after denervation injury.

BACKGROUND: Muscle denervation from trauma and motor neuron disease causes disabling morbidities. A limiting step in functional recovery is the regeneration of neuromuscular junctions (NMJs) for reinnervation. Stem cells have the potential to promote these regenerative processes, but current approaches have limited success, and the optimal types of stem cells remain to be determined. Neural crest stem cells (NCSCs), as the developmental precursors of the peripheral nervous system, are uniquely advantageous, but the role of NCSCs in neuromuscular regeneration is not clear. Furthermore, a cell delivery approach that can maintain NCSC survival upon transplantation is critical. METHODS: We established a streamlined protocol to derive, isolate, and characterize functional p75+ NCSCs from human iPSCs without genome integration of reprogramming factors. To enhance survival rate upon delivery in vivo, NCSCs were centrifuged in microwell plates to form spheroids of desirable size by controlling suspension cell density. Human bone marrow mesenchymal stem cells (MSCs) were also studied for comparison. NCSC or MSC spheroids were injected into the gastrocnemius muscle with denervation injury, and the effects on NMJ formation and functional recovery were investigated. The spheroids were also co-cultured with engineered neuromuscular tissue to assess effects on NMJ formation in vitro. RESULTS: NCSCs cultured in spheroids displayed enhanced secretion of soluble factors involved in neuromuscular regeneration. Intramuscular transplantation of spheroids enabled long-term survival and retention of NCSCs, in contrast to the transplantation of single-cell suspensions. Furthermore, NCSC spheroids significantly improved functional recovery after four weeks as shown by gait analysis, electrophysiology, and the rate of NMJ innervation. MSC spheroids, on the other hand, had insignificant effect. In vitro co-culture of NCSC or MSC spheroids with engineered myotubes and motor neurons further evidenced improved innervated NMJ formation with NCSC spheroids. CONCLUSIONS: We demonstrate that stem cell type is critical for neuromuscular regeneration and that NCSCs have a distinct advantage and therapeutic potential to promote reinnervation following peripheral nerve injury. Biophysical effects of spheroidal culture, in particular, enable long-term NCSC survival following in vivo delivery. Furthermore, synthetic neuromuscular tissue, or "tissues-on-a-chip," may offer a platform to evaluate stem cells for neuromuscular regeneration.

Androgen receptor survival signaling is blocked by anti-beta2-microglobulin monoclonal antibody via a MAPK/lipogenic pathway in human prostate cancer cells.

A new cis-acting element, sterol regulatory element-binding protein-1 (SREBP-1) binding site, within the 5'-flanking human androgen receptor (AR) promoter region and its binding transcription factor, SREBP-1, was identified to regulate AR transcription in AR-positive human prostate cancer cells. We further characterized the molecular mechanism by which a novel anti-beta2-microglobulin monoclonal antibody (beta2M mAb), shown to induce massive cell death in a number of human and mouse cancer cell lines, interrupted multiple cell signaling pathways in human prostate cancer cells. beta2M mAb decreased AR expression through inactivation of MAPK and SREBP-1. By inactivation of MAPK, beta2M mAb decreased prostate cancer cell proliferation and survival. By inhibition of SREBP-1, beta2M mAb reduced fatty acid and lipid levels, an integral component of cell membrane, cell signaling mediators, and energy metabolism. These results provide for the first time a molecular link between the beta2M intracellular signaling axis mediated by MAPK and SREBP-1 and involving lipid signaling, which collectively regulates AR expression and function. Antagonizing beta2M by beta2M mAb may be an effective therapeutic approach simultaneously targeting multiple downstream signaling pathways converging with MAPK, SREBP-1, and AR, important for controlling prostate cancer cell growth, survival, and progression.

Active sonic hedgehog signaling between androgen independent human prostate cancer cells and normal/benign but not cancer-associated prostate stromal cells.

BACKGROUND: Sonic hedgehog (Shh) signaling plays a pivotal role in stromal-epithelial interaction during normal development but its role in tumor-stromal interaction during carcinogenic progression is less well defined. Since hormone refractory prostate cancer with bone metastasis is difficult to treat, it is crucial to investigate how androgen independent (AI) human prostate cancer cells communicate with their associated stroma. METHODS: Shh and its target transcription factor, Gli1 mRNA, were assessed by RT-PCR and/or quantitative RT-PCR in co-cultured cell recombinants comprised of AI C4-2 either with NPF (prostate fibroblasts from normal/benign prostate gland) or CPF (cancer-associated stromal fibroblasts) under Shh/cyclopamine (a hedgehog signaling inhibitor) treatment. Human bone marrow stromal (HS27A) cells were used as controls. In vivo investigation was performed by checking serum PSA and immunohistochemical staining for the apoptosis-associated M30 gene in mice bearing chimeric C4-2/NPF tumors. RESULTS: We found that (1) Shh has minimal growth-stimulating effects on prostate cancer cells, but it stimulated the growth of NPF but not CPF; (2) active Shh signaling was found between AI C4-2 cells and NPF but not CPF; and (3) osteonectin (ON) is a Gli1 target gene in NPF and not in CPF, and ON up-regulation in NPF can be blocked by cyclopamine CONCLUSIONS: Based on co-culture and chimeric tumor models, active Shh-mediated signaling was demonstrated between AI prostate cancer and NPF in a paracrine- and tumor progression-dependent manner. Our study suggests that drugs like cyclopamine that interfere with Shh signaling could be beneficial in preventing AI progression in prostate cancer cells.

Salvianolic Acid C Protects against Cisplatin-Induced Acute Kidney Injury through Attenuation of Inflammation, Oxidative Stress and Apoptotic Effects and Activation of the CaMKK-AMPK-Sirt1-Associated Signaling Pathway in Mouse Models.

Acute kidney injury (AKI) is a sudden reduction in kidney activity and has a high mortality rate. Salvianolic acid C (SAC), one of the main polyphenolic components of Salvia miltiorrhiza, displays significant pharmacologically active effects. An animal model of cisplatin-induced kidney injury was used to study the potential of SAC to improve AKI. First, SAC was administered intraperitoneally in mice for 10 consecutive days, and then cisplatin was administered intraperitoneally on day 7 to establish a nephrotoxicity mouse model. SAC mitigated renal histological changes, blood creatinine (CRE) and blood urea nitrogen (BUN) production and the levels of inflammatory mediators in the cisplatin-induced AKI. Furthermore, malondialdehyde (MDA) levels were reduced and glutathione (GSH) was increased after intraperitoneal injection (i.p.) administration of SAC. In addition, based on Western blot data, SAC reduced the expression of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) activation in mouse renal tissues. Finally, SAC diminished the level of TLR-4 expression and enhanced the production of several antioxidative enzymes (superoxidase dismutase (SOD1), glutathione peroxidase (GPx3), catalase, nuclear-factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1)), Sirtuin 1 (Sirt1), p-AMP-activated protein kinase (AMPK) and p-Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). In addition, Sirt1 inhibition (EX 527) inverted the effect of SAC against cisplatin-induced nephrotoxicity. Collectively, SAC provides a therapeutic target with promising clinical potential after cisplatin treatment by attenuating oxidative stress and inflammation.