Unveiling potential: urinary exosomal mRNAs as non-invasive biomarkers for early prostate cancer diagnosis.

BACKGROUND: This study investigated the use of urinary exosomal mRNA as a potential biomarker for the early detection of prostate cancer (PCa). METHODS: Next-generation sequencing was utilized to analyze exosomal RNA from 10 individuals with confirmed PCa and 10 individuals without cancer. Subsequent validation through qRT-PCR in a larger sample of 43 PCa patients and 92 healthy controls revealed distinct mRNA signatures associated with PCa. RESULTS: Notably, mRNAs for RAB5B, WWP1, HIST2H2BF, ZFY, MARK2, PASK, RBM10, and NRSN2 showed promise as diagnostic markers, with AUC values between 0.799 and 0.906 and significance p values. Combining RAB5B and WWP1 in an exoRNA diagnostic model outperformed traditional PSA tests, achieving an AUC of 0.923, 81.4% sensitivity, and 89.1% specificity. CONCLUSIONS: These findings highlight the potential of urinary exosomal mRNA profiling, particularly focusing on RAB5B and WWP1, as a valuable strategy for improving the early detection of PCa.

Role of inflammation and immune response in atherosclerosis: Mechanisms, modulations, and therapeutic targets.

Cardiovascular diseases (CVDs) have emerged as the leading cause of mortality globally, with atherosclerosis being a prominent focus of investigation among medical researchers worldwide. Atherosclerosis is characterized as a disease of the large and medium-sized arteries that is multifocal, accumulative, and immunoinflammatory in nature, resulting from the deposition of lipids. Accumulating evidence suggests that inflammatory responses and immunoregulation play a vital role in the occurrence and development of atherosclerosis. While existing treatments for atherosclerosis can assist in symptom management and slowing disease progression, a complete cure remains elusive. Consequently, there is significant interest in research and development of potential new drugs for this condition. Therefore, this review aims to consolidate the current understanding of the pathogenesis of atherosclerosis with an emphasis on inflammation, immune response and infection. Besides, it examines the effects and mechanisms of immunological modulations in atherosclerosis, and the potential therapeutic targets and drugs for intervening in the inflammatory responses and immunoregulation associated with atherosclerosis. Additionally, novel drug options for treating atherosclerosis are explored within the context of this review.

Gastric Acid-Responsive ROS Nanogenerators for Effective Treatment of Helicobacter pylori Infection without Disrupting Homeostasis of Intestinal Flora.

Helicobacter pylori (H. pylori) has infected more than half of the world's population, and is the major cause of gastric cancer. The efficacy of standard antibiotic-based triple therapy is declining due to drug resistance development. Herein, a pH-responsive reactive oxygen species (ROS) nanogenerator (Fe-HMME@DHA@MPN) composed of acid-responsive metal polyphenol network (MPN) shell and mesoporous metal-organic nanostructure core [Fe-HMME (hematoporphyrin monomethyl ether, sonosensitizer)] loaded with dihydroartemisinin (DHA) is reported. These nanoparticles generate more ROS singlet oxygen than sonosensitizer HMME under ultrasonication, and this sonodynamic process is fueled by oxygen generated through Fenton/Fenton-like reactions of the degraded product in gastric acid Fe (II) and hydrogen peroxide (H2 O2 ) in the infection microenvironment. The encapsulated DHA, as a hydroperoxide source, is found to enhance the peroxidase-like activity of the Fe-HMME@DHA@MPN to generate ROS hydroxyl radical, beneficial for the microenvironment without sufficient H2 O2 . In vitro experiments demonstrate that the ROS nanogenerators are capable of killing multidrug-resistant H. pylori and removing biofilm, and ROS nanogenerators show high therapeutic efficacy in a H. pylori infection mouse model. Unlike the triple therapy, the nanogenerators display negligible side effects toward the normal gut microbiota. Taken together, these self-enhanced ROS nanogenerators have a great potential for treatment of H. pylori infection.

The PTEN-associated immune prognostic signature reveals the landscape of the tumor microenvironment in glioblastoma.

Glioblastoma (GBM) is a common brain tumor with a complex and diverse tumor microenvironment (TME). As PTEN mutation is the most common mutation in GBM, we aimed to investigate how PTEN mutation regulates the immune response in GBM TME and thus affects the prognosis of GBM patients. In this study, we conducted a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES), transcriptome RNA sequencing, patient survival and immune signatures, to study the relationship between PTEN mutation and TME in GBM. We developed an immune-related prognostic signature (IPS) based on the PTEN-associated immune-related genes (IRGs), and the IPS exhibited a powerful prognosis prediction capacity in different GBM cohorts. A scoring nomogram based on the IPS was also established for clinical application. In addition, the correlations of the IPS with tumor immune cell infiltration and immune checkpoints were systematically analyzed. This study illustrates the influence of PTEN mutation on the immune microenvironment of GBM. Our IPS, which is sensitive to PTEN mutation status, can enhance the prognosis prediction ability for GBM patients and provides potential targets for immunotherapy.

Oxidative stress-amplified nanomedicine for intensified ferroptosis-apoptosis combined tumor therapy.

Ferroptosis, as an effective sensitizer for apoptosis-based cancer treatments, has been elucidated to rely on high levels of intracellular oxidative stress mediated by the accumulation of reactive oxygen species (ROS). However, ferroptosis-related oxidation effect is largely counteracted by the endogenous reductive glutathione (GSH). Here, we constructed a self-assembled metal-organic nanomedicine p53/Ce6@ZF-T, which was composed of p53 plasmid-complexed chlorin e6 (Ce6)-poly(amidoamine), Fe2+-containing mesoporous zeolitic imidazolate framework-8 and naturally derived tannic acid (TA). The highly cytotoxic ROS was continuously produced via Fe2+-mediated and TA-assisted enhanced Fenton reaction as well as Ce6-induced photosensitive reaction, and meanwhile, the intratumoral upregulated p53 expression inactivated glutathione peroxidase 4 (GPX4) to suppress lipid peroxidation (LPO) resistance, thus resulting in amplified oxidative stress and intensified ferroptosis-apoptosis therapy. The notable anticancer efficacy of p53/Ce6@ZF-T both in vitro and in vivo substantially evidenced the high feasibility of oxidative stress-amplified therapeutic modality for enhanced ferroptosis-apoptosis combined therapy, which would be a promising approach in the field of cancer treatment in the future.

ATP-exhausted nanocomplexes for intratumoral metabolic intervention and photoimmunotherapy.

Tumor cells reprogram the metabolic pathways to acquire abundant nutrients and sustain malignant proliferation. This fierce metabolic competition in tumor ecosystem has been uncovered to be associated with tumor microenvironmental immunosuppression. Here we develop an adenosine triphosphate (ATP)-exhausted nanocomplex (IR@ZIF-RGD) to intervene in tumor energy metabolism and regulate tumor immune microenvironment. IR@ZIF-RGD could effectively deplete intracellular ATP and inhibit ATP synthesis by ATP-responsive ZIF-90 and siRNA targeting thioredoxin reductase-2, respectively, thus leading to tumor metabolism disorders and immunosuppressive reversion. Meanwhile, IR@ZIF-RGD induced oxidative stress and ICG triggered photothermal therapy could provoke potent immunogenic cell death to enhance antitumor immunogenicity. Such a photo-immunometabolic nanocomplex has been demonstrated to be an efficient vaccine to elicit protective anticancer immune response in vivo, achieving suppressed growth of both primary and abscopal tumors, as well as inhibited tumor metastasis.

Parallel Mixed Image Encryption and Extraction Algorithm Based on Compressed Sensing.

In the actual image processing process, we often encounter mixed images that contain multiple valid messages. Such images not only need to be transmitted safely, but also need to be able to achieve effective separation at the receiving end. This paper designs a secure and efficient encryption and separation algorithm based on this kind of mixed image. Since chaotic system has the characteristics of initial sensitivity and pseudo-randomness, a chaos matrix is introduced into the compressed sensing framework. By using sequence signal to adjust the chaotic system, the key space can be greatly expanded. In the algorithm, we take the way of parallel transmission to block the data. This method can realize the efficient calculation of complex tasks in the image encryption system and improve the data processing speed. In the decryption part, the algorithm in this paper can not only realize the restoration of images, but also complete the effective separation of images through the improved restoration algorithm.

Characterization and rational modification of aspartate 4-decarboxylase from Acinetobacter radioresistens for the production of l-alanine.

Enzymatic synthesis of l-alanine has the advantages of less byproducts, strong stereoselectivity, and high catalytic efficiency. Aspartate 4-decarboxylase (ASD) is used industrially in DL-aspartic acid resolution and l-alanine production because it catalyzes the decarboxylation of l-aspartic acid. In this study, the ASD gene from Acinetobacter radioresistens (ArASD) was cloned, and its enzymatic properties were analyzed. ArASD is a dodecamer and has the highest enzyme activity ever reported to date. The optimal conditions for ArASD catalysis are 50°C and pH 4.5. Site-directed mutagenesis was used to improve ArASD stability under acidic conditions to compensate for its weak acid resistance, and the variant N35D with higher catalytic ability was obtained. The conversion by N35 recombinant cells of l-aspartic acid to l-alanine was 92.5% at pH 4.5% and 99.9% at pH 6.0, whereas that of the wild-type recombinant cells was 29.7% and 31.4%, respectively. Aspartase from Escherichia coli (AspA) was employed with ArASD to construct a dual-enzyme system that catalyzes fumaric acid to l-alanine, and the conversion reached 97.1% using recombinant cells harboring the dual-enzyme system. This study explored the enzymatic properties of ArASD and an effective strategy for the acidic resistance modification of ASD. Moreover, the strain expressing the ArASD variant and AspA engineered in this study has great potential application for the l-alanine production industry, especially in the case of high optical purity requirements.

Naphthalene derivatives and halogenate quinoline from the coral-derived fungus Trichoderma harzianum (XS-20090075) through OSMAC approach.

OSMAC approach was performed on the soft coral-derived fungus Trichoderma harzianum (XS-20090075) leading to the significant changes of its secondary metabolites by using two different cultures. A new naphthalene derivative, trichoharzin B (1) and a new natural product, methyl-trichoharzin (2) were isolated by using rice medium. Whereas, a new natural product, ethyl 2-bromo-4-chloroquinoline-3-carboxylate (9) was obtained by using Czapek's medium. Their structures were established by extensive spectroscopic investigation. The absolute configuration of 5 was determined by single-crystal X-ray diffraction. Compound 9 was the first halogenate quinoline derivative isolated from the genus of Trichoderma.

Image Parallel Encryption Technology Based on Sequence Generator and Chaotic Measurement Matrix.

In this paper, a new image encryption transmission algorithm based on the parallel mode is proposed. This algorithm aims to improve information transmission efficiency and security based on existing hardware conditions. To improve efficiency, this paper adopts the method of parallel compressed sensing to realize image transmission. Compressed sensing can perform data sampling and compression at a rate much lower than the Nyquist sampling rate. To enhance security, this algorithm combines a sequence signal generator with chaotic cryptography. The initial sensitivity of chaos, used in a measurement matrix, makes it possible to improve the security of an encryption algorithm. The cryptographic characteristics of chaotic signals can be fully utilized by the flexible digital logic circuit. Simulation experiments and analyses show that the algorithm achieves the goal of improving transmission efficiency and has the capacity to resist illegal attacks.

Prognostic Impact of DHRS9 Overexpression in Pancreatic Cancer.

PURPOSE: Pancreatic cancer (PC) has poor prognosis despite systemic treatment. Dehydrogenase/reductase member 9 (DHRS9) has been reported to be involved in many events of tumorigenesis, but its prognostic impact in PC remains undetermined. Thus, this study aimed to explore the association between DHRS9 expression and the prognosis of PC and investigate the possible mechanism by which DHRS9 is involved in PC progression. PATIENTS AND METHODS: The study used data: from Gene Expression Omnibus (GEO) and our institution to compare the DHRS9 expression between PC and adjacent normal tissues; from The Cancer Genome Atlas (TCGA) and our institution to assess the clinicopathological characteristics and prognosis of PC patients in high and low DHRS9 expression groups; and from TCGA to predict the potential mechanism of DHRS9 in PC. Western blot assay was used to identify DHRS9 expression in specimens collected from five patients who underwent surgery in our institute. Furthermore, immunohistochemistry (IHC) was then used to identify DHRS9 expression in the specimens of 109 patients who underwent surgery at our institute. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of DHRS9 expression among PC patients. RESULTS: All the IHC, Western blot, and GEO datasets indicated that compared to normal tissues, DHRS9 was significantly overexpressed in PC tissues. IHC results demonstrated that the strong intensity of DHRS9 expression was significantly correlated with vascular infiltration (P < 0.05). Further, high DHRS9 expression was identified as a prognostic risk factor for overall survival. Functional analysis of DHRS9 co-expressed genes indicated that DHRS9 was involved in mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway. CONCLUSION: DHRS9 is upregulated in PC tissue, and high DHRS9 expression is correlated with poor prognosis in PC. DHRS9 may affect the oncological process of PC through MAPK/ERK pathway.

Terpenoids From the Coral-Derived Fungus Trichoderma harzianum (XS-20090075) Induced by Chemical Epigenetic Manipulation.

The soft coral-derived fungus Trichoderma harzianum (XS-20090075) was found to be a potential strain to produce substantial new compounds in our previous study. In order to explore its potential to produce more metabolites, chemical epigenetic manipulation was used on this fungus to wake its sleeping genes, leading to the significant changes of its secondary metabolites by using a histone deacetylase (HDAC) inhibitor. The most obvious difference was the original main products harziane diterpenoids were changed into cyclonerane sesquiterpenoids. Three new terpenoids were isolated from the fungal culture treated with 10 µM sodium butyrate, including cleistanthane diterpenoid, harzianolic acid A (1), harziane diterpenoid, harzianone E (2), and cyclonerane sesquiterpenoid, 3,7,11-trihydroxy-cycloneran (3), together with 11 known sesquiterpenoids (4-14). The absolute configurations of 1-3 were determined by single-crystal X-ray diffraction, ECD and OR calculations, and biogenetic considerations. This was the first time to obtain cleistanthane diterpenoid and africane sesquiterpenoid from genus Trichoderma, and this was the first chlorinated cleistanthane diterpenoid. These results demonstrated that the chemical epigenetic manipulation should be an efficient technique for the discovery of new secondary metabolites from marine-derived fungi.

The long noncoding RNA TUG1 is required for TGF-ß/TWIST1/EMT-mediated metastasis in colorectal cancer cells.

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide, and metastasis is the major cause of CRC-related mortality. Transforming growth factor-beta (TGF-ß) has a central role not only in the regulation of the normal colon but also in the development and metastasis of CRC. However, TGF-ß is not considered an ideal therapeutic target because it shows both pro-tumorigenic and anti-tumorigenic activity, depending on the tumor stage. Therefore, it is important to find a downstream signaling component of TGF-ß that can be targeted to impair CRC metastasis. Here, we show that TGF-ß promotes CRC migration and upregulates the expression of long-noncoding RNA Taurine Upregulated Gene 1 (TUG1). TUG1 knockdown inhibited migration, invasion, and epithelial-mesenchymal transition (EMT) of CRC cells in vitro, and reduced CRC lung metastasis in vivo. TGF-ß induced metastasis, and TUG1 knockdown inhibited these effects. In addition, TGF-ß could not reverse the anti-metastasis effects of TUG1 knockdown. These data demonstrate that TUG1 is a downstream molecular of TGF-ß. Moreover, TWIST1 expression was increased with TGF-ß treatment, and TUG1 knockdown decreased TWIST1 expression in CRC cells. TWIST1 knockdown inhibited invasion and EMT in CRC cells; these effects were not changed by simultaneous TUG1 knockdown, indicating that TWIST1 is a downstream mediator of TUG1. Moreover, TUG1 was significantly overexpressed in CRC patients. In conclusion, TGF-ß promotes metastasis of CRC via a TUG1/TWIST1/EMT signaling pathway. TUG1 may be a promising drug target to inhibit TGF-ß pathway activation in the treatment of CRC.

Co-cultivation With 5-Azacytidine Induced New Metabolites From the Zoanthid-Derived Fungus Cochliobolus lunatus.

The zoanthid-derived fungus Cochliobolus lunatus (TA26-46) has been proven to be a source of bioactive 14-membered resorcylic acid lactones (RALs). In the present study, chemical epigenetic manipulation was applied to this fungal strain with a DNA methyltransferase inhibitor resulting in the significant changes of the secondary metabolites. Cultivation of C. lunatus (TA26-46) with 10 µM 5-azacytidine in Czapek-Dox liquid medium led to the isolation of new types of metabolites, including two α-pyrones, cochliobopyrones A (1) and B (2), along with three isocoumarins (3-5) and one chromone (6). The planar structures of the new compounds (1-2) were elucidated by comprehensive analyses of NMR and HRESIMS data. Their challenging relative configurations were established by a combination of acetonide reaction, coupling constants and NOESY correlations analysis, and DP4+ probability calculation. Their absolute configurations were determined by comparing with the ECD calculation data of the fragment molecules, 6-(1,2-dihydroxypropyl)-4-methoxy-2H-pyran-2-ones. It is the first time to obtain α-pyrone compounds with the epoxy ring or bromine atom on the seven-numbered side chain. It could be concluded that chemical epigenetic agents could induce C. lunatus to produce new types of secondary metabolites differing from its original products (RALs).

Harzianumnones A and B: two hydroxyanthraquinones from the coral-derived fungus Trichoderma harzianum.

Two new hydroxyanthraquinones, harzianumnones A (1) and B (2), together with seven known analogs (3-9), were isolated from the soft coral-derived fungus Trichoderma harzianum (XS-20090075). Their chemical structures were elucidated by extensive spectroscopic investigation. The absolute configurations of 1 and 2 were determined by ECD calculation and single-crystal X-ray diffraction. Compounds 1 and 2 were identified as a pair of epimers, which are the first example of hydroanthraquinones from T. harzianum. Compounds 7 and 8 exhibited cytotoxicity against hepatoma cell line HepG2 with IC50 values of 2.10 and 9.39 µM, respectively. Compound 7 was still found to show cytotoxicity against cervical cancer cell line HeLa with an IC50 value of 8.59 µM.

Med15B Regulates Acid Stress Response and Tolerance in Candida glabrata by Altering Membrane Lipid Composition.

Candida glabrata is a promising producer of organic acids. To elucidate the physiological function of the Mediator tail subunit Med15B in the response to low-pH stress, we constructed a deletion strain, C. glabratamed15BΔ, and an overexpression strain, C. glabrata HTUΔ/CgMED15B Deletion of MED15B caused biomass production, glucose consumption rate, and cell viability to decrease by 28.3%, 31.7%, and 26.5%, respectively, compared with those of the parent (HTUΔ) strain at pH 2.0. Expression of lipid metabolism-related genes was significantly downregulated in the med15BΔ strain, whereas key genes of ergosterol biosynthesis showed abnormal upregulation. This caused the proportion of C18:1 fatty acids, the ratio of unsaturated to saturated fatty acids (UFA/SFA), and the total phospholipid content to decrease by 11.6%, 27.4%, and 37.6%, respectively. Cells failed to synthesize fecosterol and ergosterol, leading to the accumulation and a 60.3-fold increase in the concentration of zymosterol. Additionally, cells showed reductions of 69.2%, 11.6%, and 21.8% in membrane integrity, fluidity, and H+-ATPase activity, respectively. In contrast, overexpression of Med15B increased the C18:1 levels, total phospholipids, ergosterol content, and UFA/SFA by 18.6%, 143.5%, 94.5%, and 18.7%, respectively. Membrane integrity, fluidity, and H+-ATPase activity also increased by 30.2%, 6.9%, and 51.8%, respectively. Furthermore, in the absence of pH buffering, dry weight of cells and pyruvate concentrations were 29.3% and 61.2% higher, respectively, than those of the parent strain. These results indicated that in C. glabrata, Med15B regulates tolerance toward low pH via transcriptional regulation of acid stress response genes and alteration in lipid composition.IMPORTANCE This study explored the role of the Mediator tail subunit Med15B in the metabolism of Candida glabrata under acidic conditions. Overexpression of MED15B enhanced yeast tolerance to low pH and improved biomass production, cell viability, and pyruvate yield. Membrane lipid composition data indicated that Med15B might play a critical role in membrane integrity, fluidity, and H+-ATPase activity homeostasis at low pH. Thus, controlling membrane composition may serve to increase C. glabrata productivity at low pH.

Decreased expression of semaphorin 3D is associated with genesis and development in colorectal cancer.

BACKGROUND: Semaphorin 3D (SEMA3D) plays important roles in the genesis and progress of many cancers. However, the relationship between SEMA3D and colorectal cancer (CRC) remains unknown. The aim of this study was to investigate whether SEMA3D can be used as a predictive marker for the diagnosis, metastasis, and prognosis of CRC by assessing the expression of SEMA3D in the tissues and serum of CRC patients. METHODS: Real-time quantitative polymerase chain reaction (qPCR) was used to measure the expression of SEMA3D mRNA in 100 CRC tissues and matched normal tissues. qPCR was also used to detect the expression of SEMA3D mRNA in the CRC cell line RKO. RKO cells were transfected with SEMA3D small-interring RNA (siRNA) to interfere with endogenous SEMA3D. The migratory ability of control and SEMA3D siRNA-transfected RKO cells was determined by transwell assays. Enzyme-linked immunosorbent assay (ELISA) was utilized to detect the levels of SEMA3D in the serum of 80 CRC patients and 100 normal healthy controls. The expression of SEMA3D in 215 CRC tissues was assessed using immunohistochemistry (IHC). Then, statistical analyses were adopted to assess SEMA3D protein levels and clinical pathological characteristics. RESULTS: The mRNA expression of SEMA3D was significantly lower in CRC tissues than in paired normal tissues (t = 5.027, P < 0.0001). Compared with normal healthy controls, the serum levels of SEMA3D were decreased significantly in CRC patients (t = 3.656, P = 0.0003). The expression of SEMA3D protein was linked to lymph node metastasis, and low expression led to lymph node metastasis (χ 2 = 8.415, P = 0.004). The expression of SEMA3D in CRC tissues was a favorable prognostic factor. Patients with a higher expression of SEMA3D experienced longer survival (P = 0.002, log-rank [Mantel-Cox]; Kaplan-Meier). In addition, multivariate Cox's proportional hazard model revealed that SEMA3D is an independent prognostic marker (hazard ratio [HR] 1.818, 95% CI 1.063-3.110, P = 0.029). Moreover, transwell assays showed that knocking down SEMA3D significantly increased RKO cell migration (t = 9.268, P = 0.0008). CONCLUSIONS: SEMA3D might function as a tumor suppressor during the formation and development of CRC. SEMA3D might become a predictive marker for the diagnosis, metastasis, and prognosis of CRC and provide a novel target for the prevention and treatment of CRC.