Estradiol contributes to sex differences in resilience to sepsis-induced metabolic dysregulation and dysfunction in the heart via GPER-1-mediated PPARδ/NLRP3 signaling.

BACKGROUND AND AIM: Clinically, septic males tend to have higher mortality rates, but it is unclear if this is due to sex differences in cardiac dysfunction, possibly influenced by hormonal variations. Cardiac dysfunction significantly contributes to sepsis-related mortality, primarily influenced by metabolic imbalances. Peroxisome proliferator-activated receptor delta (PPARδ) is a key player in cardiac metabolism and its activation has been demonstrated to favor sepsis outcomes. While estradiol (E2) is abundant and beneficial in females, its impact on PPARδ-mediated metabolism in the heart with regards to sex during sepsis remains unknown. METHODS AND RESULTS: Here, we unveil that while sepsis diminishes PPARδ nuclear translocation and induces metabolic dysregulation, oxidative stress, apoptosis and dysfunction in the heart thereby enhancing mortality, these effects are notably more pronounced in males than females. Mechanistic experiments employing ovariectomized(OVX) mice, E2 administration, and G protein-coupled estrogen receptor 1(GPER-1) knockout (KO) mice revealed that under lipopolysaccharide (LPS)-induced sepsis, E2 acting via GPER-1 enhances cardiac electrical activity and function, promotes PPARδ nuclear translocation, and subsequently ameliorates cardiac metabolism while mitigating oxidative stress and apoptosis in females. Furthermore, PPARδ specific activation using GW501516 in female GPER-1-/- mice reduced oxidative stress, ultimately decreasing NLRP3 expression in the heart. Remarkably, targeted GPER-1 activation using G1 in males mirrors these benefits, improving cardiac electrical activity and function, and ultimately enhancing survival rates during LPS challenge. By employing NLRP3 KO mice, we demonstrated that the targeted GPER-1 activation mitigated injury, enhanced metabolism, and reduced apoptosis in the heart of male mice via the downregulation of NLRP3. CONCLUSION: Our findings collectively illuminate the sex-specific cardiac mechanisms influencing sepsis mortality, offering insights into physiological and pathological dimensions. From a pharmacological standpoint, this study introduces specific GPER-1 activation as a promising therapeutic intervention for males under septic conditions. These discoveries advance our understanding of the sex differences in sepsis-induced cardiac dysfunction and also present a novel avenue for targeted interventions with potential translational impact.

Endogenous H2S-activated Ag nanoparticles embedded in programmed DNA-cubes for specific visualization of colorectal cancer cells.

To avoid the unexpected aggregation and reduce the cytotoxicity of nanomaterials as optical probes in cell imaging applications, we propose a programmed DNA-cube as a carrier for silver nanoparticles (Ag NPs) to construct a specific hydrogen sulfide (H2S) responsive platform (Ag NP@DNA-cube) for diagnosing colorectal cancer (CRC) in this study. The DNA-cube maintains good dispersion of Ag NPs while providing excellent biocompatibility. Based on the characteristic overexpression of endogenous H2S in CRC cells, the Ag NPs are etched by H2S within target cells into silver sulfide quantum dots, thereby selectively illuminating the target cells. The Ag NP@DNA-cube exhibits a specific fluorescence response to CRC cells and achieves satisfactory imaging.

Detection of Single Nucleotide Polymorphisms of Circulating Tumor DNA by Strand Displacement Amplification Coupled with Liquid Chromatography.

The detection of multiple single nucleotide polymorphisms (SNPs) of circulating tumor DNA (ctDNA) is still a great challenge. In this study, we designed enzyme-assisted nucleic acid strand displacement amplification combined with high-performance liquid chromatography (HPLC) for the simultaneous detection of three ctDNA SNPs. First, the trace ctDNA could be hybridized to the specially designed template strand, which initiated the strand displacement nucleic acid amplification process under the synergistic action of DNA polymerase and restriction endonuclease. Then, the targets would be replaced with G-quadruplex fluorescent probes with different tail lengths. Finally, the HPLC-fluorescence assay enabled the separation and quantification of multiple signals. Notably, this method can simultaneously detect both the wild type (WT) and mutant type (MT) of multiple ctDNA SNPs. Within a linear range of 0.1 fM-0.1 nM, the detection limits of BRAF V600E-WT, EGFR T790M-WT, and KRAS 134A-WT and BRAF V600E-MT, EGFR T790M-MT, and KRAS 134A-MT were 29, 31, and 11 aM and 22, 29, and 33 aM, respectively. By using this method, the mutation rates of multiple ctDNA SNPs in blood samples from patients with lung or breast cancer can be obtained in a simple way, providing a convenient and highly sensitive analytical assay for the early screening and monitoring of lung cancer.

Stimulating thyroglobulin to TSH ratio predict long-term efficacy of 131I therapy in patients with differentiated thyroid cancer after total thyroidectomy: a retrospective study.

OBJECTIVE: This study utilized the stimulated thyroglobulin (sTg) to thyroid stimulating hormone (TSH) ratio to predict the long-term efficacy of 131I therapy in patients with moderate-to-high-risk differentiated thyroid cancer (DTC). METHODS: This study retrospectively analyzed 960 DTC patients with a median follow-up time of 30 months (6-92 months). The median age was 44 years. All patients underwent total thyroidectomy, lymph node dissection, and at least one 131I therapy. Patients were subjected to a final efficacy evaluation according to American Thyroid Association's 2015 guidelines. Patients were grouped according to their TSH levels before the initial 131I therapy and the final efficacy evaluation, and factors influencing TSH levels and final efficacy were analyzed. Construction of nomograms using independent risk factors affecting long-term outcomes. The cut-offs of sTg and sTg/TSH ratios were calculated for different long-term outcomes. Progression-free survival (PFS) of patients was analyzed by making Kaplan-Meier survival according to the cut-offs of sTg and sTg/TSH ratio. RESULTS: TSH (mU/L) levels were more concentrated at 60-90 in females (71.5%) and 30-60 in males (39.0%), while patients with younger age, more lymph node metastases, shorter time interval between surgery and the first 131I therapy, and lower dose of levothyroxine sodium taken prior to the first 131I therapy would have higher TSH levels (All P < 0.05).Patients who are male, have primary tumor involvement of the strap muscles, lymph node metastasis, distant metastasis, and higher sTg and sTg/TSH are more likely to have poor long-term outcomes (All P < 0.05).The cut-offs of sTg and sTg/TSH for long-term efficacy were 7.515 and 0.095. STg, sTg/TSH, tumor size, lymph node metastasis, and distant metastasis were shown to be independent risk factors for long-term efficacy. The mean PFSs were longer for patients who had sTg/TSH ≤ 0.095 and/or sTg≤7.515 ug/L. CONCLUSIONS: For patients with moderate-to-high-risk DTC, when sTg>7.515 ug/L and/or sTg/TSH > 0.095 before the first 131I therapy, patients are more likely to have a poor long-term efficacy after full 131I therapy. This means that this group of patients may require further surgical treatment or targeted drug therapy after 131I therapy.

Multiplex Detection of Single Nucleotide Polymorphisms by Liquid Chromatography for Nonsmall Cell Lung Cancer Staging.

In this work, an integrated strategy with excellent accuracy and high throughput is proposed for the precise indication of single nucleotide polymorphism (SNP) in nonsmall cell lung cancer diseases. Two types of point mutations (L858R and T790M) and the corresponding wild types could be identified together in a single high-performance liquid chromatographic run. Signal amplification was achieved through a series of enzyme ligation, primer extension, and enzyme cleavage strategies, and a large number of DNA probes with different fluorescence signals were finally generated. The factors affecting the spatiotemporal separation efficiency of four DNA probes were systematically investigated. The limits of detection of wild types (WTs) or mutant types (MTs) abbreviated as L858R-MT, L858R-WT, T790M-MT, and T790M-WT were 26, 24, 19, and 22 aM, respectively. In addition, the levels of mutant types and wild types in the serum of 40 nonsmall cell lung cancer patients at different stages were detected using the method, and the correlation between the mutation ratios and cancer stages was preliminarily verified. The proposed highly selective and sensitive method may serve as an alternative approach for early diagnosis and staging of nonsmall cell lung cancer.

Clinical characteristics and therapeutic response of differentiated thyroid carcinoma with obesity and diabetes.

BACKGROUND: The effects of obesity and diabetes on the clinical outcomes of differentiated thyroid cancer (DTC) remain unclear. OBJECTIVES: To explore the association between obesity and diabetes with pathological features and therapeutic response of DTC. METHODS: Patients were categorized based on body mass index (BMI) and glycemic status. Compare the correlation between BMI and glycemic status with pathological features and therapeutic response of DTC. To analyze the independent risk factors for the aggressiveness of DTC. RESULTS: The proportion of patients with bilateral tumors was higher in the overweight, obese and diabetes group (P = 0.001, 0.045). The overweight group demonstrated a higher TNM stage (P = 0.004), while the T and TNM stages were higher in the diabetes group (P = 0.032, 0.000). The probability of distant metastasis increases by 37.4% for each unit of BMI increase (odds ratio (OR) = 1.374, CI 95% 1.061-1.778, P < 0.05). The BMI of Biochemical Incomplete Response (BIR) is significantly higher than that of Excellent Response (ER) (P = 0.015), the fasting plasma glucose (FPG) of Structural Incomplete (SIR) was significantly higher than that of ER and BIR (P = 0.030, 0.014). CONCLUSION: Obesity and diabetes have effect on DTC aggressiveness. BMI and FPG have correlation with the therapeutic response of DTC patients.

Role of Exosomes in the Invasion and Metastasis of Ovarian Cancer and Application Potential of Clinical Diagnosis and Treatment.

Ovarian cancer is a highly lethal form of cancer in females, largely due to extensive metastases that often accompany the initial diagnosis. Exosomes are microvesicles size from 30 to 100nm, which can be secreted by most cells. These special extracellular vesicles play a vital role in the metastasis of ovarian cancer. In this study, we conducted a comprehensive review of current research pertaining to the role of exosomes in ovarian cancer, utilizing the PubMed® and Web of Science databases. Our review highlights the progress in elucidating the mechanisms by which exosomes facilitate ovarian cancer progression. Additionally, we discuss the potential of exosomes as a novel therapeutic target for ovarian cancer treatment. Overall, our review provides valuable insights into the current state of research on exosomes in ovarian cancer therapy.

Mueller matrix imaging polarimeter at the wavelength of 265 nm.

Mueller matrix imaging polarimeters (MMIPs) have been developed in the wavelength region of >400n m with great potential in many fields yet leaving a void of instrumentation and application in the ultraviolet (UV) region. For the first time to our knowledge, an UV-MMIP is developed for high resolution, sensitivity, and accuracy at the wavelength of 265 nm. A modified polarization state analyzer is designed and applied to suppress stray light for nice polarization images, and the errors of the measured Mueller matrices are calibrated to lower than 0.007 in pixel level. The finer performance of the UV-MMIP is demonstrated by the measurements of unstained cervical intraepithelial neoplasia (CIN) specimens. The contrasts of depolarization images obtained by the UV-MMIP are dramatically improved over those obtained by our previous VIS-MMIP at the wavelength of 650 nm. A distinct evolution of depolarization in normal cervical epithelium tissue, CIN-I, CIN-II, and CIN-III specimens can be observed by the UV-MMIP with mean depolarization promotion by up to 20 times. This evolution could provide important evidence for CIN staging but can hardly be distinguished by the VIS-MMIP. The results prove that the UV-MMIP could be an effective tool in polarimetric applications with higher sensitivity.

Three-dimensional ordered DNA network constructed by a biomarker pair for accurate monitoring of colorectal cancer.

Precise and early screening of colorectal cancer (CRC) is one crucial yet challenging task for its treatment, and the analysis of multi-targets of CRC in a single assay with high accuracy is essential for pathological research and clinical diagnosis. Here, a CRC-related biomarker pair, microRNA-211 (miRNA-211) and H2S, was detected by constructing a three-dimensional (3D) ordered DNA network. First, trace amount of miRNA-211 could initiate a hybridization chain reaction-based amplification process. A highly ordered 3D DNA network was formed based on the organized assembly of DNA-cube frameworks that were constructed by DNA origamis and Ag nanoparticles (NPs) encapsulated inside. In the presence of the H2S, Ag NPs within the network can be etched to generate Ag2S quantum dots, which could be better visualized in fluorescence in situ cell imaging. Using the 3D DNA ordered network as the sensing platform, it can acquire dual analysis of biomolecule (miRNA-211) and inorganic gas (H2S) in vitro, overcoming the limitations of single type of biomarker detection in a single assay. This assay achieved a wide linearity range of H2S from 0.05 to 10 µM, and exhibited a low limit of detection of 4.78 nM. This strategy allows us to acquire the spatial distributions of H2S and miRNA expression levels in living CRC cells simultaneously, providing a highly sensitive and selective tool for early screening and monitoring of CRC.

Self-Generation of Distinguishable Fluorescent Probes via a One-Pot Process for Multiple MicroRNA Detection by Liquid Chromatography.

To address the challenge of signal production and separation for multiple microRNA (miRNA) detection, in this work, a "one-pot" process to self-generate distinguishable fluorescent probes was developed. Based on a long and short probe amplification strategy, the generated G-quadruplex fluorescent dye-free probes can be separated and detected by a high-performance liquid chromatography-fluorescence platform. The free hairpin probes enriched in guanine with different lengths and base sequences were designed and could be opened by the target miRNAs (miRNA-10b, miRNA-21, and miRNA-210). Cleaved G-quadruplex probes with fluorescent signal could be generated in a one-pot process after a duplex-specific nuclease-based cleavage, and the detection of multiple miRNAs could be realized in one run. No solid nanomaterials were applied in the assay, which avoided the blocking of the column. Moreover, without modification of expensive fluorescein, the experimental cost was greatly reduced. The one-pot reaction process also eliminated tedious preparation steps and suggested feasibility of automation. The limits of detection of miRNA-10b, miRNA-21, and miRNA-210 were 2.19, 2.20, and 2.75 fM, respectively. Notably, this method was successfully applied to multiplex detection of miRNAs in serum samples from breast cancer patients within 30 min.

Two novel cyclohexanone-monocyclic polycyclic polyprenylated acylphloroglucinols from Garcinia multiflora fruits.

Two novel cyclohexanone-monocyclic polyprenylated acylphloroglucinol (C-MPAP) derivatives, named norgarmultinones A (1) and B (2), were isolated from the fruits of Garcinia multiflora. Their structures were clarified by NMR, HRESIMS and calculated electronic circular dichroism (ECD) spectra. Compound 2 is the first example of naturally occurring C-MPAPs containing tetrahydropyran moiety by the cyclization of an enolic hydroxyl with an isogeranyl side chain. The reasonable biosynthetic routes of 1 and 2 were also put forward.

Polyprenylated Acylphloroglucinols With Different Carbon Skeletons From the Fruits of Garcinia multiflora.

Eleven new polycyclic polyprenylated acylphloroglucinols (PPAPs, 1-11) and three new monocyclic polyprenylated acylphloroglucinols (MPAPs, 12-14), together with ten known analogues were isolated from the fruits of Garcinia multiflora. These PPAPs belong to three types including the bicyclic polyprenylated acylphloroglucinols (BPAPs), the caged PPAPs, and the complicated PPAPs. Their structures and absolute configurations were determined through HRESIMS, NMR spectroscopy data, electronic circular dichroism (ECD) calculations, and gauge-independent atomic orbital (GIAO) NMR calculations with DP4+ analyses. Moreover, compounds 2 and 7 exhibited moderate cytotoxicity against three human cancer lines (MCF-7, T98, and HepG2) with IC50 values ranging from 9.81 ± 1.56 to 17.00 ± 2.75 µM.

Homoadamantane polycyclic polyprenylated acylphloroglucinols from the fruits of Garcinia multiflora.

Five new homoadamantane polycyclic polyprenylated acylphloroglucinols (PPAPs, 1-5) were isolated from the fruits of Garcinia multiflora. Their structures and absolute configurations were determined by extensive spectroscopic analyses including NMR, HRESIMS and electronic circular dichroism (ECD). Compounds 1-3 possessed an unique core structure consisting of tetracyclo[7.3.1.13,11.03,7]tetradecane-2,12,14- trione. In comparison with those of 1-3, compound 4 had tricyclo[4.3.1.13,8]undecane- 2,9,11-trione with the loss of prenyl unit. Garcimultinone C (5) was the first example of seco-homoadamantane-type PPAPs with 5-oxatricyclo[7.3.1.03,7]tridecane skeleton derived from C(4)/C(5) carbon-carbon bond cleavage by retro-Claisen reaction.

Adamantyl and homoadamantyl derivatives from Garcinia multiflora fruits.

Nine undescribed caged polycyclic polyprenylated acylphloroglucinols (PPAPs), including adamantane type PPAPs (1-2), and homoadamantane type PPAPs (3-9), were isolated from the fruits of Garcinia multiflora, along with three known analogues. A new epimeric pair of isohypersampsonone B (5) and epi-isohypersampsonone B (6), featuring an unusual hexahydrofuro[2,3-b]furan-diepoxy ring system fused in a homoadamantane skeleton, was not separated due to the rapid equilibration between the two isomeric forms. All new caged PPAPs (1-9), sharing a common isogeranyl group, were determined on the basis of comprehensive NMR and MS spectroscopic data. Their cytotoxicity against three human tumor cell lines (SGC-7901, HepG2, HCT-116) and the nitric oxide production inhibitory activity of lipopolysaccharides-stimulated RAW 264.7 cells were tested. Compounds 8 and 12 displayed mild cytotoxicity against three human cancer cell lines with IC50 values of 10-20 µM. Furthermore, compounds 8 and 12 also exhibited NO production inhibitory effect with an IC50 value of 18.24 and 12.50 µM respectively.