Identification of the MMP family as therapeutic targets and prognostic biomarkers in the microenvironment of head and neck squamous cell carcinoma.

BACKGROUND: Head and Neck Squamous Cell Carcinoma is a malignant tumor with high morbidity and mortality. The MMP family plays an important role in tumor invasion and metastasis. However, the mechanistic value of the MMP family as a therapeutic target and prognostic biomarker in HNSC has not been fully elucidated. METHODS: Oncomine, UALCAN, GEPIA, cBioportal, GeneMANIA, STRING, DAVID6.8, TRRUST, TIMER and Linkedomics were used for analysis. RESULTS: The mRNA expression levels of MMP1, MMP3, ILF3, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13 and MMP16 were higher in HNSC than those in normal tissues, while the mRNA expression level of MMP15 was reduced. The relative expression levels of MMP1 and MMP14 were the highest in HNSC tissues. A significant correlation was found between the expression of MMP3, MMP11, MMP25 and the pathological stage of HNSC patients. There was no significant associations between all the MMP family members expression levels and DFS. Increased mRNA levels of MMP1, MMP8 and MMP25 were significantly associated with OS. In addition, we investigated the genetic changes of the MMP family in HNSC and found that all the MMP family members had genetic changes, most of which were amplification and depth loss. In the analysis of neighbor gene network and protein interaction, we found that the MMP family interacted with 25 neighboring genes, except for ILF3, MMP19, MMP20, MMP21, MMP23B, MMP27 and MMP28, other MMP proteins interacted with each other. Functional enrichment analysis showed that the MMP family could be present in the extracellular matrix, regulate peptidase activity, and participate in the catabolism of collagen. Meanwhile, we identified the transcription factor targets and kinase targets of the MMP family and found that ATM and ATR were the two most common kinase targets in the MMP family. We also found a significant correlation between the MMP family expression and immune cell infiltration. Cox proportional risk model analysis showed that macrophages, MMP14, MMP16, and MMP19 were significantly associated with clinical outcomes in HNSC patients. CONCLUSION: The MMP family might serve as therapeutic target and prognostic biomarker in HNSC.

Matrine counteracts obesity in mice via inducing adipose thermogenesis by activating HSF1/PGC-1α axis.

Promoting energy expenditure is known to curb obesity and can be exploited for its treatment. Our previous study has demonstrated that activation of HSF1/PGC-1α axis efficiently induced mitochondrial biogenesis and adaptive oxidation and thus ameliorating lipid accumulation, however, whether it can be a therapeutic approach for metabolic disorders treatment needs explored. Here, a high-efficient and specific HSF1/PGC-1α activator screening system was established and the natural clinical liver-protecting agent matrine was identified as a robust HSF1/PGC-1α activator. Matrine treatment efficiently induced mitogenesis and thermogenic program in primary mouse adipose stem cell derived adipocytes by enriching HSF1 to the promoter of Pgc-1α. Deficiency of PGC-1α in adipocytes diminished the browning induction ability of matrine. Oral administration of matrine to the obese mice induced by high fat and high cholesterol diet increased energy expenditure and corrected the degeneration of thermogenesis in brown adipose tissue (BAT). Also, matrine treatment markedly induced the transformation of brown-like adipocytes in subcutaneous white adipose tissue (sWAT) via a mechanism of HSF1/PGC-1α, thereby attenuating obesity and myriads of metabolic disorders. This led to an improvement in adaptive thermogenesis to cold stimuli. These findings are of great significance in understanding the regulation mechanisms of the HSF1/PGC-1α axis in thermogenesis and providing a novel therapeutic approach for obesity treatment. Matrine may have potential therapeutic implications for the treatment of obesity in clinics.

Palladium oxidative addition complex-enabled synthesis of amino-substituted indolyl-4(3H)-quinazolinones and their antitumor activity evaluation.

The indolyl-4(3H)-quinazolinone core is an important structural motif in functional molecules. However, few methods exist for its direct modification, which limits its potential application. Reported herein is a palladium-mediated amination of halogen-containing indolyl-4(3H)-quinazolinones with a variety of primary and secondary amines via the corresponding palladium oxidative addition complexes. The protocol allows the facile synthesis of indolyl-4(3H)-quinazolinone derivatives with amino groups at all the positions of the benzene ring in moderate to good yields with mild reaction conditions and good functional group tolerance. Furthermore, the antitumor activity of these products was evaluated.

Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy.

Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N-ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual-target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N-ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug-resistant cell line MCF-7/ADR and the atypical drug-resistant tumor cell line HL-60/MX2. Our study identified quinacrine as a potential dual-target inhibitor of Topo II and Hsp90, depending on the ATP-binding domain, positioning it as a hit compound for further structural modification.

The Conserved IgSF9 Protein Borderless Regulates Axonal Transport of Presynaptic Components and Color Vision in Drosophila.

Normal brain function requires proper targeting of synaptic-vesicle (SV) and active-zone components for presynaptic assembly and function. Whether and how synaptogenic signals (e.g., adhesion) at axo-dendritic contact sites promote axonal transport of presynaptic components for synapse formation, however, remain unclear. In this study, we show that Borderless (Bdl), a member of the conserved IgSF9-family trans-synaptic cell adhesion molecules, plays a novel and specific role in regulating axonal transport of SV components. Loss of bdl disrupts axonal transport of SV components in photoreceptor R8 axons, but does not affect the transport of mitochondria. Genetic mosaic analysis, transgene rescue and cell-type-specific knockdown indicate that Bdl is required both presynaptically and postsynaptically for delivering SV components in R8 axons. Consistent with a role for Bdl in R8 axons, loss of bdl causes a failure of R8-dependent phototaxis response to green light. bdl interacts genetically with imac encoding for a member of the UNC-104/Imac/KIF1A-family motor proteins, and is required for proper localization of Imac in R8 presynaptic terminals. Our results support a model in which Bdl mediates specific axo-dendritic interactions in a homophilic manner, which upregulates the Imac motor in promoting axonal transport of SV components for R8 presynaptic assembly and function.SIGNIFICANCE STATEMENT Whether and how synaptogenic adhesion at axo-dendritic contact sites regulates axonal transport of presynaptic components remain unknown. Here we show for the first time that a trans-synaptic adhesion molecule mediates specific interactions at axo-dendritic contact sites, which is required for upregulating the UNC-104/Imac/KIF1A motor in promoting axonal transport of synaptic-vesicle components for presynaptic assembly and function.

Pd/Pt embedded CN monolayers as efficient catalysts for CO oxidation.

Single atom catalysts (SACs) based on 2D materials have been identified to be efficient in many catalytic reactions. In this work, the catalytic performance of Pd/Pt embedded planar carbon nitride (CN) for CO oxidation has been investigated via spin-polarized density functional theory calculations. We find that Pd/Pt can be firmly anchored in the porous CN monolayer due to the strong hybridization between Pd/Pt-d orbitals and adjacent N-2p orbitals. The resulting high adsorption energy and large diffusion barrier of Pd/Pt ensures the remarkable stability of the catalyst Pd/Pt@CN during the CO oxidation reaction. The three distinct CO reaction mechanisms, namely, Eley-Rideal (ER), Langmuir-Hinshelwood (LH), and tri-molecular Eley-Rideal (TER), are taken into consideration comparatively. Intriguingly, the oxidation reaction on Pd@CN prefers to proceed through the less common TER mechanism, where two CO molecules and one O2 molecule need to cross a small reaction barrier of 0.48 eV, and finally dissociate into two CO2 molecules. However, the LH mechanism is the most relevant one on Pt@CN with a rate-limiting reaction barrier of 0.68 eV. Moreover, the origin of the SAC's reactivity enhancement is the electronic "acceptance-donation" interaction caused by orbital hybridization between Pd/Pt and preadsorbed O2/CO. Our findings are expected to widen the catalytic application of carbon-based 2D materials.

Euphorhelipanes A and B, Triglyceride-Lowering Euphorbia Diterpenoids with a Bicyclo[4.3.0]nonane Core from Euphorbia helioscopia.

Euphorhelipanes A (1) and B (2), two Euphorbia diterpenoids with a new 4-(5,5-dimethylheptan-2-yl)-2,7-dimethylbicyclo[4.3.0]nonane skeleton, were isolated from a 95% ethanol extract of the whole plants of Euphorbia helioscopia. Their structures were elucidated by spectroscopic data analysis, quantum chemical calculations, and single-crystal X-ray diffraction data. Compounds 1 and 2 represent the first examples of Euphorbia diterpenoids with a 5/6 fused carbon ring system, and their plausible biosynthetic pathways originating from jatrophanes are proposed. Compounds 1 and 2 showed a triglyceride-lowering effect in oleic-acid-stimulated HuH7 cells at concentrations of 1-50 µM.

C2N: an excellent catalyst for the hydrogen evolution reaction.

Based on first-principles calculations, we study the hydrogen evolution reaction (HER) on metal-free C2N and make efforts to improve its catalytic performance. At H* coverages (θ) of 3/6 and 4/6, the free energy of hydrogen adsorption (ΔGH*) is 0.10 eV and 0.07 eV, respectively, which is competitive with the precious catalyst Pt. Moreover, ΔGH* can be modulated to zero under a tensile strain, and the strength of the strain depends on the H concentration. Experimentally, it is possible to achieve a strain of around 2% through coupling C2N with graphene, and the HER performance of the hybrids would be generally enhanced. Moreover, the catalytic activity of the hybrids is tunable via electron and hole doping of graphene. In the strong H binding cases (θ = 1/6), anchoring Mn atoms into C2N exhibits a perfect catalytic property with ΔGH* of -0.04 eV. Therefore, C2N-based catalysts are expected to be easily synthesized and highly active catalysts for the HER. These findings may shed light on replacing Pt by metal-free or/and non-precious metal counterparts.

Modulation of electronic and magnetic properties of edge hydrogenated armchair phosphorene nanoribbons by transition metal adsorption.

Based on first-principles calculations, we present a systematic investigation of the electronic and magnetic properties of armchair phosphorene nanoribbons (APNRs) functionalized by 3d transition metal (TM) atoms. We found that the central hollow site is the most favorable adsorption site for Mn, Co and Ni, while Fe preferentially occupies the edge hollow site. All of the TM atoms bind to the adjacent P and their adsorption energies are in the range of -4.29 eV to -1.59 eV. Meanwhile, the large ratio of the adsorption energy to the cohesive energy of the metal bulk phase indicates that TM atoms have a preferred 2D growth mode on the edge hydrogenated armchair phosphorene nanoribbons (H-APNRs). The magnetic moments reduce by about 2-4 µB, relative to their free atom states, depending on whether the TM atom is in the high-spin or low-spin state. This reduction is mainly attributed to the electrons transferring from the high-level TM 4s shell to the low-lying 3d shell. Our results demonstrate that TM atom adsorption is a feasible approach to functionalizing the H-APNRs chemically, which results in peculiar electronic and magnetic properties for potential applications in nano-electronics and spintronics.

Borderless regulates glial extension and axon ensheathment.

Ensheathment of axons by glial processes is essential for normal brain function. While considerable progress has been made to define molecular and cellular mechanisms underlying the maintenance of axon ensheathment, less is known about molecular details of early events for the wrapping of axons by glial processes in the developing nervous system. In this study, we investigate the role of the transmembrane protein Borderless (Bdl) in the developing Drosophila visual system. Bdl belongs to the immunoglobulin (Ig) superfamily, and its in vivo function is unknown. We show that Bdl is expressed in wrapping glia (WG) in the developing eye disc. Cell-type-specific transgene rescue and knockdown indicate that Bdl is specifically required in WG for the extension of glial processes along photoreceptor axons in the optic lobe, and axon ensheathment. Our results identify Bdl as a novel glia-specific cell-surface recognition molecule in regulating glial extension and axon ensheathment.

One-Pot Synthesis of Indoles by a Sequential Ugi-3CR/Wittig Reaction Starting from Odorless Isocyanide-Substituted Phosphonium Salts.

A new one-pot preparation of indoles by a Ugi-3CR/Wittig sequence has been developed. The reaction of odorless isocyanide-substituted phosphonium salt 5, aldehyde 6, and amine 7 produced the indoles 9 in 45-82% yields via a sequential Ugi-3CR/Wittig reaction in the presence of H3PO4 and solid K2CO3, respectively.

Electrical and optical behaviors of SiC(GeC)/MoS2 heterostructures: a first principles study.

Hybrid structures have attracted a great deal of attention because of their excellent properties, which can open up a way we could not foresee in materials science and device physics. Here, we investigate the electrical and optical behaviors of SiC(GeC)/MoS2 heterostructures, using first principles calculations based on density functional theory. Non-covalent bonding exists between the junctions due to the weak orbital coupling. Both junctions have optically active band gaps, smaller than that of the SiC or GeC and MoS2 layers, which result in enhanced optical adsorption under visible-light irradiation. A small number of electrons transfer from SiC/GeC to MoS2 causing its n-doping. Furthermore, the charge density states of the valence band maximum and the conduction band minimum are localized at different sides, and thus the electron-hole pairs are spatially separated. Our results provide a potential scheme for photovoltaic materials.

Control of axon-axon attraction by Semaphorin reverse signaling.

Semaphorin family proteins are well-known axon guidance ligands. Recent studies indicate that certain transmembrane Semaphorins can also function as guidance receptors to mediate axon-axon attraction or repulsion. The mechanisms by which Semaphorin reverse signaling modulates axon-surface affinity, however, remain unknown. In this study, we reveal a novel mechanism underlying upregulation of axon-axon attraction by Semaphorin-1a (Sema1a) reverse signaling in the developing Drosophila visual system. Sema1a promotes the phosphorylation and activation of Moesin (Moe), a member of the ezrin/radixin/moesin family of proteins, and downregulates the level of active Rho1 in photoreceptor axons. We propose that Sema1a reverse signaling activates Moe, which in turn upregulates Fas2-mediated axon-axon attraction by inhibiting Rho1.

One-Pot Synthesis of Multisubstituted Benzimidazoles via Sequential Ugi and Catalytic Aza-Wittig Reaction Starting from 2-Aminobenzoyl Azides.

A simple and one-pot synthesis of multisubstituted benzimidazoles by a Ugi 4CC/catalytic aza-Wittig sequence was developed. The reaction of 2-aminobenzoyl azide 2, aldehyde 3, acid 4, and isocyanide 5 produced the benzimidazoles 8 in moderate to good yields via a sequential Ugi condensation and catalytic aza-Wittig in the presence of a catalytic amount of phospholene oxide.

Discovery of natural alkaloid bouchardatine as a novel inhibitor of adipogenesis/lipogenesis in 3T3-L1 adipocytes.

Bouchardatine (1), a naturally occurring ß-indoloquinazoline alkaloid, was synthesized. For the first time, the lipid-lowering effect and mechanism of 1 was investigated in 3T3-L1 adipocytes. Our study showed that 1 could significantly reduce lipid accumulation without cytotoxicity and mainly inhibited early differentiation of adipocyte through proliferation inhibition and cell cycle arrested in dose-dependent manner. Furthermore, the inhibition of early differentiation was reflected by down-regulation of key regulators of adipogenesis/lipogenesis, including CCAAT enhancer binding proteins (C/EBPß, C/EBPδ, C/EBPα), peroxisome proliferator-activated receptors γ (PPARγ) and sterol-regulatory element binding protein-1c (SREBP-1c), in both of mRNA and protein levels. Subsequently decreasing the protein levels of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearyl coenzyme A desaturated enzyme 1 (SCD-1), the rate-limited metabolic enzymes of fatty acid synthesis, were also observed. Further studies revealed that 1 persistently activated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) during differentiation, suggesting that the AMPK may be an upstream mechanism for the effect of 1 on adipogenesis and lipogenesis. Our data suggest that 1 can be a candidate for the development of new therapeutic drugs against obesity and related metabolic disorders.

Visual circuit assembly requires fine tuning of the novel Ig transmembrane protein Borderless.

Establishment of synaptic connections in the neuropils of the developing nervous system requires the coordination of specific neurite-neurite interactions (i.e., axon-axon, dendrite-dendrite and axon-dendrite interactions). The molecular mechanisms underlying coordination of neurite-neurite interactions for circuit assembly are incompletely understood. In this report, we identify a novel Ig superfamily transmembrane protein that we named Borderless (Bdl), as a novel regulator of neurite-neurite interactions in Drosophila. Bdl induces homotypic cell-cell adhesion in vitro and mediates neurite-neurite interactions in the developing visual system. Bdl interacts physically and genetically with the Ig transmembrane protein Turtle, a key regulator of axonal tiling. Our results also show that the receptor tyrosine phosphatase leukocyte common antigen-related protein (LAR) negatively regulates Bdl to control synaptic-layer selection. We propose that precise regulation of Bdl action coordinates neurite-neurite interactions for circuit formation in Drosophila.

Neurexin-1-dependent circuit activity is required for the maintenance of photoreceptor subtype identity in Drosophila.

In the human and Drosophila color vision system, each photoreceptor neuron (cone cell in humans and R7/R8 photoreceptor cell in Drosophila) makes a stochastic decision to express a single photopigment of the same family with the exclusion of the others. While recent studies have begun to reveal the mechanisms that specify the generation of cone subtypes during development in mammals, nothing is known about how the mosaic of mutually exclusive cone subtypes is maintained in the mammalian retina. In Drosophila, recent work has led to the identification of several intrinsic factors that maintain the identity of R8 photoreceptor subtypes in adults. Whether and how extrinsic mechanisms are involved, however, remain unknown. In this study, we present evidence that supports that the Drosophila transsynaptic adhesion molecule Neurexin 1 (Dnrx-1) is required non-cell autonomously in R8p subtypes for the maintenance of R8y subtype identity. Silencing the activity of R8p subtypes caused a phenotype identical to that in dnrx-1 mutants. These results support a novel role for Nrx-1-dependent circuit activity in mediating the communication between R8 photoreceptor subtypes for maintaining the subtype identity in the retina.

Harnessing the potential of de-sulfated heparin for targeted drug delivery: A three-component approach exemplified by conjugation with galactose and paclitaxel.

Heparin, an anticoagulant with a century-long history of use, has been investigated over the past decade as a potential drug delivery vehicle. Despite its safety and efficacy, its interactions with many proteins through specific sulfate patterns can complicate drug delivery by mediating diverse biological functions. Here, we present the synthesis of a three-component drug delivery system comprising de-sulfated heparin as the carrier, galactose as the targeting moiety, and paclitaxel as the therapeutic drug. Removal of sulfates eliminated most of its anticoagulant effects in all intermediates. Through coupling with galactose and paclitaxel, the system improved the solubility of the drug and achieved selective targeting and efficient drug delivery to HepG2 cells, a liver carcinoma cell line with high galactose receptor expression. While the three-component system exhibited a slightly higher IC50 value than native paclitaxel, demonstrating its efficacy as a drug carrier, the IC50 value for the normal human liver cell line QSG7701 was significantly higher, indicating its selectivity and safety. Our study introduces a novel approach utilizing desulfated heparin as a carrier, warranting further investigation to unlock its potential in targeted drug delivery strategies.

Identification of a natural PLA2 inhibitor from the marine fungus Aspergillus sp. c1 for MAFLD treatment that suppressed lipotoxicity by inhibiting the IRE-1α/XBP-1s axis and JNK signaling.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

Marine fungus Aspergillus c1. sp metabolite activates the HSF1/PGC-1α axis, inducing a thermogenic program for treating obesity.

Background and aims: Obesity is one of the most prevalent diseases worldwide with less ideal approved agents in clinic. Activating the HSF1/PGC-1α axis in adipose tissues has been reported to induce thermogenesis in mice, which presents a promising therapeutic avenue for obesity treatment. The present study aimed to identified novel natural HSF1 activator and evaluated the therapeutic effects of the newly discovered compound on obesity-associated metabolic disorders and the molecular mechanisms of these effects. Methods: Our previous reported HSF1/PGC-1α activator screening system was used to identify novel natural HSF1 activator. The PGC-1α luciferase activity, immunoblot, protein nuclear-translocation, immunofluorescence, chromatin immunoprecipitation assays were used to evaluate the activity of compound HN-001 in activating HSF1. The experiments of mitochondrial number measurement, TG assay and imaging, cellular metabolic assay, gene assays, and CRISPR/Cas 9 were applied for investigating the metabolic effect of HN-001 in C3H10-T1/2 adipocytes. The in vivo anti-obesity efficacies and beneficial metabolic effects of HN-001 were evaluated by performing body and fat mass quantification, plasma chemical analysis, GTT, ITT, cold tolerance test, thermogenesis analysis. Results: HN-001 dose- and time-dependently activated HSF1 and induced HSF1 nuclear translocation, resulting in an enhancement in binding with the gene Pgc-1α. This improvement induced activation of adipose thermogenesis and enhancement of mitochondrial oxidation capacity, thus inhibiting adipocyte maturation. Deletion of HSF1 in adipocytes impaired mitochondrial oxidation and abolished the above beneficial metabolic effects of HN-001, including adipocyte browning induction, improvements in mitogenesis and oxidation capacity, and lipid-lowering ability. In mice, HN-001 treatment efficiently alleviated diet-induced obesity and metabolic disorders. These changes were associated with increased body temperature in mice and activation of the HSF1/PGC-1α axis in adipose tissues. UCP1 expression and mitochondrial biogenesis were increased in both white and brown adipose tissues of HN-001-treated mice. Conclusion: These data indicate that HN-001 may have therapeutic potential for obesity-related metabolic diseases by increasing the capacity of energy expenditure in adipose tissues through a mechanism involving the HSF1/PGC-1α axis, which shed new light on the development of novel anti-obesity agents derived from marine sources.