Metabolic reprogramming in prostate cancer.

Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic prostate cancer remains incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures and metabolic reprogramming, all of which enable the tumour to serially adapt to drugs during the course of treatment. In this review, we focus on alterations in the metabolism of prostate cancer, including genetic signatures and molecular pathways associated with metabolic reprogramming. Advances in our understanding of prostate cancer metabolism might help to explain many of the adaptive responses that are induced by therapy, which might, in turn, lead to the attainment of more durable therapeutic responses.

PAK5 mediates cell: cell adhesion integrity via interaction with E-cadherin in bladder cancer cells.

Urothelial bladder cancer is a major cause of morbidity and mortality worldwide, causing an estimated 150 000 deaths per year. Whilst non-muscle-invasive bladder tumours can be effectively treated, with high survival rates, many tumours recur, and some will progress to muscle-invasive disease with a much poorer long-term prognosis. Thus, there is a pressing need to understand the molecular transitions occurring within the progression of bladder cancer to an invasive disease. Tumour invasion is often associated with a down-regulation of E-cadherin expression concomitant with a suppression of cell:cell junctions, and decreased levels of E-cadherin expression have been reported in higher grade urothelial bladder tumours. We find that expression of E-cadherin in a panel of bladder cancer cell lines correlated with the presence of cell:cell junctions and the level of PAK5 expression. Interestingly, exogenous PAK5 has recently been described to be associated with cell:cell junctions and we now find that endogenous PAK5 is localised to cell junctions and interacts with an E-cadherin complex. Moreover, depletion of PAK5 expression significantly reduced junctional integrity. These data suggest a role for PAK5 in maintaining junctional stability and we find that, in both our own patient samples and a commercially available dataset, PAK5mRNA levels are reduced in human bladder cancer compared with normal controls. Taken together, the present study proposes that PAK5 expression levels could be used as a novel prognostic marker for bladder cancer progression.

Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma.

Elevated expression of enhancer of zeste homolog 2 (EZH2), a histone H3K27 methyltransferase, was observed in gliomas harboring telomerase reverse transcriptase (TERT) promoter mutations. Given the known involvement of TERT and EZH2 in glioma progression, the correlation between the two and subsequently its involvement in metabolic programming was investigated. Inhibition of human telomerase reverse transcriptase either pharmacologically or through genetic manipulation not only decreased EZH2 expression, but also (i) abrogated FASN levels, (ii) decreased de novo fatty acid accumulation, and (iii) increased ataxia-telangiectasia-mutated (ATM) phosphorylation levels. Conversely, diminished TERT and FASN levels upon siRNA-mediated EZH2 knockdown indicated a positive correlation between TERT and EZH2. Interestingly, ATM kinase inhibitor rescued TERT inhibition-mediated decrease in FASN and EZH2 levels. Importantly, TERT promoter mutant tumors exhibited greater microsatellite instability, heightened FASN levels and lipid accumulation. Coherent with in vitro findings, pharmacological inhibition of TERT by costunolide decreased lipid accumulation and elevated ATM expression in heterotypic xenograft glioma mouse model. By bringing TERT-EZH2 network at the forefront as driver of dysregulated metabolism, our findings highlight the non-canonical but distinct role of TERT in metabolic reprogramming and DNA damage responses in glioblastoma.

Polyphenolic Polymersomes of Temperature-Sensitive Poly(N-vinylcaprolactam)-block-Poly(N-vinylpyrrolidone) for Anticancer Therapy.

We report a versatile synthesis for polyphenolic polymersomes of controlled submicron (<500 nm) size for intracellular delivery of high and low molecular weight compounds. The nanoparticles are synthesized by stabilizing the vesicular morphology of thermally responsive poly(N-vinylcaprolactam)n-b-poly(N-vinylpyrrolidone)m (PVCLn-PVPONm) diblock copolymers with tannic acid (TA), a hydrolyzable polyphenol, via hydrogen bonding at a temperature above the copolymer's lower critical solution temperature (LCST). The PVCL179-PVPONm diblock copolymers are produced by controlled reversible addition-fragmentation chain transfer (RAFT) polymerization of PVPON using PVCL as a macro-chain transfer agent. The size of the TA-locked (PVCL179-PVPONm) polymersomes at room temperature and upon temperature variations are controlled by the PVPON chain length and TA:PVPON molar unit ratio. The particle diameter decreases from 1000 to 950, 770, and 250 nm with increasing PVPON chain length (m = 107, 166, 205, 234), and it further decreases to 710, 460, 290, and 190 nm, respectively, upon hydrogen bonding with TA at 50 °C. Lowering the solution temperature to 25 °C results in a slight size increase for vesicles with longer PVPON. We also show that TA-locked polymersomes can encapsulate and store the anticancer drug doxorubicin (DOX) and higher molecular weight fluorescein isothiocyanate (FITC)-dextran in a physiologically relevant pH and temperature range. Encapsulated DOX is released in the nuclei of human alveolar adenocarcinoma tumor cells after 6 h incubation via biodegradation of the TA shell with the cytotoxicity of DOX-loaded polymersomes being concentration-dependent. Our approach offers biocompatible and intracellular degradable nanovesicles of controllable size for delivery of a variety of encapsulated materials. Considering the particle monodispersity, high loading capacity, and a facile two-step aqueous assembly based on the reversible temperature-responsiveness of PVCL, these polymeric vesicles have significant potential as novel drug nanocarriers and provide a new perspective for fundamental studies on thermo-triggered polymer assemblies in solutions.

CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma.

Understanding mechanisms that link aberrant metabolic adaptation and pro-survival responses in glioma cells is crucial towards the development of new anti-glioma therapies. As we have previously reported that CK2 is associated with glioma cell survival, we evaluated its involvement in the regulation of glucose metabolism. Inhibition of CK2 increased the expression of metabolic regulators, PDK4 and AMPK along with the key cellular energy sensor CREB. This increase was concomitant with altered metabolic profile as characterized by decreased glucose uptake in a PDK4 and AMPK dependent manner. Increased PDK4 expression was CREB dependent, as exogenous inhibition of CREB functions abrogated CK2 inhibitor mediated increase in PDK4 expression. Interestingly, PDK4 regulated AMPK phosphorylation which in turn affected cell viability in CK2 inhibitor treated glioma cells. CK2 inhibitor 4,5,6,7-Tetrabromobenzotriazole (TBB) significantly retarded the growth of glioma xenografts in athymic nude mouse model. Coherent with the in vitro findings, elevated senescence, pAMPK and PDK4 levels were also observed in TBB-treated xenograft tissue. Taken together, CK2 inhibition in glioma cells drives the PDK4-AMPK axis to affect metabolic profile that has a strong bearing on their survival.

TGF-ß-induced hCG-ß regulates redox homeostasis in glioma cells.

Transforming growth factor (TGF-ß) is associated with the progression of glioblastoma multiforme (GBM)-the most malignant of brain tumors. Since there is a structural homology between TGF-ß and human chorionic gonadotropin (hCG) and as both TGF-ß and hCG-ß are known regulators of oxidative stress and survival responses in a variety of tumors, the role of TGF-ß in the regulation of hCG-ß and its consequences on redox modulation of glioblastoma cells was investigated. A heightened hCG-ß level was observed in GBM tumors. TGF-ß treatment increased hCG-ß expression in glioma cell lines, and this heightened hCG-ß was found to regulate redox homeostasis in TGF-ß-treated glioma cells, as siRNA-mediated knockdown of hCG-ß (i) elevated reactive oxygen species (ROS) generation, (ii) decreased thioredoxin Trx1 expression and thioredoxin reductase (TrxR) activity, and (iii) abrogated expression of TP53-induced glycolysis and apoptosis regulator (TIGAR). Silencing of hCG-ß abrogated Smad2/3 levels, suggesting the existence of TGF-ß-hCG-ß cross-talk in glioma cells. siRNA-mediated inhibition of elevated TIGAR levels in TGF-ß-treated glioma cells was accompanied by an increase in ROS levels. As a farnesyltransferase inhibitor, Manumycin is known to induce glioma cell apoptosis in a ROS-dependent manner, and we investigated whether Manumycin could induce apoptosis in TGF-ß-treated cells with elevated hCG-ß exhibiting ROS-scavenging property. Manumycin-induced apoptosis in TGF-ß-treated cells was accompanied by elevated ROS levels and decreased expression of hCG-ß, Trx1, Smad2/3, and TIGAR. These findings indicate the existence of a previously unknown TGF-ß-hCG-ß link that regulates redox homeostasis in glioma cells.

Supernumerary testis or polyorchidism: A rare urogenital anomaly (case report and literature review).

INTRODUCTION AND IMPORTANCE: Polyorchidism, or supernumerary testis, is a rare urogenital congenital disorder. Because of its rarity, there is no approved standard treatment protocol for preserving or removing the extra testicle, yet orchiopexy is frequently performed as a preferred treatment in most medical facilities. CASE PRESENTATION: We present a 23-year-old single male with a bilaterally empty scrotum. He was unaware of his condition and had not seen a doctor before being admitted to our surgical unit. During his younger sibling's circumcision by a local circumcisionist (a medical staff member, idealy a nurse, whose duty is to perform circumcision, preferably at home), he saw something different (his emptey scrotum) and came to us with his problem. Laboratory findings revealed severe oligospermia, and tumor markers (Alpha fetoprotein, beta-human chorionic gonadotropin, and lactate dehydrogenase) were negative for malignancy. The patient underwent bilateral herniorrhaphy and orchiopexy of all six testicles (three in each inguinal canal) and had an uneventful recovery. CLINICAL DISCUSSION: As polyorchidism is not a common problem, its management remains a contentious issue due to the lack of evidence-based consensus. However, with the introduction of new imaging modalities and on-table frozen section biopsy, the decision to continue with orchiopexy or orchiectomy can be easily justified; however, conservative treatment is preferable in cases of no coexisting anomalies, particularly cryptorchidism. CONCLUSION: Polyorchidism could run unnoticed for years, especially if there is no direct and consistent access to a medical facility. In cases where polyorchidism is detected accidentally by imaging or during surgical exploration, the treatment must be justified accordingly.

Genetic Characterization of the Dengue Virus Type 3 Genotype I Prevailing in Dhaka, Bangladesh, 2021.

Background: In Bangladesh, dengue has been prevalent since its resurgence in 2018, and the dominant causative virus in 2019 was considered dengue virus serotype 3 (DENV-3). However, limited information is available for DENV serotype/genotype circulating after 2020. Materials and Methods: Viral RNA was extracted from NS1 antigen-positive blood samples of febrile patients in Dhaka, in 2021. DENV gene was detected by semi-nested RT-PCR, and sequences of envelope (E) gene and C-prM gene were determined by direct sequencing of RT-PCR products for genetic analysis. Results: Among 172 NS1-positive samples collected, 91 samples were assigned to DENV-3 and DENV-2 (88 and 3 samples, respectively) by RT-PCR targeting the C-prM gene. Phylogenetic analysis of the E gene for the 17 representative DENV-3 samples showed that all the viruses belonged to genotype I, forming a cluster (B-cluster) with those of DENV-3 reported in Bangladesh in 2017. Analysis of the deduced amino acid sequences of E protein revealed 16 amino acid substitutions, including two novel ones (G221W, L285P), and a substitution T223I that was specifically found in DENV-3 B-cluster. Conclusion: This study showed the persistent predominance of DENV-3 genotype I in Bangladesh having unique genetic traits in the E gene. (Approval number: MMC/IRB/2022/468).

DHODH inhibition impedes glioma stem cell proliferation, induces DNA damage, and prolongs survival in orthotopic glioblastoma xenografts.

Glioma stem cells (GSCs) promote tumor progression and therapeutic resistance and exhibit remarkable bioenergetic and metabolic plasticity, a phenomenon that has been linked to their ability to escape standard and targeted therapies. However, specific mechanisms that promote therapeutic resistance have been somewhat elusive. We hypothesized that because GSCs proliferate continuously, they may require the salvage and de novo nucleotide synthesis pathways to satisfy their bioenergetic needs. Here, we demonstrate that GSCs lacking EGFR (or EGFRvIII) amplification are exquisitely sensitive to de novo pyrimidine synthesis perturbations, while GSCs that amplify EGFR are utterly resistant. Furthermore, we show that EGFRvIII promotes BAY2402234 resistance in otherwise BAY2402234 responsive GSCs. Remarkably, a novel, orally bioavailable, blood-brain-barrier penetrating, dihydroorotate dehydrogenase (DHODH) inhibitor BAY2402234 was found to abrogate GSC proliferation, block cell-cycle progression, and induce DNA damage and apoptosis. When dosed daily by oral gavage, BAY2402234 significantly impaired the growth of two different intracranial human glioblastoma xenograft models in mice. Given this observed efficacy and the previously established safety profiles in preclinical animal models and human clinical trials, the clinical testing of BAY2402234 in patients with primary glioblastoma that lacks EGFR amplification is warranted.

Afghan Health Related Concerns Following the US Withdrawal: Results of a Survey Given via Social Media.

Background: The United States Armed Forces completed their withdrawal from Afghanistan on August 30th, 2021, ending 20 years of war in Afghanistan. This rapid timeline from announcement to withdrawal and subsequent power transfer had profound consequences on the Afghan people, particularly in the domains of health and healthcare. Methods: On 15 September 2021, we posted an anonymous online cross-sectional survey on social media (Twitter, Facebook, and WhatsApp groups) to collect data about respondents from Afghanistan. Questions focused on COVID-19 symptoms, concerns, and individual care with a focus on changes related to the United States (US) withdrawal from Afghanistan. The form was composed of 17 questions which included multiple choice, single choice, and numeric options. All questions were optional including demographic data. Results: Our survey yielded 1,074 responses from the Farsi version and 572 responses from the Pashto version for a total of 1,646 responses. 1,286 (80%) of respondents were in Afghanistan at the time of survey submission. Concerning the US withdrawal from Afghanistan, 26% (412) respondents were extremely concerned and 12% (181) were moderately concerned. A majority of respondents report concerns regarding mental health due to the US withdrawal. 27% (418) report extreme concern, 12% (186) report moderate concern, and 15% (229) report a little concern. There is a significant difference in the proportions of concern (for US withdrawal generally, as well as physical and mental health) across gender. 49% of Female respondents report extreme concern regarding the US withdrawal compared to 22% of Male respondents (P < 0.001). With respect to physical health concerns 36% of Females report extreme concern compared to 16% of Males (P < 0.001). Finally on the mental health concerns, 54% of Females report extreme concern compared to 22% of Males (P < 0.001). Conclusion: The results from this survey are susceptible to the possibility of internal validity and/or external validity. However, we are accepting of those possibilities considering this survey wasn't designed to be bulletproof, but rather serve as a voice for those who can't be heard and to inform the public of the hardships occurring across the globe due to a steadfast retraction of the US footprint from their soil. Our findings indicate salient changes and public health concerns among Afghans following the US withdrawal from the region. These concerns varied across gender and ethnic groups. Our findings may serve as the first step in addressing the health concerns of Afghans following two decades of US military presence. The results should be understood through the limitations associated with a survey study design. Future research and policy aimed at tackling short and long-term health and social concerns in Afghanistan should consider the role of US withdrawal.

Pyramiding of multiple strong-culm genes originating from indica and tropical japonica to the temperate japonica rice.

Severe lodging has recurrently occurred at strong typhoon's hitting in recent climate change. The identification of quantitative trait loci and their responsible genes associated with a strong culm and their pyramiding are important for developing high-yielding varieties with a superior lodging resistance. To evaluate the effects of four strong-culm genes on lodging resistance, the temperate japonica near isogenic line (NIL) with the introgressed SCM1 or SCM2 locus of the indica variety, Habataki and the other NIL with the introgeressed SCM3 or SCM4 locus of the tropical japonica variety, Chugoku 117 were developed. Then, we developed the pyramiding lines with double,triple and quadruple combinations derived from step-by-step crosses among NIL-SCM1-NIL-SCM4. Quadruple pyramiding line (NIL-SCM1 + 2 + 3 + 4) showed the largest culm diameter and the highest culm strength among the combinations and increased spikelet number due to the pleiotropic effects of these genes. Pyramiding of strong culm genes resulted in much increased culm thickness, culm strength and spikelet number due to their additive effect. SCM1 mainly contributed to enhance their pyramiding effect. These results in this study suggest the importance of identifying the combinations of superior alleles of strong culm genes among natural variation and pyramiding these genes for improving high-yielding varieties with a superior lodging resistance.

Paleolithic spread of Y-chromosomal lineage of tribes in eastern and northeastern India.

BACKGROUND: The Indian peninsula provides a suitable region for examination of the demographic impact of migrations and invasions in historical times, because its complex recent history has involved the long-term residence of different populations with distinct geographical origins and their own particular cultural characteristics. AIM: The aim of the present study was to analyse Y chromosome haplotypes in tribes from eastern and north-eastern India, which provided the necessary phylogeographic resolution. SUBJECTS AND METHODS: A total of 32 Y-chromosome SNPs and 17 Y-STRs were genotyped in 607 males from nine populations (Munda, Birhor, Oraon, Paharia, Santhal, Ho, Lachung, Mech and Rajbanshi) residing in East and Northeastern India. RESULTS: Y-chromosomal analysis revealed high frequency of the O2a haplogroup in Austroasiatic tribes and high haplotype diversity within specific haplogroups demonstrating a lesser degree of admixture of these populations with neighbouring populations in eastern India. In addition, the presence of O3a haplogroups in Sino-Tibetan populations reflects the influx from Southeast Asia during the demographic expansion through the Northeastern corridor. CONCLUSION: The study suggested that the majority of the male gene flow of Austroasiatic tribes occurred during the late Pleistocene period. The results suggest gene flow from Southeast Asia to Northeast India, albeit more significantly among Tibeto-Burman than Austroasiatic-speaking populations.

Emergence and Re-emergence of Human Coronaviruses: Spike Protein as the Potential Molecular Switch and Pharmaceutical Target.

BACKGROUND: Recent emergence of COVID-19 caused by a new human coronavirus (CoV) strain (SARS-CoV-2), which originated from China, poses the future emergence of additional CoVs. In most of the cases of emergence of human CoVs, bats, palm civets, raccoon dogs and camels have been identified as the sources of human infections and as reservoir hosts. A review of comparative genomic and phenotypic characteristics of human CoV strains vis-à-vis their comparison with the corresponding animal isolates shall provide clues regarding the potential genomic, phenotypic and molecular factors responsible for host-switching, which may lead to prospective emergence and re-emergence of human CoV outbreaks in the future. METHODS: The seven known human strains of CoV were analyzed for the host and viral factors responsible for human outbreaks. The molecular factors responsible for host-susceptibility, virulence and pathogenesis were reviewed to predict the emergence and re-emergence of additional human CoV strains. CoV spike protein was evaluated as a potential viral receptor for host switching and the target for pharmaceutical design. RESULTS: A review of the factors associated with host-susceptibility, virulence and pathogenesis of seven known human CoV strains presents significant possibilities for the emergence of new CoV strain(s), leading to more human outbreaks. Continuous exposure of animals' handlers to the infected animals, environmental changes, improper sanitations, non-disposal of the solid waste and resumption of exotic animals markets provides favorable conditions for "host switching" and the emergence of new and potentially more virulent human CoV strains. Mutations in target genes (like spike protein), which facilitate the viral entry into the host-cells, provide a potential "molecular switch" for preferences of new host-receptors, genetic diversity, genetic-recombination and high virulence. Additionally, the clinical and environmental factors, asymptomatic carriers, the paucity of efficacious vaccines & therapeutics, inefficient disease management and infection control measures, lack of public awareness, and effective communication of information about more virulent human-adapted virus isolates are critical for the emergence of new and virulent SARS-CoV strains with high mortality and varied incubation period in the near future. Small molecules binding with conserved druggable regions of the CoV spike proteins may be effective against multiple strains of CoVs. CONCLUSION: High propensity of mutations and "molecular adaptations" in coronaviruses creates the hot spots and high potential for "host switching", leading to the emergence of more virulent strains of human CoVs. The public/global health agencies, medical communities and research scientists should be prepared for the emergence and re-emergence of new human CoV strain(s) leading to potential disease outbreaks. The inhibitors binding with conserved druggable regions of spike proteins from multiple strains CoV may have utility as broad-spectrum antiviral drugs to combat future emergence of CoVs.

Nationwide Distribution of Dengue Virus Type 3 (DENV-3) Genotype I and Emergence of DENV-3 Genotype III during the 2019 Outbreak in Bangladesh.

Bangladesh is an endemic region of dengue fever and experienced an unprecedented large outbreak with more than 100,000 confirmed cases in 2019. To understand the prevalence of dengue antibody in patients and molecular epidemiological characteristics of dengue virus (DENV) in this outbreak, a total of 179 blood samples were collected from patients in 10 districts (seven divisions) covering nearly the whole country from August to December 2019. DENV NS-1 was detected in 162 samples, among which DENV-specific IgM was positive in 119 samples (73.5%), including 60.5% samples also positive for DENV-specific IgG. Sequencing of the partial C-prM gene and its phylogenetic analysis revealed predominance of DENV type 3 genotype I, accounting for 93% of samples examined. DENV-3 genotype III was identified in two samples from separate districts, and only one DENV-2 cosmopolitan genotype was found in the capital city, Dhaka. These findings suggest the predominance of DENV-3 genotype I and occurrence of DENV-3 genotype III, associated with increased incidence of recent secondary infection in Bangladesh in 2019.

Targeting Chikungunya Virus Replication by Benzoannulene Inhibitors.

A benzo[6]annulene, 4-(tert-butyl)-N-(3-methoxy-5,6,7,8-tetrahydronaphthalen-2-yl) benzamide (1a), was identified as an inhibitor against Chikungunya virus (CHIKV) with antiviral activity EC90 = 1.45 µM and viral titer reduction (VTR) of 2.5 log at 10 µM with no observed cytotoxicity (CC50 = 169 µM) in normal human dermal fibroblast cells. Chemistry efforts to improve potency, efficacy, and drug-like properties of 1a resulted in a novel lead compound 8q, which possessed excellent cellular antiviral activity (EC90 = 270 nM and VTR of 4.5 log at 10 µM) and improved liver microsomal stability. CHIKV resistance to an analog of 1a, compound 1c, tracked to a mutation in the nsP3 macrodomain. Further mechanism of action studies showed compounds working through inhibition of human dihydroorotate dehydrogenase in addition to CHIKV nsP3 macrodomain. Moderate efficacy was observed in an in vivo CHIKV challenge mouse model for compound 8q as viral replication was rescued from the pyrimidine salvage pathway.

The Emergence of Human Pathogenic Coronaviruses: Lectins as Antivirals for SARS-CoV-2.

BACKGROUND: Human coronaviruses (HCoV) are common viruses and known to be associated with respiratory diseases, including pneumonia. Currently, seven human coronaviruses have been identified and known to cause upper and lower respiratory infections as well as nosocomial viral infections in humans. The bats, palm civets, and camels are identified as the reservoir of human coronaviruses. In 2002-2003, the emergence of SARS-CoV resulted in an outbreak and led towards the more awareness and importance of scientific research and medical urgency. METHODS: The recently identified SARS-CoV-2 was identified from the seafood market of the city Wuhan, China, in December 2019 and caused a global pandemic. This virus has now spread to more than 213 countries. This is the third highly pathogenic human coronavirus after SARS and MERS-CoV. The coronaviruses have RNA as genetic material and are known to have frequent recombination and mutations in their genome, which lead to the emergence and re-emergence of new virus strains and isolates with novel properties and extended hosts. The genetic mutations and suitable environmental conditions result in the emergence and re-emergence of pathogenic coronaviruses and cause a serious issue to human health and the economy globally. Lectins are the ubiquitous group of proteins that bind to glycosylated molecules. CONCLUSION: The plant lectins are known to have significant antiviral activities against coronaviruses. Additionally, the plant lectins can be used as potential therapeutics against bacteria, fungus, yeast, and protozoa. In this review, we have discussed the current status of human pathogenic coronavirus emergence and the use of plant lectins as antivirals against SARS-CoV-2.

Cholesterol Metabolism: A Potential Therapeutic Target in Glioblastoma.

Glioblastoma is a highly lethal adult brain tumor with no effective treatments. In this review, we discuss the potential to target cholesterol metabolism as a new strategy for treating glioblastomas. Twenty percent of cholesterol in the body is in the brain, yet the brain is unique among organs in that it has no access to dietary cholesterol and must synthesize it de novo. This suggests that therapies targeting cholesterol synthesis in brain tumors might render their effects without compromising cell viability in other organs. We will describe cholesterol synthesis and homeostatic feedback pathways in normal brain and brain tumors, as well as various strategies for targeting these pathways for therapeutic intervention.

LXRß controls glioblastoma cell growth, lipid balance, and immune modulation independently of ABCA1.

Cholesterol is a critical component of membranes and a precursor for hormones and other signaling molecules. Previously, we showed that unlike astrocytes, glioblastoma cells do not downregulate cholesterol synthesis when plated at high density. In this report, we show that high cell density induces ABCA1 expression in glioblastoma cells, enabling them to get rid of excess cholesterol generated by an activated cholesterol biosynthesis pathway. Because oxysterols are agonists for Liver X Receptors (LXRs), we investigated whether increased cholesterol activates LXRs to maintain cholesterol homeostasis in highly-dense glioblastoma cells. We observed that dense cells had increased oxysterols, which activated LXRß to upregulate ABCA1. Cells with CRISPR-mediated knockdown of LXRß, but not ABCA1, had decreased cell cycle progression and cell survival, and decreased feedback repression of the mevalonate pathway in densely-plated glioma cells. LXRß gene expression poorly correlates with ABCA1 in glioblastoma patients, and expression of each gene correlates with poor patient prognosis in different prognostic subtypes. Finally, gene expression and lipidomics analyses cells revealed that LXRß regulates the expression of immune response gene sets and lipids known to be involved in immune modulation. Thus, therapeutic targeting of LXRß in glioblastoma might be effective through diverse mechanisms.

microRNA Crosstalk Influences Epithelial-to-Mesenchymal, Endothelial-to-Mesenchymal, and Macrophage-to-Mesenchymal Transitions in the Kidney.

microRNAs (miRNAs) are small, non-coding nucleotides that regulate diverse biological processes. Altered microRNA biosynthesis or regulation contributes to pathological processes including kidney fibrosis. Kidney fibrosis is characterized by deposition of excess extracellular matrix (ECM), which is caused by infiltration of immune cells, inflammatory cells, altered chemokines, and cytokines as well as activation and accumulation of fibroblasts in the kidney. These activated fibroblasts can arise from epithelial cells via epithelial-to-mesenchymal transition (EMT), from bone marrow-derived M2 phenotype macrophages via macrophage-to-mesenchymal transition (MMT), from endothelial cells via endothelial-to-mesenchymal transition (EndMT), from resident fibroblasts, and from bone marrow-derived monocytes and play a crucial role in fibrotic events. Disrupted microRNA biosynthesis and aberrant regulation contribute to the activation of mesenchymal programs in the kidney. miR-29 regulates the interaction between dipeptidyl peptidase-4 (DPP-4) and integrin ß1 and the associated active transforming growth factor ß (TGFß) and pro-EndMT signaling; however, miR-let-7 targets transforming growth factor ß receptors (TGFßRs) to inhibit TGFß signaling. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is an endogenous anti-fibrotic peptide, which is associated with fibroblast growth factor receptor 1 (FGFR1) phosphorylation and subsequently responsible for the production of miR-let-7. miR-29 and miR-let-7 family clusters participate in crosstalk mechanisms, which are crucial for endothelial cell homeostasis. The physiological level of AcSDKP is vital for the activation of anti-fibrotic mechanisms including restoration of anti-fibrotic microRNA crosstalk and suppression of profibrotic signaling by mitigating DPP-4-associated mesenchymal activation in the epithelial cells, endothelial cells, and M2 phenotype macrophages. The present review highlights recent advancements in the understanding of both the role of microRNAs in the development of kidney disease and their potential as novel therapeutic targets for fibrotic disease states.