Lactate is an epigenetic metabolite that drives survival in model systems of glioblastoma.

Lactate accumulates to a significant amount in glioblastomas (GBMs), the most common primary malignant brain tumor with an unfavorable prognosis. However, it remains unclear whether lactate is metabolized by GBMs. Here, we demonstrated that lactate rescued patient-derived xenograft (PDX) GBM cells from nutrient-deprivation-mediated cell death. Transcriptome analysis, ATAC-seq, and ChIP-seq showed that lactate entertained a signature of oxidative energy metabolism. LC/MS analysis demonstrated that U-13C-lactate elicited substantial labeling of TCA-cycle metabolites, acetyl-CoA, and histone protein acetyl-residues in GBM cells. Lactate enhanced chromatin accessibility and histone acetylation in a manner dependent on oxidative energy metabolism and the ATP-citrate lyase (ACLY). Utilizing orthotopic PDX models of GBM, a combined tracer experiment unraveled that lactate carbons were substantially labeling the TCA-cycle metabolites. Finally, pharmacological blockage of oxidative energy metabolism extended overall survival in two orthotopic PDX models in mice. These results establish lactate metabolism as a novel druggable pathway for GBM.

Highly Functional Materials Based on Nano-Lignin, Lignin, and Lignin/Silica Hybrid Capped Silver Nanoparticles with Antibacterial Activities.

Rice husk is one of the most abundant biomass resources in the world, yet it is not effectively used. This study focuses on the sustainably rice-husk-extracted lignin, nano-lignin (n-Lignin), lignin-capped silver nanoparticles (LCSN), n-Lignin-capped silver nanoparticles (n-LCSN), and lignin-capped silica-silver nanoparticles (LCSSN), and using them for antibacterial activities. The final n-Lignin-based products had a sphere-like structure, of which the size varied between 50 and 80 nm. We found that while n-Lignin and lignin were less effective against Escherichia coli than against Staphylococcus aureus, n-Lignin/lignin-based hybrid materials, i.e., n-LCSN, LCSN, and LCSSN, were better against E. coli than against S. aureus. Interestingly, the antimicrobial behaviors of n-LCSNs could be further improved by decreasing the size of n-Lignin. Considering the facile, sustainable, and eco-friendly method that we have developed here, it is promising to use n-Lignin/lignin-based materials as highly efficient antimicrobials without environmental concerns.

Dried blood spots perform well to identify patients with active HCV infection in Vietnam.

Recently, treatment advances in direct-acting antivirals have radically changed the management of HCV patients. However, in resource-limited countries, identification of patients with active HCV infection is still challenging in remote settings due to the limited access to laboratories able to measure HCV viral load. This study evaluated whether dried blood spots (DBS) transferred to a central laboratory could overcome this challenge. A total of 315 HCV-infected patients, naïve to anti-HCV treatment, provided each three type of samples: plasma, DBS with calibrated quantities of venous blood and DBS with uncalibrated quantities of capillary blood. Qualitative comparison was conducted in terms of detection of HCV viral load on DBS as opposed to plasma to estimate sensitivity and specificity. Quantitative comparisons were conducted by means of correlation estimation. Of the 250 patients with detected plasma HCV viral load, 245 also had detectable DBS HCV viral load (capillary or venous) leading to a sensitivity of 98.0% (95% confidence interval (CI): 95.4%-99.3%); importantly, all measurements with a plasma HCV viral load >118 IU/mL were also detected in DBS. When HCV was not detected in plasma, it was also not detected in DBS resulting in 100% specificity (95% CI: 94.5%-100%). Quantitative HCV viral load results were very similar when utilizing plasma or DBS sample types as illustrated by correlations >0.99. In conclusion, DBS sample types, with either uncalibrated capillary blood or calibrated venous blood, performed well to distinguish patients with active HCV infection, and who therefore need treatment, from other patients.

Genetic characterization of VP1 of coxsackieviruses A2, A4, and A10 associated with hand, foot, and mouth disease in Vietnam in 2012-2017: endemic circulation and emergence of new HFMD-causing lineages.

While conducting sentinel surveillance of hand, foot, and mouth disease (HFMD) in Vietnam, we found a sudden increase in the prevalence of coxsackievirus A10 (CV-A10) in 2016 and CV-A2 and CV-A4 in 2017, the emergence of which has been reported recently to be associated with various clinical manifestations in other countries. However, there have been only a limited number of molecular studies on those serotypes, with none being conducted in Vietnam. Therefore, we sequenced the entire VP1 genes of CV-A10, CV-A4, and CV-A2 strains associated with HFMD in Vietnam between 2012 and 2017. Phylogenetic analysis revealed a trend of endemic circulation of Vietnamese CV-A10, CV-A4, and CV-A2 strains and the emergence of thus-far undescribed HFMD-causing lineages of CV-A4 and CV-A2. The Vietnamese CV-A10 strains belonged to a genotype comprising isolates from patients with HFMD from several other countries; however, most of the Vietnamese strains were grouped into a local lineage. Recently, emerging CV-A4 strains in Vietnam were grouped into a unique lineage within a genotype comprising strains isolated from patients with acute flaccid paralysis from various countries. New substitutions were detected in the putative BC and HI loops in the Vietnamese CV-A4 strains. Except for one strain, Vietnamese CV-A2 isolates were grouped into a unique lineage of a genotype that includes strains from various countries that are associated with other clinical manifestations. Enhanced surveillance is required to monitor their spread and to specify their roles as etiological agents of HFMD or "HFMD-like" diseases, especially for CV-A4 and CV-A2. Further studies including whole-genome sequencing should be conducted to fully understand the evolutionary changes occurring in these newly emerging strains.

Sodium-assisted passivation of grain boundaries and defects in Cu2ZnSnSe4 thin films.

The long stagnation of the photo-conversion efficiency of kesterites below 13% is a source of frustration in the scientific community. In this study, we investigated the effects of sodium on the passivation of grain boundaries and defects in Cu2ZnSnSe4 (CZTSe) grown on a soda-lime glass (SLG) and borosilicate (BS) glass. Because BS glass does not inherently contain sodium, we placed a thin layer of NaF between CZTSe and Mo. The composition of the samples is Cu-poor and Zn-rich. The distribution of sodium and its contributions to phase formation and defects were examined by cross-sectional energy-dispersive X-ray profiling, Raman scattering spectroscopy and imaging, surface potential and photoluminescence. From the experimental results, it can be strongly claimed that sodium ions segregate predominantly near the grain boundaries and reduce CuZn-related defects. These local surface imaging analyses provided the exact locations of the secondary phases. In particular, the photo-assisted scanning probe method enabled us to observe the changes in the optoelectrical properties of the thin films and the carrier behavior within the materials. Further studies with distinct alkali ions and optimal processing conditions will pave a way to improve the performance of kesterite solar cells.

PLEKHG3 enhances polarized cell migration by activating actin filaments at the cell front.

Cells migrate by directing Ras-related C3 botulinum toxin substrate 1 (Rac1) and cell division control protein 42 (Cdc42) activities and by polymerizing actin toward the leading edge of the cell. Previous studies have proposed that this polarization process requires a local positive feedback in the leading edge involving Rac small GTPase and actin polymerization with PI3K likely playing a coordinating role. Here, we show that the pleckstrin homology and RhoGEF domain containing G3 (PLEKHG3) is a PI3K-regulated Rho guanine nucleotide exchange factor (RhoGEF) for Rac1 and Cdc42 that selectively binds to newly polymerized actin at the leading edge of migrating fibroblasts. Optogenetic inactivation of PLEKHG3 showed that PLEKHG3 is indispensable both for inducing and for maintaining cell polarity. By selectively binding to newly polymerized actin, PLEKHG3 promotes local Rac1/Cdc42 activation to induce more local actin polymerization, which in turn promotes the recruitment of more PLEKHG3 to induce and maintain cell front. Thus, autocatalytic reinforcement of PLEKHG3 localization to the leading edge of the cell provides a molecular basis for the proposed positive feedback loop that is required for cell polarization and directed migration.

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP.

We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. Though such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell context-dependent manner (in about two-thirds of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin-interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells.

Anti-Staphylococcus aureus potential of compounds from Ganoderma sp.: A comprehensive molecular docking and simulation approaches.

In this study, a series of secondary metabolites from Ganoderma sp. were screened against Staphylococcus aureus protein targets, including as phosphotransacetylase, clumping factor A, and dihydrofolate reductase, using molecular docking simulations. The chemicals that showed the strongest binding energy with the targeted proteins were ganodermanontriol, lucidumol B, ganoderic acid J, ergosterol, ergosterol peroxide, 7-oxoganoderic acid Z, ganoderic acid AM1, ganosinoside A, ganoderic acid D, and 24R-ergosta-7,2E-diene-3ß,5α,6ß-triol. Interestingly, ganosinoside A showed the greatest affinity for the protein clumping factor A, a result validated by molecular dynamic simulation. Additionally, three natural Ganoderma sp. Strains as Ganoderma lingzhi VNKKK1903, Ganoderma lingzhi VNKK1905A2, and Amauroderma subresinosum VNKKK1904 were collected from Kon Ka Kinh National Park in central land of Vietnam and evaluated for their antibacterial activity against Staphylococcus aureus using an agar well diffusion technique. These results suggest that the fungal extracts and secondary metabolites may serve as valuable sources of antibiotics against Staphylococcus aureus. These findings provided an important scientific groundwork for further exploration of the antibacterial mechanisms of compounds derived from Ganoderma sp. in future research.

Advanced hybrid nanomaterials based on carboxymethyl-modified biopolymer: Green synthesis and application in sustainable antimicrobial products.

The utilization of agricultural by-products for the synthesis of hybrid nanomaterials represents an environmentally sustainable approach. This research aims to comprehensively investigate high-performance silver and copper nanoparticles hybrid materials based on carboxymethyl-modified cellulose / lignin derived from rice husks (CMC / CML-AgNPs and CMC / CML-CuONPs) and apply them for antimicrobial activities. CMC / CML was used to reduce Ag / Cu cations to the atomic level and then efficiently stabilize Ag / CuO nanoparticles, an eco-friendly method and sustainable development. The hybrid nanomaterials were successfully synthesized with spherical shapes and particle sizes ranging from 4 to 16 nm. The diffraction peaks at 38.46°, 46.57°, 64.93°, and 77.55° were ascribed to the face-centered cubic crystal lattice (111), (200), (220), and (311) of silver nanoparticles in the CMC / CML-AgNPs. The peaks were 32.26°, 46.06°, 52.16°, 61.71°, 63.80°, and 71.23° associating with the (110,20-2), (112), (11-3), (310), and (221) plane orientations of CuO nanoparticles. The proposed materials demonstrated highly efficient antimicrobial performances. Particularly, CMC-AgNPs and CML-CuONPs exhibited an inhibitory capability of up to 100 % against E. coli and S. aureus within 72 h. Simultaneously, the antifungal results showed that hybrid nanomaterials have a better ability to inhibit the A. niger than A. flavus fungus. When experimenting on peanut seeds, hybrid nanomaterials showed an inhibitory capability of up to 99.0 % against A. niger. IC50 values of the hybrid nanomaterials range from 0.872 mg/mL to 1.188 mg/mL, confirming that these materials are non-cytotoxic. These materials exhibit significant stability and enduring antimicrobial efficacy, making them ideal for sustainable development of various antibacterial and antifungal blocks for the near future.

Targeting cellular respiration as a therapeutic strategy in glioblastoma.

While glycolysis is abundant in malignancies, mitochondrial metabolism is significant as well. Mitochondria harbor the enzymes relevant for cellular respiration, which is a critical pathway for both regeneration of reduction equivalents and energy production in the form of ATP. The oxidation of NADH2 and FADH2 are fundamental since NAD and FAD are the key components of the TCA-cycle that is critical to entertain biosynthesis in cancer cells. The TCA-cycle itself is predominantly fueled through carbons from glucose, glutamine, fatty acids and lactate. Targeting mitochondrial energy metabolism appears feasible through several drug compounds that activate the CLPP protein or interfere with NADH-dehydrogenase, pyruvate-dehydrogenase, enzymes of the TCA-cycle and mitochondrial matrix chaperones. While these compounds have demonstrated anti-cancer effects in vivo, recent research suggests which patients most likely benefit from such treatments. Here, we provide a brief overview of the status quo of targeting mitochondrial energy metabolism in glioblastoma and highlight a novel combination therapy.

Phylogenetic analysis and morphology of Ganoderma multipileum, a Ganoderma species associated with dieback of the metropolitan woody plant Delonix regia (Boj. ex Hook.) Raf. in Vietnam.

Ganoderma multipileum, a wood decay mushroom, was initially discovered and classified in Taiwan through the analysis of its morphology and the internal transcribed spacer (ITS) region of nuclear ribosomal DNA. In this study, we identified a mushroom associated with the dieback of Delonix regia (Boj. ex Hook.) Raf., a woody ornamental street tree in Vietnam, as Ganoderma multipileum. This classification was based on phylogenetic analysis of ITS, RPB2, and TEF1 sequences, as well as morphology assessment and scanning electron microscope observation of basidiospores. The phylogenetic analysis revealed that the specimens collected in Vietnam formed a monophyletic group of Ganoderma multipileum with a high bootstrap value and posterior probability (100%/1.00). Furthermore, the morphological features consistent with laccate Ganoderma, including a thin pileipellis composed of enlarged and bulbous hyphae, and the basidiomes exhibited two different phenotypes. Notably, scanning electron microscopy of the basidiospores revealed ovoid spores with numerous echinules, providing the first documented evidence of this characteristic for Ganoderma multipileum. This research represents the first recorded instance of Ganoderma multipileum in Vietnam associated with the dieback of Delonix regia.

Sustainable Lignin-Based Nano Hybrid Biomaterials with High-Performance Antifungal Activity.

Aspergillus flavus (A. flavus) and Aspergillus niger (A. niger) mainly spread through airborne fungal spores. An effective control to impede the dissemination of the spores of Aspergillus in the air affecting the environment and food was carried out. This study focuses on the sustainable rice husk-extracted lignin, nanolignin, lignin/n-lignin capped silver nanoparticles used for fungal growth inhibition. These biomaterials inhibit the growth of fungi by altering the permeability of cell membranes and influencing intracellular biosynthesis. The antifungal indexes for A. flavus and A. niger on day 5 at a concentration of 2000 µg/100 µL are 50.8 and 43.6%, respectively. The results demonstrate that the hybrid biomaterials effectively prevent the growth or generation of fungal spores. The findings of this research hold significant implications for future investigations focused on mitigating the dissemination of Aspergillus during the cultivation of agricultural products or in the process of assuring agricultural product management, such as peanuts and onions.

Ag/SiO2 nanoparticles stabilization with lignin derived from rice husk for antifungal and antibacterial activities.

Antibacterial materials have been developed for a long time but bacteria adapt very quickly and become resistant to these materials. This study focuses on the synthesis of a hybrid material system from lignin and silver/silica nanoparticles (Lig@Ag/SiO2 NPs) which were used against bacteria including Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) and inhibited the growth of the fungal Aspergillus flavus (A. flavus). The results showed that the spherical diameter of Lig@Ag/SiO2 NPs has narrow Gaussian distribution with a range from 15 nm to 40 nm in diameter. Moreover, there was no growth of E. coli in samples containing Lig@Ag/SiO2 NPs during 72-h incubation while colonies of S. aureus were only observed at high concentrations (106 CFU/mL) although both species of bacteria were able to thrive even at low bacterial concentration when they were exposed to Ag/SiO2 or lignin. For fungal resistance results, Lig@Ag/SiO2 NPs not only reduced mycelial growth but also inhibited sporulation in A. flavus, leading to decreasing the spreading of spores into the environment. This result represents a highly effective fungal growth inhibition of Lig@Ag/SiO2 NPs compared to lignin or Ag/SiO2, which could not inhibit the growth of sporulation.

Six New Species of Tomentella (Thelephorales, Basidiomycota) From Tropical Pine Forests in Central Vietnam.

Up to this point, studies on the taxonomy and phylogeny of the basidiomycetous genus Tomentella stemmed mainly from the temperate to boreal zones of the Northern hemisphere but were scarce in tropical Asia. In this study, six new species-T. bidoupensis, T. brevisterigmata, T. cinereobrunnea, T. longiechinula, T. stipitobasidia, and T. verruculata from central Vietnam in Southeast Asia-are described and illustrated on the basis of morphological characteristics and molecular phylogenetic analyses of the nuclear ribosomal ITS (internal transcribed spacer: ITS1-5.8S-ITS2) and LSU (large subunit: 28S) markers. Maximum likelihood and Bayesian analyses were used to confirm the phylogenetic positions of these new species and all of them can be well recognized by the macroscopical and anatomical characteristics. The new species and closely related species in the phylogenetic tree, and the new species and morphologically similar species are discussed, whereas the host plant for these new species were speculated on the basis of the phylogenetic analyses and the tree species information of the investigated forests.

Multiple-marker phylogeny and morphological evidence reveal two new species in Steccherinaceae (Polyporales, Basidiomycota) from Asia.

Two new wood-inhabiting fungi, Mycorrhaphium subadustum sp. nov. and Trullella conifericola sp. nov., are proposed and described from Asia based on ITS, nrLSU and tef1 molecular phylogeny and morphological characteristics. Mycorrhaphium subadustum is characterized by a stipitate basidiocarp, velutinate pileal surface concentrically zoned, hydnoid hymenophore, a dimitic hyphal system in spine trama and monomitic in context, absence of gloeocystidia, presence of cystidioles and the non-amyloid, cylindrical to ellipsoid basidiospores. Trullella conifericola is characterized by a laterally stipitate basidiocarp with flabelliform to semicircular pileus, hirtellous pileal surface with appressed coarse hair and concentrically zoned and sulcate, tiny pores (10-12 per mm), a dimitic hyphal system, absence of any type of cystidia, short clavate basidia and thin-walled, smooth, cylindrical to allantoid basidiospores. Phylogenetic analyses based on a three-marker dataset were performed using maximum likelihood and Bayesian inference methods. The two new species formed isolated lineages with full support in Steccherinaceae. The distinguishing characters of the two new species as well as allied species are discussed, and a key to species of Mycorrhaphium is provided.

Aortic prosthetic size predictor in aortic valve replacement.

BACKGROUND: Patient-prosthesis mismatch (PPM) is a major concern in aortic valve replacement (AVR) and leads to perioperative morbidity and rehospitalization. Predicting aortic annulus diameter pre-procedurally is crucial to managing patients with high-risk of PPM. OBJECTIVES: To compare preoperative measurements of aortic annulus from echocardiography and CT scan with surgical sizing and develop an imaging-based algorithm to predict PPM. METHODS: From January 2017 to December 2020, patients underwent AVR at a teaching hospital were examined. The relationship between imaging measurements with operative values was assesed using scatter plots and Pearson's correlation coefficient. Univariable linear regression was then used to build the predictive model. RESULTS: A total of 144 patients underwent AVR during the study period. Suture types and surgical approaches were not significantly associated with prosthesis size. CT scan-based measurements showed strong correlation with prosthesis size: mean diameter (R = 0.79), perimeter-derived diameter (R = 0.76), and area-derived diameter (R = 0.75). Mechanical valve and tissue valve shared similar correlation coefficients. Prosthesis size predictive models based on CT scan were 12.89 + 0.335 × d for mean diameter, 13.275 + 0.315 × d for perimeter-derived diameter and 13.626 + 0.309 × d for area-derived diameter. CONCLUSIONS: Preoperative CT scan measurements are a reliable predictor of aortic prosthesis size. Transthoracic echocardiography is a possible alternative, though it is highly performer-dependent and unable to represent the aortic annulus fully. Together, these two imaging modalities can be used to quantitatively anticipate PPM preoperatively.

Functionalization of zirconium-based metal-organic frameworks for gas sensing applications.

The functionalization and incorporation of noble metals in metal-organic frameworks have been widely used as efficient methods to enhance their applicability. Herein, a sulfone-functionalized Zr-MOF framework labeled Zr-BPDC-SO2 (BPDC-SO2 =dibenzo[b,d]-thiophene-3,7-dicarboxylate 5,5-dioxide) and its Pd-embedded composite were efficiently synthesized by adjusting their functional groups. The obtained compounds were characterized to assess their potential for gas sensing applications. X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, specific surface area measurements, and thermogravimetric analysis were employed to characterize the new sensor materials. The gas sensing properties of the novel functionalized sensor materials were systematically investigated under various temperature, concentration, and gas type conditions. Owing to the strong hydrogen bonds of the sulfonyl groups and Zr6 clusters in the framework with the hydroxyl groups of ethanol, Zr-BPDC-SO2 emerged as an effective sensor for ethanol detection. In addition, Pd@Zr-BPDC-SO2 exhibited efficient hydrogen sensing performance, in terms of sensor dynamics and response. More importantly, the material showed a higher sensing response to hydrogen than to other gases, highlighting the important role of Pd in the Zr-MOF-based hydrogen sensor. The results of the sensing tests carried out in this study highlight the promising potential of the present materials for practical gas monitoring applications.

Tailoring chemical compositions of biodegradable mesoporous organosilica nanoparticles for controlled slow release of chemotherapeutic drug.

Biodegradable periodic mesoporous organosilica nanoparticles (B-PMO) are an outstanding nanocarrier due to their biodegradability and high drug load capacities. The present study describes a synthesis of a phenylene-containing tetrasulfide based B-PMO, named P4S. The incorporation of aromatic phenylene groups into the framework creates a strong interaction between nanoparticles (NPs) with aromatic rings in the cordycepin molecules. This results in the low release profile under various conditions. In addition, the replacement of this linker slowed the degradation of nanoparticles. The physicochemical properties of the nanoparticles are evaluated and compared with a biodegradable ethane-containing tetrasulfide based PMO and a non-degradable MCM-41. The biodegradability of P4S is also demonstrated in a reducing environment and the 100 nm spherical nanoparticles completely decomposed within 14 days. The porous structure of P4S has a high loading of hydrophilic cordycepin (approximately 731.52 mg g-1) with a slow releasing speed. The release rates of P4S NPs are significantly lower than other materials, such as liposomes, gelatin nanoparticles, and photo-crosslinked hyaluronic acid methacrylate hydrogels, in the same solution. This specific release behavior could guarantee drug therapeutic effects with minimum side-effects and optimized drug dosages. Most importantly, according to the in vitro cytotoxicity study, cordycepin-loaded P4S NPs could retain the toxicity against liver cancer cell (HepG2) while suppressed the cytotoxicity against normal cells (BAEC).

HDAC inhibitors elicit metabolic reprogramming by targeting super-enhancers in glioblastoma models.

The Warburg effect is a tumor-related phenomenon that could potentially be targeted therapeutically. Here, we showed that glioblastoma (GBM) cultures and patients' tumors harbored super-enhancers in several genes related to the Warburg effect. By conducting a transcriptome analysis followed by ChIP-Seq coupled with a comprehensive metabolite analysis in GBM models, we found that FDA-approved global (panobinostat, vorinostat) and selective (romidepsin) histone deacetylase (HDAC) inhibitors elicited metabolic reprogramming in concert with disruption of several Warburg effect-related super-enhancers. Extracellular flux and carbon-tracing analyses revealed that HDAC inhibitors blunted glycolysis in a c-Myc-dependent manner and lowered ATP levels. This resulted in the engagement of oxidative phosphorylation (OXPHOS) driven by elevated fatty acid oxidation (FAO), rendering GBM cells dependent on these pathways. Mechanistically, interference with HDAC1/-2 elicited a suppression of c-Myc protein levels and a concomitant increase in 2 transcriptional drivers of oxidative metabolism, PGC1α and PPARD, suggesting an inverse relationship. Rescue and ChIP experiments indicated that c-Myc bound to the promoter regions of PGC1α and PPARD to counteract their upregulation driven by HDAC1/-2 inhibition. Finally, we demonstrated that combination treatment with HDAC and FAO inhibitors extended animal survival in patient-derived xenograft model systems in vivo more potently than single treatments in the absence of toxicity.

Activation of LXR Receptors and Inhibition of TRAP1 Causes Synthetic Lethality in Solid Tumors.

Cholesterol is a pivotal factor for cancer cells to entertain their relentless growth. In this case, we provide a novel strategy to inhibit tumor growth by simultaneous activation of liver-X-receptors and interference with Tumor Necrosis Factor Receptor-associated Protein 1 (TRAP1). Informed by a transcriptomic and subsequent gene set enrichment analysis, we demonstrate that inhibition of TRAP1 results in suppression of the cholesterol synthesis pathway in stem-like and established glioblastoma (GBM) cells by destabilizing the transcription factor SREBP2. Notably, TRAP1 inhibition induced cell death, which was rescued by cholesterol and mevalonate. Activation of liver X receptor (LXR) by a clinically validated LXR agonist, LXR623, along with the TRAP1 inhibitor, gamitrinib (GTPP), results in synergistic reduction of tumor growth and cell death induction in a broad range of solid tumors, which is rescued by exogenous cholesterol. The LXR agonist and TRAP1 inhibitor mediated cell death is regulated at the level of Bcl-2 family proteins with an elevation of pro-apoptotic Noxa. Silencing of Noxa and its effector BAK attenuates cell death mediated by the combination treatment of LXR agonists and TRAP1 inhibition. Combined inhibition of TRAP1 and LXR agonists elicits a synergistic activation of the integrated stress response with an increase in activating transcription factor 4 (ATF4) driven by protein kinase RNA-like endoplasmic reticulum kinase (PERK). Silencing of ATF4 attenuates the increase of Noxa by using the combination treatment. Lastly, we demonstrate in patient-derived xenografts that the combination treatment of LXR623 and gamitrinib reduces tumor growth more potent than each compound. Taken together, these results suggest that TRAP1 inhibition and simultaneous activation of LXR might be a potent novel treatment strategy for solid malignancies.