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Background Currently, the most effective oral targeted therapies for NSCLC in clinical practice are EGFR‐TKIs. However, acquired drug resistance often leads to tumor progression and recurrence. EGFR overexpression and activation of its downstream pathways are primary contributors to both mutations in tumor cells and their development of drug resistance. Silibinin has been identified as a promising agent that can suppress EGFR signaling through multiple mechanisms. However, its poor water solubility and difficulty penetrating cell membranes result in rapid metabolism in vivo, and significantly affect its concentration in the blood. Methods We conducted a comprehensive search of the English PubMed database using various combinations of keywords, including “silibinin,” “epidermal growth factor receptor,” “phosphorylation,” “chemotherapy,” “nano,” and “non‐small cell lung cancer.” The results were then filtered for their relevance and impact on current treatment paradigms. Results This review presents a comprehensive exploration of the mechanisms underlying the EGFR autophosphorylation pathways that contribute to acquire drug resistance in. Additionally, this study delves into the potential of silibinin as a novel therapeutic agent for NSCLC, evaluating its advantages and limitations on the basis of existing research. The majority of the available data suggest that combining silibinin with first‐generation TKIs would yield promising outcomes because of additive or synergistic effects, suggesting that optimizing the time and dosage of each of these treatments is crucial for achieving the best results. Conclusion The existing evidence is inadequate to endorse the clinical application of nano silibinin for NSCLC treatment. Developing multifunctional nanomedicines that incorporate silibinin, EGFR‐TKIs, and other bioactive compounds is a recommended future strategy for NSCLC treatment.

Giardia duodenalis , also known as G . intestinalis or G . lamblia , is the major cause of giardiasis leading to diarrheal disease with 280 million people infections annually worldwide. Extracellular vesicles (EVs) have emerged as a ubiquitous mechanism participating in cells communications. The aim of this study is to explore the roles of G . duodenalis EVs (GEVs) in host-pathogen interactions using primary mouse peritoneal macrophages as a model. Multiple methods of electron microscopy, nanoparticle tracking analysis, proteomic assays, flow cytometry, immunofluorescence, qPCR, western blot, ELISA, inhibition assays, were used to characterize GEVs, and explore its effects on the host cell innate immunity as well as the underlying mechanism using primary mouse peritoneal macrophages. Results showed that GEVs displayed typical cup-shaped structure with 150 nm in diameter. GEVs could be captured by macrophages and triggered immune response by increasing the production of inflammatory cytokines Il1β, Il6, Il10, Il12, Il17, Ifng, Tnf, Il18, Ccl20 and Cxcl2. Furthermore, activation of TLR2 and NLRP3 inflammasome signaling pathways involved in this process. In addition, CA-074 methyl ester (an inhibitor of cathepsin B) or zVAD-fmk (an inhibitor of pan-caspase) pretreatment entirely diminished these effects triggered by GEVs exposure. Taken together, these findings demonstrated that GEVs could be internalized into mouse peritoneal macrophages and regulate host cell innate immunity via TLR2 and NLRP3 inflammasome signaling pathways.

Introduction Acute respiratory distress syndrome (ARDS) is characterized by hypoxemia and increased lung permeability and would result in acute respiratory failure and with high mortality. In patients who survive from acute lung injury (ALI)/ARDS, it is an active process of the transition from injury to resolution depending on the coordinated immune system. The roles of regulatory CD4+T cells (Tregs) are now gradually being clarified during inflammation and resolution of ARDS. However, clear conclusions about roles of Tregs in ALI/ARDS are only a few. Objective This review provides an overview of phenotype, differentiation, and suppressive mechanisms of Tregs and focuses on keys of biology of Tregs in alveolar space during the inflammatory response and resolution of ALI/ARDS. Data Source Literature search of Web of Science, PubMed, and EMBASE was made to find relative articles about Tregs in ALI/ARDS. We used the following search terms: Tregs, ALI, ARDS, inflammation, and resolution. Conclusion More and more studies have indicated Tregs involved in the processes of inflammation and resolution of ALI/ARDS. A deep understanding of the roles of Tregs may indicate new treatments for patients of ARDS. Therapies aimed at expansion or adaptive transfer of Tregs could be an effective therapy to ARDS patients. The roles of regulatory CD4+T lymphocytes (Tregs) are now increasingly being recognized during resolution of ARDS. A dissection of the roles of Tregs may indicate the design of new treatments for ARDS patients. Therapies aimed at expansion or adaptive transfer of Tregs could be an effective therapy to ARDS patients.

Clonorchis sinensis is an important food-borne zoonotic parasite which has been linked to biliary fibrosis and cholangiocarcinoma. However, the details of the pathogenesis of C . sinensis were unclear. To explore the role and regulatory mechanism of toll-like receptor 2 (TLR2) in C . sinensis- induced biliary fibrosis, we established the C . sinensis -infected C57BL/6 mouse model with TLR2 -/- and wild type (WT) mice. The mortality rate, liver lesions, TLR2 and TGF-β1 expression, phosphorylation of Smad2/3, AKT, p38, ERK and p65, and cytokine productions were analyzed. Furthermore, similar parameters were examined in mouse biliary epithelial cells (BECs) co-cultured with C . sinensis excretory/secretory proteins (ESPs). The results showed that TLR2 expression was enhanced significantly in C . sinensis -infected WT mice and mouse BECs. C . sinensis -infected TLR2 -/- mice exhibited an increased weight and a decreased mortality rate; significantly alleviated liver lesions and biliary fibrosis, reduced numbers of myofibroblasts; decreased expression of TGF-β1 and phosphorylation level of AKT, p38 and Smad2/3; significantly decreased production of IL-6, TNF-α and IL-4, while increased production of IFN-γ compared with C . sinensis -infected WT mice. Furthermore, C . sinensis ESPs could activate TLR2-mediated AKT and p38 pathways to increase the production of IL-6 in mouse BECs. In conclusion, these data indicate that C . sinensis infection activated TGF-β1-Smad2/3 through TLR2-mediated AKT and p38 pathways to promote IL-6 production, which resulted in myofibroblast activation and aggravating biliary fibrosis in mice.

Background Infection with Trichomonas vaginalis can lead to cervicitis, urethritis, pelvic inflammatory disease, prostatitis and perinatal complications and increased risk of HIV transmission. Here, we used an RPA-based CRISPR-Cas12a assay system in combination with a lateral flow strip (LFS) (referred to as RPA-CRISPR-Cas12a) to establish a highly sensitive and field-ready assay and evaluated its ability to detect clinical samples. Methods We developed a one-pot CRISPR-Cas12a combined with RPA-based field detection technology for T. vaginalis , chose actin as the target gene to design crRNA and designed RPA primers based on the crRNA binding site. The specificity of the method was demonstrated by detecting genomes from nine pathogens. To improve the usability and visualize the RPA-CRISPR-Cas12a assay results, both fluorescence detection and LFS readouts were devised. Results The RPA-CRISPR-Cas12a assay platform was completed within 60 min and had a maximum detection limit of 1 copy/µl and no cross-reactivity with Candida albicans , Mycoplasma hominis , Neisseria gonorrhoeae , Escherichia coli , Cryptosporidium parvum , G. duodenalis or Toxoplasma gondii after specificity validation. Thirty human vaginal secretions were tested by RPA-CRISPR-Cas12a assays, and the results were read by a fluorescent reporter and LFS biosensors and then compared to the results from nested PCR detection of these samples. Both RPA-CRISPR-Cas12a assays showed 26.7% (8/30) T. vaginalis -positive samples and a consistency of 100% (8/8). The RPA-CRISPR-Cas12a assays had a higher sensitivity than nested PCR (only seven T. vaginalis -positive samples were detected). Conclusions The T. vaginalis RPA-CRISPR-Cas12a assay platform in this study can be used for large-scale field testing and on-site tests without the need for trained technicians or costly ancillary equipment. Graphical abstract

Clonorchis sinensis ( C. sinensis ) is a food-borne zoonotic parasite link to liver fibrosis and cholangiocarcinoma. Limited understanding of its mechanisms in causing liver fibrosis has impeded therapeutic advances for C. sinensis -induced liver lesions. Ferroptosis, a novel form of cell death involving iron overload and lipid peroxidation, exacerbates liver fibrosis; however, its role in C. sinensis infection remains unexplored. In this study, ferroptosis were detected in C. sinensis -infected C57BL/6 mice as well as in AML12 cells stimulated by C. sinensis excretory/secretory products (ESPs). 12 ferroptosis related genes were screened and we found glutathione peroxidase 4 (GPX4, 7 d), solute carrier family 7 member 11 (SLC7A11, 7 d) and nuclear factor erythroid 2 related factor 2 (Nrf2, 35 d) was significantly decreased in mice. Western blot results confirmed C. sinensis and ESPs down-regulated the expression of GPX4, SLC7A11 and Nrf2. GSH depletion, malondialdehyde (MDA) accumulation, mitochondrial structure damage, and iron overload were found in C. sinensis- infected mice and ESPs-stimulated AML12 cells, suggesting that ferroptosis occurred in vivo and in vitro . Treatment with ferroptosis inhibitor Fer-1 in C. sinensis- infected mice alleviated ferroptosis, reduced the productions of IFN-γ, TNF-α, IL-12 and IL-6, and downregulated transforming growth factor (TGF)-β/Smad pathway activation. In AML12 cells, Fer - 1 pretreatment reduced ESPs - induced ferroptosis and IL-6, TNF-α production. Fer - 1 also alleviated liver lesions, reduced parasite load (65%), α-SMA expression and collagen fiber deposition in infected mice. In conclusion, C. sinensis could cause ferroptosis, which promoted the secretions of IL-6 and TNF-α as well as the activation of TGF-β/Smad pathway, leading to exacerbated liver fibrosis.

Giardia duodenalis is an important zoonotic protozoan that mainly causes diarrhea, has a significant negative impact on public health worldwide. Macrophage migration inhibitory factor (MIF) as an inflammatory mediator in both innate and adaptive immune responses, and parasite-derived MIF is involved in inducing the host’s immune response or causing disease. However, the role of G. duodenalis MIF (GdMIF) in giardiasis remains to be elucidated. In the present study, CD74-NF-κB-NLRP3 inflammasome activation induced by rGdMIF was systematically investigated in vitro and in vivo , and its effect on intestinal damage was examined in G. duodenalis- infected gerbils. We found that GdMIF was an exocrine protein with dopamine tautomerase activity. GdMIF could activate NF-κB and the NLRP3 inflammasome, increase GSDMD-processing and promote Lactate Dehydrogenase (LDH) and pro-inflammatory cytokine release. The interaction of CD74 molecule with rGdMIF was validated by Co-IP and BiFC. Furthermore, knockdown of CD74 and NF-κB significantly inhibited NLRP3 inflammasome activation and pro-inflammatory cytokine production in macrophages stimulated by rGdMIF. Gerbils were infected with G. duodenalis in the presence of a GdMIF blocking antibody showed lower NLRP3 expression, and milder intestinal damage compared with that of the normal G. duodenalis infection group. Inhibition of NLRP3 alleviated intestinal damage caused by G. duodenalis infection. In summary, these findings suggest that GdMIF induces NLRP3 inflammasome activation and pyroptosis by interacting with CD74 receptor, subsequently eliciting a pro-inflammatory response which lead to intestinal damage.

Clonorchis sinensis is a zoonotic parasite associated with liver fibrosis and cholangiocarcinoma development. The role of toll-like receptors (TLRs) in C . sinensis infection has not yet been fully elucidated. Here, the TLR3 signaling pathway, cytokine expression and liver fibrosis were examined in C . sinensis- infected wildtype (WT) and TLR3 -/- mice. Polyinosinic-polycytidylic acid (Poly (I:C)) was used to treat C . sinensis infections. The results showed that TLR3 deficiency caused severe clonorchiasis with increased parasite burden, exacerbated proinflammatory cytokine expression and liver lesions, promoted the TGF-β1/Smad2/3 pathway and myofibroblast activation, exacerbated liver fibrosis (compared to WT mice). Poly (I:C) intervention increased the body weight, decreased mouse mortality and parasite burden, reduced liver inflammation, and alleviated C . sinensis- induced liver fibrosis. Furthermore, C . sinensis extracellular vesicles (CsEVs) promote the production of IL-6, TNF in WT biliary epithelial cells (BECs) via p38/ERK pathway, compared with control group, while TLR3 deletion induced much higher levels of IL-6 and TNF in TLR3 -/- BECs than that in WT BECs. Taken together, TLR3 inhibit IL-6 and TNF production via p38/ERK signaling pathway, a phenomenon that resulted in the alleviation of C . sinensis -induced liver fibrosis. Poly (I:C) is a potential treatment for clonorchiasis.

Pentatrichomonas hominis is a parasitic trichomonads protozoa that parasitizes in the colon and cecum of humans and other animals. Our previous studies have demonstrated that infection with P. hominis is associated with the incidence of colon cancer (37.93%). However, the mechanism by which P. hominis infections increase the incidence of colon cancer remains unclear. Previous studies have suggested that certain parasites promote colon cancer by regulating gut microbiota. This study aimed to elucidate whether the association between P. hominis infections and the increased incidence of colon cancer is related to changes in gut microbiota. Therefore, the gut microbiota patients with colon cancer who were infected with P. hominis and uninfected patients with colon cancer were analyzed by 16S rRNA high-throughput sequencing. The results demonstrated that patients with colon cancer who were not infected with P. hominis showed increased gut bacterial diversity, a higher relative abundance of Alcaligenes sp., Leucobacter sp., Paraprevotella sp., Ruminococcaceae UCG-002 , and a significant reduction in the abundance of Veillonella sp., compared to individuals without colon cancer. Additionally, the relative abundance of the Ruminococcaceae UCG-002 and the Eubacterium eligens groups was reduced, while the relative abundance of bacteria associated with colon cancer, including Flavonifractor sp., Lachnoclostridium sp., and the Ruminococcus gnavus group, increased significantly in patients with colon cancer who were infected with P. hominis , compared to those of uninfected patients with colon cancer. In conclusion, these results suggested that P. hominis infections may aggravate the development of colon cancer and the findings provide new insights for subsequent in-depth studies on the pathogenesis, diagnosis, and prevention of colon cancer.

Compared to magnetic resonance imaging (MRI) and X-ray computed tomography (CT), ultrasound imaging is safer, faster, and more widely applicable. However, the use of conventional ultrasound in transcranial brain imaging for adults is predominantly hindered by the high acoustic impedance contrast between the skull and soft tissue. This study introduces a 3D AI algorithm, Brain Imaging Full Convolution Network (BIFCN), combining waveform modeling and deep learning for precise brain ultrasound reconstruction. We constructed a network comprising one input layer, four convolution layers, and one pooling layer to train our algorithm. In the simulation experiment, the Pearson correlation coefficient between the reconstructed and true images was exceptionally high. In the laboratory, the results showed a slightly lower but still impressive coincidence degree for 3D reconstruction, with pure water serving as the initial model and no prior information required. The 3D network can be trained in 8 h, and 10 samples can be reconstructed in just 12.67 s. The proposed 3D BIFCN algorithm provides a highly accurate and efficient solution for mapping wavefield frequency domain data to 3D brain models, enabling fast and precise brain tissue imaging. Moreover, the frequency shift phenomenon of blood may become a hallmark of BIFCN learning, offering valuable quantitative information for whole-brain blood imaging.