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C-reactive protein (CRP) is a non-specific diagnostic marker of inflammation and an evolutionarily conserved protein with roles in innate immune signaling. Natural CRP is composed of five identical globular subunits that form a pentamer, but the role of pentameric CRP (pCRP) during inflammatory pathogenesis remains controversial. Emerging evidence suggests that pCRP can be dissociated into monomeric CRP (mCRP) that has major roles in host defenses and inflammation. Here, we discuss our current knowledge of the dissociation mechanisms of pCRP and summarize the stepwise conformational transition model to mCRP to elucidate how CRP dissociation contributes to proinflammatory activity. These discussions will evoke new understanding of this ancient protein.

Clinical evidence indicates that drug resistance is a great obstacle in breast cancer therapy. It renders the disease uncontrollable and causes high mortality. Multiple mechanisms contribute to the development of drug resistance, but the underlying cause is usually a shift in the genetic composition of tumor cells. It is increasingly feasible to engineer the genome with the clustered regularly interspaced short palindromic repeats (CRISPR)/associated (Cas)9 technology recently developed, which might be advantageous in overcoming drug resistance. This article discusses how the CRISPR/Cas9 system might revert resistance gene mutations and identify potential resistance targets in drug‐resistant breast cancer. In addition, the challenges that impede the clinical applicability of this technology and highlight the CRISPR/Cas9 systems are presented. The CRISPR/Cas9 system is poised to play an important role in preventing drug resistance in breast cancer therapy and will become an essential tool for personalized medicine. The application of the CRISPR/Cas9 system for editing drug resistant genes and identifying potential targets in drug resistant breast cancer is discussed. It is proposed that, with further development, the CRISPR/Cas9 system can play a more important role in preventing drug resistance in breast cancer therapy and that it will become essential in personalized and precision medicine.

Human mesenchymal stem cells (MSCs) are adult multipotent stem cells which can be isolated from bone marrow, adipose tissue as well as other tissues and have the capacity to differentiate into a variety of mesenchymal cell types such as adipocytes, osteoblasts and chondrocytes. Differentiation of stem cells into mature cell types is guided by growth factors and hormones, but recent studies suggest that metabolic shifts occur during differentiation and can modulate the differentiation process. We therefore investigated mitochondrial biogenesis, mitochondrial respiration and the mitochondrial membrane potential during adipogenic differentiation of human MSCs. In addition, we inhibited mitochondrial function to assess its effects on adipogenic differentiation. Our data show that mitochondrial biogenesis and oxygen consumption increase markedly during adipogenic differentiation, and that reducing mitochondrial respiration by hypoxia or by inhibition of the mitochondrial electron transport chain significantly suppresses adipogenic differentiation. Furthermore, we used a novel approach to suppress mitochondrial activity using a specific siRNA-based knockdown of the mitochondrial transcription factor A (TFAM), which also resulted in an inhibition of adipogenic differentiation. Taken together, our data demonstrates that increased mitochondrial activity is a prerequisite for MSC differentiation into adipocytes. These findings suggest that metabolic modulation of adult stem cells can maintain stem cell pluripotency or direct adult stem cell differentiation.

Objective: Our preliminary research indicates that acacetin modulates the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3) inflammasome, providing protection against Alzheimer’s Disease (AD) and cerebral ischemic reperfusion injury. The mechanisms of acacetin to inhibit the activation of the NLRP3 inflammasome remain fully elucidated. This study aims to investigate the effects and potential mechanisms of acacetin on various agonists induced NLRP3 inflammasome activation. Methods: A model for the NLRP3 inflammasome activation was established in mouse bone marrow-derived macrophages (BMDMs) using Monosodium Urate (MSU), Nigericin, Adenosine Triphosphate (ATP), and Pam3CSK4, separately. Western blot analysis (WB) was employed to detect Pro-caspase-1, Pro-Interleukin-1β (Pro-IL-1β) in cell lysates, and caspase-1, IL-1β in supernatants. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measured the release of IL-1β, IL-18, and Tumor Necrosis Factor-alpha (TNF-α) in cell supernatants to assess the impact of acacetin on NLRP3 inflammasome activation. The lactate dehydrogenase (LDH) release was also assessed. The Nuclear Factor Kappa B (NF-κB) and Mitogen-Activated Protein Kinase (MAPK) signaling pathways related proteins were evaluated by WB, and NF-κB nuclear translocation was observed via laser scanning confocal microscopy (LSCM). Disuccinimidyl Suberate (DSS) cross-linking was employed to detect oligomerization of Apoptosis-associated Speck-like protein containing a Caspase Recruitment Domain (ASC), and LSCM was also used to observe Reactive Oxygen Species (ROS) production. Inductively Coupled Plasma (ICP) and N-(6-methoxyquinolyl) acetoethyl ester (MQAE) assays were utilized to determined the effects of acacetin on the efflux of potassium (K+) and chloride (Cl-) ions. Results: Acacetin inhibited NLRP3 inflammasome activation induced by various agonists, reducing the release of TNF-α, IL-1β, IL-18, and LDH. It suppressed the expression of Lipopolysaccharides (LPS)-activated Phosphorylated ERK (p-ERK), p-JNK, and p-p38, inhibited NF-κB p65 phosphorylation and nuclear translocation. Acacetin also reduced ROS production and inhibited ASC aggregation, thus suppressing NLRP3 inflammasome activation. Notably, acacetin did not affect K+ and Cl-ions efflux during the activation process. Conclusion: Acacetin shows inhibitory effects on both the priming and assembly processes of the NLRP3 inflammasome, positioning it as a promising new candidate for the treatment of NLRP3 inflammasome-related diseases.

Cisplatin is a widely used drug for the treatment of solid organ cancer, but its renal toxicity cannot be ignored. Amentoflavone (AME), a natural flavonoid compound, has remarkable pharmacological effects, including anti-inflammatory and antioxidative effects. The effect and mechanism of AME on cisplatin-induced acute kidney injury (CI-AKI) remain unclear. We investigated the effect of AME on CI-AKI using the HK-2 cell line and C57BL/6 mice. Renal function, tissue damage, and molecular markers were assessed to explore the effects of AME on oxidative stress and cell death pathways. , AME significantly suppressed the cytotoxic effects of cisplatin on HK-2 cells. Furthermore, AME significantly inhibited cisplatin-induced ferroptosis and PANoptosis (apoptosis, pyroptosis and necroptosis). In mice with acute kidney injury induced by a single intraperitoneal injection of cisplatin, the daily administration of AME during AKI effectively improved renal function and alleviated renal tubular injury, characterized by the normalization of blood urea nitrogen (BUN) and serum creatinine (SCr) levels; it also inhibited cisplatin-induced renal ferroptosis and PANoptosis. AME is a natural antioxidant that activates the Nrf2 antioxidant pathway both and . In Nrf2 knockout mice and knockdown cells, the protective effect of AME against cisplatin-induced nephrotoxicity disappeared. However, after Nrf2 knockout, the effect of AME on ferroptosis completely disappeared, and that on PANoptosis partially disappeared. Amentoflavone has a protective effect on cisplatin-induced acute kidney injury via a mechanism related to the Nrf2-dependent antioxidant pathway and the regulation of ferroptosis and PANoptosis.

Colorectal cancer (CRC) is a prevalent malignancy with significant mortality rates globally. Understanding the genetic and molecular mechanisms underlying CRC development is crucial for improving therapeutic strategies. In this study, we utilized cis-eQTL summary data to identify genes potentially causally associated with CRC. The expression levels of candidate genes in tumor and normal tissues were compared using the GEPIA2 database. The correlations between FUT8 expression and cellular functions, tumor mutation burden, immune checkpoint genes, and immune infiltration were analyzed. Molecular docking was performed to identify potential drugs targeting FUT8, and the effects of the selected drug on cell proliferation were evaluated using the MTT assay. Additionally, the cellular thermal shift assay (CETSA) was employed to assess the interaction between the drug and the target protein. We identified 19 genes with eQTLs potentially associated with CRC, among which six eQTLs were associated with increased CRC risk, including FUT8. FUT8 was significantly overexpressed in CRC tumor tissues and correlated with various cellular functions such as stemness, invasion, EMT, and metastasis. Higher FUT8 expression was associated with higher tumor mutation burden and significant correlations with multiple immune checkpoint genes. Molecular docking identified VE-822 as a promising drug candidate targeting FUT8, which demonstrated inhibitory effects on CRC cell proliferation. The CETSA results indicated that VE ‒ 822 could bind to FUT8 and improve its thermal stability. FUT8 is a crucial gene that causes colon cancer and is linked to tumour immunity. VE-822 is a promising candidate for treating CRC by targeting FUT8.

Due to the interaction between floating weak targets and sea clutter in complex marine environments, it is necessary to distinguish targets and sea clutter from different dimensions by designing universal deep learning models. Therefore, in this paper, we introduce the concept of multimodal data fusion from the field of artificial intelligence (AI) to the marine target detection task. Using deep learning methods, a target detection network model based on the multimodal data fusion of radar echoes is proposed. In the paper, according to the characteristics of different modalities data, the temporal LeNet (T-LeNet) network module and time-frequency feature extraction network module are constructed to extract the time domain features, frequency domain features, and time-frequency features from radar sea surface echo signals. To avoid the impact of redundant features between different modalities data on detection performance, a Self-Attention mechanism is introduced to fuse and optimize the features of different dimensions. The experimental results based on the publicly available IPIX radar and CSIR datasets show that the multimodal data fusion of radar echoes can effectively improve the detection performance of marine floating weak targets. The proposed model has a target detection probability of 0.97 when the false alarm probability is 10−3 under the lower signal-to-clutter ratio (SCR) sea state. Compared with the feature-based detector and the detection model based on single-modality data, the new model proposed by us has stronger detection performance and universality under various marine detection environments. Moreover, the transfer learning method is used to train the new model in this paper, which effectively reduces the model training time. This provides the possibility of applying deep learning methods to real-time target detection at sea.

Background Triple negative breast cancer (TNBC) is a major subtype of breast cancer, with limited therapeutic drugs in clinical. Epidermal growth factor receptor (EGFR) is reported to be overexpressed in various TNBC cells. Cantharidin is an effective ingredient in many clinical traditional Chinese medicine preparations, such as Delisheng injection, Aidi injection, Disodium cantharidinate and vitamin B6 injection. Previous studies showed that cantharidin had satisfactory pharmacological activity on a variety of tumors. In this study, we aimed to study the therapeutic potential of cantharidin for TNBC treatment by targeting EGFR, and expound its novel regulator miR-607. Methods The effect of cantharidin on breast cancer in vivo was evaluated by 4T1 mice model. Then the effects of cantharidin on TNBC cells was assessed by the MTT, colony formation, and AnnexinV-PE/7AAD staining. Cantharidin acts on EGFR were verified using the cell membrane chromatography, RT-PCR, Western blotting, MTT, and so on. Mechanistic studies were explored by dual-luciferase report assay, RT-PCR, western blotting, and immunofluorescence staining assay. Results Cantharidin inhibited TNBC cell growth and induce apoptosis by targeting EGFR. miR-607 was a novel EGFR regulator and exhibited suppressive functions on TNBC cell behaviors. Mechanistic study showed that cantharidin blocked the downstream PI3K/AKT/mTOR and ERK/MAPK signaling pathway. Conclusion Our results revealed that cantharidin may be served as a potential candidate for TNBC treatment by miR-607-mediated downregulation of EGFR. Graphical Abstract

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.

The hypoxia of the tumor microenvironment (TME) seriously restricts the photodynamic therapy (PDT) effect of conventional type‐II photosensitizers, which are highly dependent on O2. In this work, a new type‐I photosensitizer (TPE‐TeV‐PPh3) consisting of a tetraphenylethylene group (TPE) as a bioimaging moiety, triphenyl‐phosphine (PPh3) as a mitochondria‐targeting group, and telluroviologen (TeV2+) as a reactive oxygen species (O2•−, •OH) generating moiety is developed. The luminescence intensity of TPE‐TeV‐PPh3 increased significantly after specific oxidation by excess H2O2 in the TME without responding to normal tissues via the formation of Te═O bond, which can be used for monitoring abnormal H2O2, positioning, and imaging of tumors. TPE‐TeV‐PPh3 with highly reactive radicals generation and stronger hypoxia tolerance realizes efficient cancer cell killing under hypoxic conditions, achieving 88% tumor growth inhibition. Therefore, TPE‐TeV‐PPh3 with low phototoxicity in normal tissue achieves tumor imaging and effective PDT toward solid tumors in response to high concentrations of H2O2 in the TME, which provides a new strategy for the development of type‐I photosensitizers. A new type‐I photosensitizer, TPE‐TeV‐PPh3, based on telluroviologen was synthesized. The luminescence intensity of TPE‐TeV‐PPh3 increased significantly after specific oxidation by excess H2O2 in the tumor microenvironment without responding to normal tissues, which can be used for the positioning and imaging of tumors. The light‐reduced generation of telluroviologen cationic radicals which could react with O2 to form ROS (O2•−, •OH) efficiently via electron transfer mechanism, realizes efficient cancer cell killing under hypoxic conditions, achieving 88% tumor growth inhibition.