Targeting macrophagic RasGRP1 with catechin hydrate ameliorates sepsis-induced multiorgan dysfunction.

BACKGROUND: The proinflammatory response induced by macrophages plays a crucial role in the development of sepsis and the resulting multiorgan dysfunction. Identifying new regulatory targets for macrophage homeostasis and devising effective treatment strategies remains a significant challenge in contemporary research. PURPOSE: This study aims to identify new regulatory targets for macrophage homeostasis and develop effective strategies for treating sepsis. STUDY DESIGN AND METHODS: Macrophage infiltration in septic patients and in lungs, kidneys, and brains of caecum ligation and puncture (CLP)-induced septic mice was observed using CIBERSORT and immunofluorescence (IF). Upon integrating the MSigDB database and GSE65682 dataset, differently expressed macrophage-associated genes (DEMAGs) were identified. Critical DEMAGs were confirmed through machine learning. The protein level of the critical DEMAG was detected in PBMCs of septic patients, RAW264.7 cells, and mice lungs, kidneys, and brains using ELISA, western blot, immunohistochemistry, and IF. siRNA was applied to investigate the effect of the critical DEMAG in RAW264.7 cells. A natural product library was screened to find a compound targeting the critical DEMAG protein. The binding of compounds and proteins was analyzed through molecular docking, molecular dynamics simulations, CETSA, and MST analysis. The therapeutic efficacy of the compounds against sepsis was then evaluated through in vitro and in vivo experiments. RESULTS: Macrophage infiltration was inversely correlated with survival in septic patients. The critical differentially expressed molecule RasGRP1 was frequently observed in the PBMCs of septic patients, LPS-induced RAW264.7 cells, and the lungs, kidneys, and brains of septic mice. Silencing RasGRP1 alleviated proinflammatory response and oxidative stress in LPS-treated RAW264.7 cells. Catechin Hydrate (CH) was identified as an inhibitor of RasGRP1, capable of maintaining macrophage homeostasis and mitigating lung, kidney, and brain damage during sepsis. CONCLUSION: This study demonstrates that RasGRP1, a novel activator of macrophage proinflammatory responses, plays a crucial role in the excessive inflammation and oxidative stress associated with sepsis. CH shows potential for treating sepsis by inhibiting RasGRP1.

Danlou tablet alleviates sepsis-induced acute lung and kidney injury by inhibiting the PARP1/HMGB1 pathway.

Background: Sepsis-associated acute lung injury (ALI) and acute kidney injury (AKI) are common complications that significantly impact patient prognosis. Danlou tablet (DLT) is a traditional herbal preparation with anti-inflammatory and antioxidant properties. However, its therapeutic potential in sepsis remains unknown. Methods: The impact of DLT on ALI and AKI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of DLT on macrophages were observed through LPS-stimulated RAW264.7 cell line. Inflammatory cytokines, oxidative stress indicators, HE, PAS, and DHE staining, lung wet-to-dry weight ratio, and serum creatinine and urea nitrogen levels were used to assess tissue injury. Network pharmacology, molecular docking, and molecular dynamics simulations were used to explore the potential regulatory mechanisms of DLT in sepsis. Western blot and immunohistochemical staining were used to validate the expression of mechanism-related proteins. Results: DLT inhibited the inflammatory response and oxidative stress, improved structural and functional abnormalities in lung and kidney tissues in CLP mice, and alleviated pro-inflammatory responses of LPS-stimulated macrophages. PARP1 and HMGB1 were identified as key regulatory targets. The results of in vitro and in vivo experiments suggest that DLT can effectively inhibit PARP1/HMGB1 and improve sepsis-associated ALI and AKI. Conclusion: The present study demonstrated that DLT suppressed pro-inflammatory responses of macrophage and alleviated ALI and AKI in the CLP mice by inhibiting the transition activation of PARP1/HMGB1. These findings partially elucidate the mechanism of DLT in sepsis-associated ALI and AKI and further clarify the active components of DLT, thereby providing a scientific theoretical basis for treating sepsis with DLT.

QiShenYiQi pills preserve endothelial barrier integrity to mitigate sepsis-induced acute lung injury by inhibiting ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: The QiShengYiQi pill (QSYQ) is a traditional Chinese medicinal formulation. The effectiveness and safety of QSYQ in treating respiratory system disorders have been confirmed. Its pharmacological actions include anti-inflammation, antioxidative stress, and improving energy metabolism. However, the mechanism of QSYQ in treating sepsis-induced acute lung injury (si-ALI) remains unclear. AIM OF THE STUDY: Si-ALI presents a clinical challenge with high incidence and mortality rates. This study aims to confirm the efficacy of QSYQ in si-ALI and to explore the potential mechanisms, providing a scientific foundation for its application and insights for optimizing treatment strategies and identifying potential active components. MATERIALS AND METHODS: The impact of QSYQ on si-ALI was evaluated using the cecal ligation and puncture (CLP) experimental sepsis animal model. The effects of QSYQ on endothelial cells were observed through coculturing with LPS-stimulated macrophage-conditioned medium. Inflammatory cytokine levels, HE staining, Evans blue staining, lung wet/dry ratio, and cell count and protein content in bronchoalveolar lavage fluid were used to assess the degree of lung injury. Network pharmacology was utilized to investigate the potential mechanisms of QSYQ in treating si-ALI. Western blot and immunofluorescence analyses were used to evaluate barrier integrity and validate mechanistically relevant proteins. RESULTS: QSYQ reduced the inflammation and alleviated pulmonary vascular barrier damage in CLP mice (all P < 0.05). A total of 127 potential targets through which QSYQ regulates si-ALI were identified, predominantly enriched in the RAGE pathway. The results of protein-protein interaction analysis suggest that COX2, a well-established critical marker of ferroptosis, is among the key targets. In vitro and in vivo studies demonstrated that QSYQ mitigated ferroptosis and vascular barrier damage in sepsis (all P < 0.05), accompanied by a reduction in oxidative stress and the inhibition of the COX2 and RAGE (all P < 0.05). CONCLUSIONS: This study demonstrated that QSYQ maintains pulmonary vascular barrier integrity by inhibiting ferroptosis in CLP mice. These findings partially elucidate the mechanism of QSYQ in si-ALI and further clarify the active components of QSYQ, thereby providing a scientific theoretical basis for treating si-ALI with QSYQ.

NDUFC2 deficiency exacerbates endothelial mesenchymal transformation during ischemia-reperfusion via NLRP3.

Ischemic stroke is the main type of cerebrovascular disease. Emergency thrombectomy combined with medication therapy is currently the primary treatment for stroke. Inflammation and oxidative stress induced by ischemia-reperfusion cause secondary damage to blood vessels, especially endothelial mesenchymal transformation (EndoMT). However, much is still unclear about the role of EndoMT in ischemia-reperfusion. In this study, an in vivo ischemia-reperfusion model was established by transient middle cerebral artery occlusion (tMCAO) in wild-type (WT) C57BL/6 mice and NLRP3 (NOD-like receptor thermal protein domain associated protein 3) knockout (KO) C57BL/6 mice. An in vitro ischemia-reperfusion model was established by oxygen glucose deprivation and reoxygenation (OGD/R) of human brain microvascular endothelial cells (HBMECs). α-SMA (alpha smooth muscle actin), CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1/CD31), NDUFC2 (NADH: ubiquinone oxidoreductase subunit C2), and NLRP3 were used to evaluate EndoMT and inflammation. Real-time PCR measured superoxide dismutase 1 (SOD1) and catalase (CAT) mRNA expression to evaluate oxidative stress levels. NLRP3 was activated by ischemia-reperfusion injury and NLRP3 inactivation inhibited the EndoMT in tMCAO mice. Further experiments demonstrated that OGD/R treatment induced NLRP3 activation and EndoMT in HBMECs, which resulted in NDUFC2 deficiency. NDUFC2 overexpression suppressed NLRP3 activation and EndoMT in HBMECs induced by OGD/R. Moreover, NDUFC2 overexpression rescued SOD1 and CAT mRNA expression. These results demonstrated that NDUFC2 deficiency decreased the antioxidant levels, leading to NLRP3 activation and EndoMT during ischemia-reperfusion injury and suggesting that NDUFC2 is a potential drug target for the treatment of ischemic stroke.

68Ga-FAPI PET/CT Imaging of Intracranial Syphilitic Gumma: Comparison to 18F-FDG PET/CT.

ABSTRACT: Intracranial syphilitic gumma is a rare neurological disease. We present 68Ga-DOTA-FAPI-04 and 18F-FDG PET/CT findings of intracranial syphilitic gumma in a 46-year-old man with HIV. In this case, 68Ga-DOTA-FAPI-04 PET/CT outperforms 18F-FDG in helping to visualizing syphilitic gumma. Syphilitic gumma can also cause increase FAPI activity. Our findings suggest the potential value of 68Ga-DOTA-FAPI-04 in the diagnosis of syphilis.

Increased FAPI Activity in Pulmonary Tuberculosis.

ABSTRACT: A 50-year-old man presented with cough and hemoptysis for 1 month. Chest CT showed an irregular mass in the right lung, with enlarged lymph nodes in the mediastinum and right hilum. These findings were suggestive of lung cancer with lymph node metastases. The patient was subsequently enrolled in a 68Ga-DOTA-FAPI-04 PET/CT clinical trial. 68Ga-DOTA-FAPI-04 PET/CT revealed a mass in the upper lobe of right lung, with intense tracer uptake. Meanwhile, PET/CT showed enlarged lymph nodes in the mediastinum and right hilum, with mild FAPI uptake. However, pathological examination confirmed the mass was tuberculous granuloma.

Increased 68Ga-FAPI Uptake in Psammomatous Meningioma in a Patient With Gallbladder Cancer.

ABSTRACT: A 70-year-old woman with a gallbladder mass was enrolled in our clinical trial of 68Ga-FAPI PET/CT study in tumors. Increased tracer uptake was noted in the gallbladder. In addition, focal uptake was localized in a lesion beside the falx cerebri. According to the location and radiological and clinical characteristics, a diagnosis of meningioma was made.

68Ga-FAPI-04 PET/CT in the Detection of Non-FDG-Avid Solid Pseudopapillary Neoplasm of the Pancreas.

ABSTRACT: Solid pseudopapillary neoplasm of the pancreas is a rare tumor. A 46-year-old woman presented with chest pain for 6 months. Chest CT revealed a large mass of the right mediastinum. Then, she underwent 18F-FDG and 68Ga-FAPI-04 PET/CT scans for staging. However, we accidentally found that a non-FDG focus nodule in the body of the pancreas with elevated FAPI activity. Finally, biopsy of the nodule in the body of the pancreas confirmed the diagnosis of solid pseudopapillary neoplasm.

A systematic review of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in the diagnostic value of malignant tumor bone metastasis.

Objective: This study aims to perform a systemic analysis of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography (PET)/computerized tomography (CT) and [18F]FDG PET/CT for the diagnosis of malignant tumor bone metastasis based on existing clinical evidence. Methods: This systematic review followed the guidelines of the Preferred Reporting Project (PRISMA) for systematic reviews and meta-analysis. This is a retrospective study of articles published in PubMed. Embase was searched online from the start of May 2022. The main endpoints were the maximum standardized uptake value and the tumor-to-background ratio to determine the examination performance of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG for bone transfer stoves. Based on the entry and discharge standards, two researchers extracted documents and data and then performed the quality evaluation. Results: A total of eight studies on the metastasis of malignant tumors on bone were included, which involved 358 patients in the final analysis. Conclusion: [68Ga]Ga-DOTA-FAPI-04 showed better detection performance for bone metastasis. The sensitivity of [68Ga]Ga-DOTA-FAPI-04 for the diagnosis of the primary tumor was higher than that of [18F]FDG, whereas the specificity of [18F]FDG was higher than that of [68Ga]Ga-DOTA-FAPI-04. However, further randomized controlled trials and prospective clinical trials are warranted to compare the diagnostic performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT and [18F]FDG PET/CT. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022313019).

Identification of the key ferroptosis-related genes involved in sepsis progression and experimental validation in vivo.

Background: Ferroptosis has a vital role in sepsis, but the mechanism is not known. Understanding the mechanism of ferroptosis during sepsis will aid in developing improved therapeutic strategies. Methods: We used the Gene Expression Omnibus database and FerrDb database to obtain ferroptosis-related differentially expressed genes (DEGs) between sepsis patients and healthy volunteers (HVs). Analyses of PPI networks, functional enrichment, as well as use of the MCODE algorithm were used to identify key ferroptosis-related DEGs. Expression of key ferroptosis-related DEGs was verified using: GSE57065 and GSE65682 datasets; rats in which ferroptosis was induced with erastin; sepsis-induced acute lung injury (siALI) rats. The effects of acupoint catgut embedding (ACE) on ferroptosis and expression of key ferroptosis-related DEGs in the lungs of siALI rats were also observed. A Cox proportional hazard model was used to verify the effect of key ferroptosis-related DEGs on the survival of sepsis patients. Cytoscape was used to construct ceRNA networks and gene-transcription factor networks. Results: Between sepsis patients and HVs, we identified 33 ferroptosis-related DEGs. According to analyses of PPI networks and the MCODE algorithm, we obtained four modules, of which the most significant module contained nine ferroptosis-related DEGs. Functional-enrichment analyses showed that four of the nine DEGs were enriched in the MAPK signaling pathway: MAPK14, VEGFA, TGFBR1, and DUSP1. We verified expression of these four genes in GSE57065 and GSE65682 datasets and ferroptosis rats. In addition, expression of these four genes and that of the oxidative-stress indicators GSSG and MDA was upregulated, and glutathione peroxidase-4 (GPX4) expression was downregulated, in siALI rats, but ACE reversed these changes. The Cox proportional hazard model showed that survival of sepsis patients in the high-risk group was shorter than that in the low-risk group. We found that the XIST-hsa-let-7b-5p-TGFBR1/DUSP1 ceRNA network and transcription factor E2F1 may be important regulators of these four DEGs. Conclusion: Our results suggest that MAPK14, VEGFA, TGFBR1, and DUSP1 may be key regulatory targets of ferroptosis in sepsis, and that ACE pretreatment may be antioxidant treatment for sepsis and alleviate ferroptosis. These findings provide a basis for further ferroptosis-related study in sepsis and provide new targets for its treatment.

Cross-correlation effects in the solution NMR spectra of near-equivalent spin-1/2 pairs.

The nuclear magnetic resonance (NMR) spectra of spin-1/2 pairs contain four peaks, with two inner peaks much stronger than the outer peaks in the near-equivalence regime. We have observed that the strong inner peaks have significantly different linewidths when measurements were performed on a 13C2-labelled triyne derivative. This linewidth difference may be attributed to strong cross-correlation effects. We develop the theory of cross-correlated relaxation in the case of near-equivalent homonuclear spin-1/2 pairs, in the case of a molecule exhibiting strongly anisotropic rotational diffusion. Good agreement is found with the experimental NMR lineshapes.

Elevated 68 Ga-FAPI Uptake by Primary Benign Intraosseous Meningioma.

ABSTRACT: Intraosseous meningioma is an extremely rare benign tumor. We present the 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/CT findings of primary intraosseous meningioma in a 71-year-old woman. 68 Ga-FAPI PET/CT revealed an intraosseous mass in the right parietal bone with increased FAPI activity. Primary skull malignancy was suspected. However, pathological examination after resection of the mass in the right parietal bone confirmed the diagnosis of benign meningioma (WHO I). A final diagnosis of benign intraosseous meningioma was made.

Intense 68Ga-FAPI Uptake in a Patient With Myositis Ossificans: Mimicking Bone Malignancy.

ABSTRACT: A 72-year-old man presented with right hip pain, difficulty in walking, and a mass in his right hip for 3 months. CT suggested osteonecrosis of the right femoral head and a mass in the right hip with calcification. A malignancy was suspected, and the patient was subsequently enrolled in the clinical trial of 68Ga-FAPI. 68Ga-FAPI PET/CT showed a mass in his right hip with intense FAPI activity. It was also highly suggestive of malignancy. The pathological examination after right-hip surgery confirmed the diagnosis of myositis ossificans.

Schmorl Node Can Cause Increased 68Ga-FAPI Activity on PET/CT.

ABSTRACT: 68Ga-FAPI is a newly developed tumor imaging agent with promising clinical applications. However, benign lesions may also show increased FAPI activity. We accidentally discovered that Schmorl node expressed FAPI activity in a patient with sweat gland cancer. Thus, greater awareness is needed that Schmorl nodes are a potential reason for false-positive uptake on 68Ga-FAPI PET/CT.

Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a meta-analysis of the efficacy and safety of 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer based on existing clinical evidence. METHODS: Search for retrospective studies about 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer from establishment to July 2021 in PubMed and EMBASE. The primary endpoint was 225Ac-PSMA-617 biochemical response evaluation criteria after treatment [any prostate specific antigen (PSA) decrease and PSA decrease >50% from baseline] to evaluate the treatment effect. Secondary endpoints included assessment of overall survival (OS), progression-free survival (PFS), molecular response, and toxicity for all studies. Two researchers conducted literature screening, data extraction and quality evaluation according to the inclusion and exclusion criteria. Use stata16.0 software for analysis, fixed-effects model for data merging and forest plots for display. RESULTS: A total of 6 retrospective studies, namely, 201 patients, were included in the final analysis. The pooled proportions of patients with decreased PSA and PSA decreased by more than 50% were 87.0% (95% confidence interval, 0.820 to 0.920) and 66.1% (95% confidence interval, 0.596 to 0.726), respectively. The pooled proportions of OS and PFS were 12.5 months (95%CI: 6.2-18.8 months) and 9.1 months (95%CI: 2.6-15.7 months). The patients showing molecular responses were 54% (95% confidence interval: 25-84%). In all studies, the most common side effect of 225Ac-PSMA-617 TAT was xerostomia, with any degree of xerostomia occurring in 77.1% (155 out of 201), and grade III only accounted for 3.0%. The second was 30.3% (61 out of 201) anemia of any degree, and grade III accounts for 7.5% (15 out of 201). Grade III leukopenia and thrombocytopenia were 4.5% (9 out of 201) and 5.5% (11 out of 201), respectively. Only 6 (3.0%) of 201 patients had Grade III nephrotoxicity. CONCLUSION: 225Ac-PSMA-617 is an effective and safe treatment option for mCRPC patients, and the toxicity caused by it is relatively low. However, future randomized controlled trials and prospective trials are required in the future to judge the therapeutic effects and survival benefits compared with existing clinical treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021281967.

Primary Adrenal Sarcomatoid Carcinoma Detected by 18F-FDG PET/CT.

ABSTRACT: Adrenal sarcomatoid carcinoma is extremely rare. A 53-year-old man was admitted to our hospital due to pain in the upper right abdomen for 1 month. Abdominal CT revealed a huge mass in the right adrenal gland, and a malignancy was suspected. 18F-FDG PET/CT showed a mass in the right adrenal gland with intense FDG uptake. Finally, postoperative pathology confirmed the diagnosis of adrenal sarcomatoid carcinoma.

Progressive Multifocal Leukoencephalopathy Mimicking Malignancy on 68Ga-FAPI PET/CT: Potential Advantages of FAPI.

ABSTRACT: A 43-year-old man presented with weakness in his right upper limb for 2 months. Head MRI showed intracranial multiple abnormal signal foci. Malignancy was suspected. The patient was subsequently enrolled in the clinical trial of 68Ga-FAPI PET/CT. 68Ga-FAPI PET/CT showed intracranial multiple FAPI-avid foci. It was also highly suggestive of malignancy. However, the combination of clinical manifestations, imaging findings, cerebral spinal fluid examinations, and effective immunotherapy confirmed the diagnosis of progressive multifocal leukoencephalopathy. 68Ga-FAPI may have potential advantages in the diagnosis of progressive multifocal leukoencephalopathy.

Bone Tuberculous Granulomatous Inflammation Mimicking Malignancy on 68Ga-FAPI PET/CT.

ABSTRACT: A 50-year-old woman presented with back pain for 1 month. Chest CT showed osteolytic destruction of T6 vertebral body. A malignancy was suspected. The patient was subsequently enrolled in the clinical trial of 68Ga-FAPI PET/CT. 68Ga-FAPI PET/CT revealed multiple bone destruction with increased FAPI activity. It was also highly suggestive of malignancy or metastases. However, pathological examination after T6 vertebral surgery confirmed the diagnosis of tuberculous granulomatous inflammation.

Increased 68Ga-FAPI Uptake in Facet Joint Osteoarthritis in a Patient With Esophageal Cancer.

ABSTRACT: A 69-year-old man presented with newly diagnosed esophageal cancer was enrolled in our clinical trial of 68Ga-FAPI PET/CT study in tumors. Increased tracer uptake was noted in esophageal cancer. In addition, the facet joint osteoarthritis of T7/8 vertebrae also revealed elevated 68Ga-FAPI uptake.

Increased 68Ga-FAPI Activity in Malignant Melanoma of the Nasal Cavity.

ABSTRACT: We report the case of a 56-year-old man who presented with a 1-month history of recurrent right-sided epistaxis. Nasal endoscopy revealed a mass in the right nasal cavity, and CT scans showed a nasal space-occupying lesion. 68Ga-FAPI PET/CT demonstrated a high FAPI uptake of the mass in the right nasal cavity. Biopsy revealed a malignant melanoma.