Corrigendum: Mechanism of LncRNA Gm2044 in germ cell development.

[This corrects the article DOI: 10.3389/fcell.2024.1410914.].

Disrupting the protein-protein interaction network of Hsp72 inhibits adipogenic differentiation and lipid synthesis in adipocytes.

The biological function against obesity of heat shock protein Hsp72 in adipose tissue has remained unclear. Our findings demonstrated that the expression levels of Hsp72 increased during the triglyceride (TG) accumulation process both in adipose tissue and 3T3-L1 cells. A significant decrease in adipogenic gene expression and TG levels was observed upon Hsp72 knockdown in 3T3-L1 cells, suggesting that Hsp72 promoted adipogenic differentiation and lipid synthesis processes. Encouraged by these findings, we further confirmed the allosteric Hsp72 inhibitors YK5 and MKT-077 also exhibited inhibition of both these processes. Further evaluation revealed that Hsp72 played a key role in interacting with numerous novel metabolic and cytomorphologic-related client proteins, thereby mediating the adipogenesis and lipogenesis process. Hsp72 inhibitors had the potential to disrupt these interactions, leading to the downregulation of adipogenic and lipogenic gene expression, as well as the suppression of TG accumulation. These findings suggested that inhibiting Hsp72 to disrupt adipogenic differentiation and lipid synthesis in adipocytes may be a promising anti-obesity strategy.

Development of Novel N-Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group.

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.

Mechanism of LncRNA Gm2044 in germ cell development.

Germ cell development in mammals is a complex physiological process that involves the proliferation of primordial germ cells, meiosis, and the formation of male and female gametes. Long non-coding RNA (lncRNA) is a type of RNA with more than 200 nucleotides that does not code for proteins. A small number of lncRNAs have been shown to participate in spermatogenesis in the testes and in follicular development in the ovaries, but the role of the vast majority of lncRNAs and their molecular mechanisms still need further study. LncRNA Gm2044 was identified as a differentially expressed lncRNA in mouse spermatogenesis by microarray technology. In mouse testis, lncRNA Gm2044 can act as competing endogenous RNA to regulate SYCP1 expression in GC-2 cells derived from mouse spermatocyte cells, and it can also act as a host gene for miR-202 to regulate RBFOX2 protein expression. In female mouse ovaries, lncRNA Gm2044 regulates 17ß-estradiol synthesis through the miRNA-138-5p-Nr5a1 pathway or by interacting with EEF2. In addition, studies suggest that lncRNA Gm2044 is also involved in the progression of reproductive system diseases such as male nonobstructive azoospermia. Here, we summarize the roles and molecular mechanisms of lncRNA Gm2044 in male and female gametogenesis and its potential role in some infertility disorders.

Clinical evaluation of droplet digital PCR in the early identification of suspected sepsis patients in the emergency department: a prospective observational study.

Background: Rapid and accurate diagnosis of the causative agents is essential for clinical management of bloodstream infections (BSIs) that might induce sepsis/septic shock. A considerable number of suspected sepsis patients initially enter the health-care system through an emergency department (ED), hence it is vital to establish an early strategy to recognize sepsis and initiate prompt care in ED. This study aimed to evaluate the diagnostic performance and clinical value of droplet digital PCR (ddPCR) assay in suspected sepsis patients in the ED. Methods: This was a prospective single-centered observational study including patients admitted to the ED from 25 October 2022 to 3 June 2023 with suspected BSIs screened by Modified Shapiro Score (MSS) score. The comparison between ddPCR and blood culture (BC) was performed to evaluate the diagnostic performance of ddPCR for BSIs. Meanwhile, correlative analysis between ddPCR and the inflammatory and prognostic-related biomarkers were conducted to explore the relevance. Further, the health economic evaluation of the ddPCR was analyzed. Results: 258 samples from 228 patients, with BC and ddPCR performed simultaneously, were included in this study. We found that ddPCR results were positive in 48.13% (103 of 214) of episodes, with identification of 132 pathogens. In contrast, BC only detected 18 positives, 88.89% of which were identified by ddPCR. When considering culture-proven BSIs, ddPCR shows an overall sensitivity of 88.89% and specificity of 55.61%, the optimal diagnostic power for quantifying BSI through ddPCR is achieved with a copy cutoff of 155.5. We further found that ddPCR exhibited a high accuracy especially in liver abscess patients. Among all the identified virus by ddPCR, EBV has a substantially higher positive rate with a link to immunosuppression. Moreover, the copies of pathogens in ddPCR were positively correlated with various markers of inflammation, coagulation, immunity as well as prognosis. With high sensitivity and specificity, ddPCR facilitates precision antimicrobial stewardship and reduces health care costs. Conclusions: The multiplexed ddPCR delivers precise and quantitative load data on the causal pathogen, offers the ability to monitor the patient's condition and may serve as early warning of sepsis in time-urgent clinical situations as ED. Importance: Early detection and effective administration of antibiotics are essential to improve clinical outcomes for those with life-threatening infection in the emergency department. ddPCR, an emerging tool for rapid and sensitive pathogen identification used as a precise bedside test, has developed to address the current challenges of BSI diagnosis and precise treatment. It characterizes sensitivity, specificity, reproducibility, and absolute quantifications without a standard curve. ddPCR can detect causative pathogens and related resistance genes in patients with suspected BSIs within a span of three hours. In addition, it can identify polymicrobial BSIs and dynamically monitor changes in pathogenic microorganisms in the blood and can be used to evaluate antibiotic efficacy and survival prognosis. Moreover, the copies of pathogens in ddPCR were positively correlated with various markers of inflammation, coagulation, immunity. With high sensitivity and specificity, ddPCR facilitates precision antimicrobial stewardship and reduces health care costs.

AZIN2 is associated with apoptosis of germ cells in undescended testis.

Undescended testis (UDT), known as cryptorchidism (CRY), is a common congenital disorder in which one or both testicles do not descend normally into the scrotum. A unilateral UDT model was established by inducing UDT in mice through surgery. The results showed that the testis in the UDT model group was abnormal; the lumen of the seminiferous tubule was atrophic; apoptosis, necrosis and shedding were observed in many of the germ cells; the level of sex hormones was abnormal; and mature sperm was reduced. Subsequently, transcriptome sequencing was conducted on the testicular tissue of UDT model mice. Through analysis and verification of differential genes, AZIN2 was identified as playing a key role in the decline in male fertility caused by cryptorchidism. AZIN2 expression and spermine content was down-regulated in the testis of the UDT group. We then used a combination of hypoxanthine and xanthine to create a GC-1 cell damage model. In this model, AZIN2 expression and spermine content was down-regulated. When si-Azin2 transfected GC-1 cells, cell viability and proliferation were decreased. However, in the GC-1 cell damage model transfected with Azin2 over-expressed plasmid, AZIN2 expression and spermine content was up-regulated, reversing the cell damage caused by hypoxanthine and xanthine, and restoring the proliferation ability of GC-1 cells. These results indicate that in UDT, down-regulated AZIN2 expression is a factor in testicular damage. This discussion of the connection between AZIN2 and germ cells has important clinical significance as it provides an important reference for the diagnosis and treatment of cryptorchidism.

Near-infrared Light-Triggered Size-Shrinkable theranostic nanomicelles for effective tumor targeting and regression.

Most nanomedicines with suitable sizes (normally 100-200 nm) exhibit favorable accumulation in the periphery of tumors but hardly penetrate into deep tumors. Effective penetration of nanomedicines requires smaller sizes (less than 30 nm) to overcome the elevated tumor interstitial fluid pressure. Moreover, integrating an efficient diagnostic agent in the nanomedicines is in high demand for precision theranostics of tumors. To this end, a near-infrared light (NIR) -triggered size-shrinkable micelle system (Fe3O4@AuNFs/DOX-M) coloaded antitumor drug doxorubicin (DOX) and biomodal imaging agent magnetic gold nanoflower (Fe3O4@AuNFs) was developed to achieve efficient theranostic of tumors. Upon the accumulation of Fe3O4@AuNFs/DOX-M in the tumor periphery, a NIR laser was irradiated near the tumor sites, and the loaded Fe3O4@Au NFs could convert the light energy to heat, which triggered the cleavage of DOX-M to the ultra-small micelles (∼5 nm), thus realizing the deep penetration of micelles and on-demand drug release. Moreover, Fe3O4@AuNFs in the micelles could also be used as CT/MRI dual-modal contrast agent to "visualize" the tumor. Up to 92.6 % of tumor inhibition was achieved for the developed Fe3O4@AuNFs/DOX-M under NIR irradiation. This versatile micelle system provided a promising drug carrier platform realizing efficient tumor dual-modal diagnosis and photothermal-chemotherapy integration.

Integrated analysis reveals critical cisplatin-resistance regulators E2F7 contributed to tumor progression and metastasis in lung adenocarcinoma.

BACKGROUND: Drug resistance poses a significant challenge in cancer treatment, particularly as a leading cause of therapy failure. Cisplatin, the primary drug for lung adenocarcinoma (LUAD) chemotherapy, shows effective treatment outcomes. However, the development of resistance against cisplatin is a major obstacle. Therefore, identifying genes resistant to cisplatin and adopting personalized treatment could significantly improve patient outcomes. METHODS: By examining transcriptome data of cisplatin-resistant LUAD cells from the GEO database, 181 genes associated with cisplatin resistance were identified. Using univariate regression analysis, random forest and multivariate regression analyses, two prognostic genes, E2F7 and FAM83A, were identified. This study developed a prognostic model utilizing E2F7 and FAM83A as key indicators. The Cell Counting Kit 8 assay, Transwell assay, and flow cytometry were used to detect the effects of E2F7 on the proliferation, migration, invasiveness and apoptosis of A549/PC9 cells. Western blotting was used to determine the effect of E2F7 on AKT/mTOR signaling pathway. RESULTS: This study has pinpointed two crucial genes associated with cisplatin resistance, E2F7 and FAM83A, and developed a comprehensive model to assist in the diagnosis, prognosis, and evaluation of relapse risk in LUAD. Analysis revealed that patients at higher risk, according to these genetic markers, had elevated levels of immune checkpoints (PD-L1 and PD-L2). The prognostic and diagnosis values of E2F7 and FAM83A were further confirmed in clinical data. Furthermore, inhibiting E2F7 in lung cancer cells markedly reduced their proliferation, migration, invasion, and increased apoptosis. In vivo experiments corroborated these findings, showing reduced tumor growth and lung metastasis upon E2F7 suppression in lung cancer models. CONCLUSION: Our study affirms the prognostic value of a model based on two DEGs, offering a reliable method for predicting the success of tumor immunotherapy in patients with LUAD. The diagnostic and predictive model based on these genes demonstrates excellent performance. In vitro, reducing E2F7 levels shows antitumor effects by blocking LUAD growth and progression. Further investigation into the molecular mechanisms has highlighted E2F7's effect on the AKT/mTOR signaling pathway, underscoring its therapeutic potential. In the era of personalized medicine, this DEG-based model promises to guide clinical practice.

Unveiling the role of PD-L1 in vascular endothelial dysfunction: Insights into the mtros/NLRP3/caspase-1 mediated pyroptotic pathway.

BACKGROUND: Programmed death ligand-1(PD-L1) has been postulated to play a crucial role in the regulation of barrier functions of the vascular endothelium, yet how this novel molecule mediates dysfunction in endothelial cells (ECs) during acute lung injury (ALI) remains largely unknown. METHODS: PD-L1 siRNA and plasmids were synthesized and applied respectively to down- or up-regulate PD-L1 expression in human lung microvascular endothelial cells (HMVECs). RNA sequencing was used to explore the differentially expressed genes following PD-L1 overexpression. The expression levels of tight junction proteins (ZO-1 and occludin) and the signaling pathways of NLRP-3/caspase-1/pyroptosis were analyzed. A mouse model of indirect ALI was established through hemorrhagic shock (HEM) followed by cecal ligation and puncture (CLP), enabling further investigation into the effects of intravenous delivery of PD-L1 siRNA. RESULTS: A total of 1502 differentially expressed genes were identified, comprising 532 down-regulated and 970 up-regulated genes in ECs exhibiting PD-L1overexpression. Enrichment of PD-L1-correlated genes were observed in the NOD-like receptor signaling pathway and the TNF signaling pathway. Western blot assays confirmed that PD-L1 overexpression elevated the expression of NLRP3, cleaved-caspase-1, ASC and GSDMD, and concurrently diminished the expression of ZO-1 and occludin. This overexpression also enhanced mitochondrial oxidative phosphorylation and mitochondrial reactive oxygen species (mtROS) production. Interestingly, mitigating mitochondrial dysfunction with mitoQ partially countered the adverse effects of PD-L1 on the functionality of ECs. Furthermore, intravenous administration of PD-L1 siRNA effectively inhibited the activation of the NLRP3 inflammasome and pyroptosis in pulmonary ECs, subsequently ameliorating lung injury in HEM/CLP mice. CONCLUSION: PD-L1-mediated activation of the inflammasome contributes significantly to the disruption of tight junction and induction of pyroptosis in ECs, where oxidative stress associated with mitochondrial dysfunction serves as a pivotal mechanism underpinning these effects.

The link between neutrophils, NETs, and NLRP3 inflammasomes: The dual effect of CD177 and its therapeutic potential in acute respiratory distress syndrome/acute lung injury.

Neutrophils are important inflammatory effector cells that protect against foreign invasion but also cause self-harm. Numerous neutrophils infiltrate the lungs in acute respiratory distress syndrome/acute lung injury (ARDS/ALI) patients. However, the exact impact of neutrophil infiltration on ARDS's onset and progression remains unclear. To investigate this, we analyzed two ARDS-related datasets from the Gene Expression Omnibus public database and discovered an association between CD177, a neutrophil-specific surface protein, and ARDS progression. We used quantitative flow cytometry to assess CD177+ neutrophils in the peripheral blood of clinical ARDS patients vs healthy controls, finding a significant increase in CD177+ neutrophils percentage among total neutrophils in ARDS patients. This finding was further confirmed in ALI mouse models. Subsequent animal experiments showed that anti-CD177 effectively reduces pulmonary edema, neutrophil infiltration, and inflammatory cytokine release, along with a decrease in reactive oxygen species (ROS) and myeloperoxidase (MPO) levels. We also established an in vitro co-culture system to mimic neutrophil and lung epithelial cell interactions. In the anti-CD177 group, we observed decreased expression of NLRP3, caspase 1, peptidyl arginine deiminase (PAD4), MPO, and ROS, along with a reduction in certain inflammatory cytokines. These results indicate a crucial role for the CD177 gene in ARDS's development and progression. Inhibiting CD177 may help mitigate excessive activation of NLRP3 inflammasomes, ROS, and neutrophil extracellular traps (NETs), thus alleviating ARDS.

Discovery of Novel Coumarin-quinolinium Derivatives as Pan-KRAS Translation Inhibitors by Targeting 5'-UTR RNA G-Quadruplexes.

Hyperactivated KRAS mutations fuel tumorigenesis and represent attractive targets for cancer treatment. While covalent inhibitors have shown clinical benefits against the KRASG12C mutant, advancements for non-G12C mutants remain limited, highlighting the urgent demand for pan-KRAS inhibitors. RNA G-quadruplexes (rG4s) in the 5'-untranslated region of KRAS mRNA can regulate KRAS translation, making them promising targets for pan-KRAS inhibitor development. Herein, we designed and synthesized 50 novel coumarin-quinolinium derivatives, leveraging our previously developed rG4-specific ligand, QUMA-1. Notably, several compounds exhibited potent antiproliferative activity against cancer cells as pan-KRAS translation inhibitors. Among them, 15a displayed exceptional capability in stabilizing KRAS rG4s, suppressing KRAS translation, and consequently modulating MAPK and PI3K-AKT pathways. 15a induced cell cycle arrest, prompted apoptosis in KRAS-driven cancer cells, and effectively inhibited tumor growth in a KRAS mutant xenograft model. These findings underscore the potential of 15a as a pan-KRAS translation inhibitor, offering a novel and promising approach to target various KRAS-driven cancers.

Bisphenol A triggers apoptosis in mouse pre-antral follicle granulosa cells via oxidative stress.

BACKGROUND: Bisphenol A (BPA), an endocrine disrupting chemical with weak estrogenic and anti-androgenic activity, is widely present in various environmental media and organisms. It has certain reproductive toxicity and can cause a variety of female reproductive system diseases. Although BPA-stimulated apoptosis of granulosa cells has been widely elaborated, the effect of BPA on mouse pre-antral follicle granulosa cells (mpGCs) has not been well elucidated. RESULTS: In this study, the results of live-dead cell staining showed that high concentrations of BPA severely impaired mpGCs growth viability and affected the cell cycle transition of mpGCs. We confirmed that BPA promotes the production of reactive oxygen species (ROS) and facilitates oxidative stress in mpGCs. In addition, immunofluorescence, transmission electron microscopy, and flow cytometry experiments demonstrated that BPA treatment for mpGCs resulted in apoptotic features, such as rounding, cytoplasmic crinkling, and mitochondrial damage. This was accompanied by a large production of ROS and apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus. RNA-seq data showed that several apoptosis-related pathways were enriched in the high concentration BPA-treated group compared with the normal group, such as the p53 pathway, MAPK pathway, etc. CONCLUSIONS: These results suggest that cells undergo oxidative stress effects and apoptosis after BPA treatment for mpGCs, which affects normal follicle development. The potential mechanism of BPA-induced female reproductive toxicity was elucidated, while providing a research basis for the prevention and treatment of female reproductive diseases.

Enhancing surgical precision: unveiling the impact of preoperative colonoscopy in anal fistula patients.

BACKGROUND: Anal fistula is a common benign anorectal disease that often requires surgical intervention for effective treatment. In recent years, preoperative colonoscopy as a diagnostic tool in patients with anal fistula has garnered increasing attention due to its potential clinical application value. By investigating underlying inflammatory bowel disease (IBD), polyps, and other abnormalities, preoperative colonoscopy can offer insights to refine surgical strategies and improve patient outcomes. METHODS: This retrospective study focused on 1796 patients with various benign anorectal diseases who underwent preoperative intestinal endoscopy and met surgical criteria within the preceding three years at the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine. Among these patients, 949 diagnosed with anal fistula comprised group A, while 847 patients without anal fistula were assigned to group B for comparison. The investigation encompassed an analysis of general patient information, endoscopic findings, polyp histopathology, distribution of bowel inflammation sites, and results of inflammatory bowel disease assessments between the two patient cohorts. A subgroup analysis was also conducted on 2275 anal fistula patients with no surgical contraindications. This subgroup was categorized into Group A (949 patients who underwent preoperative intestinal endoscopy) and Group C (1326 patients who did not undergo preoperative colonoscopy). The study compared the rates of detecting endoscopic lesions and IBD-related findings between the two subgroups. RESULTS: The study initially confirmed the comparability of general patient information between groups A and B. Notably, the abnormal detection rate in group A was significantly higher than in group B (P < 0.01). In terms of endoscopic findings, the anal fistula group (group A) exhibited higher rates of detecting bowel inflammation, inflammatory bowel disease, and polyps compared to the non-anal fistula group (group B) (P < 0.05). The distribution of inflammation locations indicated higher detection rates in the terminal ileum, ileocecal region, and ascending colon for group A compared to group B (P < 0.05). Although the incidence of IBD in group A was higher than in group B, this difference did not reach statistical significance (P > 0.05). Subsequently, the analysis of the subgroup (groups A and C) revealed a significant disparity in intestinal endoscopic detection rates (P < 0.01) and statistically significant differences in detecting IBD (P < 0.05) and Crohn's disease (P < 0.05) between the two anal fistula subgroups. CONCLUSIONS: The findings of this study underscore the substantial clinical value of preoperative colonoscopy in the comprehensive evaluation of patients with anal fistula. Preoperative colonoscopy aids in ruling out localized perianal lesions caused by underlying inflammatory bowel disease, thereby mitigating the likelihood of missed diagnoses and enhancing treatment outcomes. This research highlights the importance of incorporating preoperative colonoscopy as a valuable diagnostic tool in managing anal fistula patients.

A novel MRI feature, the cut green pepper sign, can help differentiate a suprasellar pilocytic astrocytoma from an adamantinomatous craniopharyngioma.

OBJECTIVE: There are no specific magnetic resonance imaging (MRI) features that distinguish pilocytic astrocytoma (PA) from adamantinomatous craniopharyngioma (ACP). In this study we compared the frequency of a novel enhancement characteristic on MRI (called the cut green pepper sign) in PA and ACP. METHODS: Consecutive patients with PA (n = 24) and ACP (n = 36) in the suprasellar region were included in the analysis. The cut green pepper sign was evaluated on post-contrast T1WI images independently by 2 neuroradiologists who were unaware of the pathologic diagnosis. The frequency of cut green pepper sign in PA and ACP was compared with Fisher's exact test. RESULTS: The cut green pepper sign was identified in 50% (12/24) of patients with PA, and 5.6% (2/36) with ACP. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the cut green pepper sign for diagnosing PA were 50%, 94.4%, 85.7% and 73.9%, respectively. There was a statistically significant difference in the age of patients with PA with and without the cut green pepper sign (12.3 ± 9.2 years vs. 5.5 ± 4.4 years, p = 0.035). CONCLUSION: The novel cut green pepper sign can help distinguish suprasellar PA from ACP on MRI.

A novel neutrophil extracellular traps-related lncRNA signature predicts prognosis in patients with early-stage lung adenocarcinoma.

BACKGROUND: Neutrophil extracellular traps (NETs) could entrap tumour cells and promote their dissemination and metastasis. Further analysis of NETs-related molecules is expected to provide a new strategy for prognosis prediction and treatment of lung adenocarcinoma (LUAD) patients. METHODS: The model construction was established through co-expression analysis, Lasso Cox regression, univariate and multivariate COX regression, Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway. The potential drugs and analysed drug sensitivity were screened by pRRophetic packages. RESULTS: In this study, we constructed a 15 NETs-related long non-coding RNAs (lncRNAs) prognostic prediction model (AC091057.1, SPART-AS1, AC023796.2, AL031600.2, AC084781.1, AC032011.1, FAM66C, C026355.2, AL096870.2, AC092718.5, PELATON, AC008635.1, AL162632.3, AC087501.4 and AC123768.3) for patients with early-stage LUAD based on public databases and datasets. The signature is associated with immune cell functions, tumour mutation burden and treatment sensitivity in LUAD patients. Additionally, we found that FAM66C is highly expressed in lung cancer patients for the first time, which is associated with poor prognosis. FAM66C knockdown significantly inhibited the proliferation and migration ability of the tumour cells. CONCLUSIONS: In conclusion, this model is a new and effective prognostic and efficacy predictive biomarker, FAM66C plays an oncogene role in the process of LUAD development. It may provide a new theoretical basis for the clinical diagnosis and treatment in LUAD patients in early stage.

Design, synthesis and evaluation of 2-pyrimidinylindole derivatives as anti-obesity agents by regulating lipid metabolism.

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment.

Diversity, community structure, and quantity of eukaryotic phytoplankton revealed using 18S rRNA and plastid 16S rRNA genes and pigment markers: a case study of the Pearl River Estuary.

Understanding consistencies and discrepancies in characterizing diversity and quantity of phytoplankton is essential for better modeling ecosystem change. In this study, eukaryotic phytoplankton in the Pearl River Estuary, South China Sea were investigated using nuclear 18S rRNA and plastid 16S or 23S rRNA genes and pigment analysis. It was found that 18S abundance poorly explained the variations in total chlorophyll a (Chl-a). However, the ratios of log-transformed 18S abundance to Chl-a in the major phytoplankton groups were generally environment dependent, suggesting that the ratio has potential as an indicator of the physiological state of phytoplankton. The richness of 18S-based operational taxonomic units was positively correlated with the richness of 16S-based amplicon sequence variants of the whole phytoplankton community, but insignificant or weak for individual phytoplankton groups. Overall, the 18S based, rather than the 16S based, community structure had a greater similarity to pigment-based estimations. Relative to the pigment data, the proportion of haptophytes in the 18S dataset, and diatoms and cryptophytes in the 16S dataset, were underestimated. This study highlights that 18S metabarcoding tends to reflect biomass-based community organization of eukaryotic phytoplankton. Because there were lower copy numbers of plastid 16S than 18S per genome, metabarcoding of 16S probably approximates cell abundance-based community organization. Changes in biomass organization of the pigment-based community were sensitive to environmental changes. Taken together, multiple methodologies are recommended to be applied to more accurately profile the diversity and community composition of phytoplankton in natural ecosystems. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00186-x.

Comprehensive analysis and establishment of a prognostic model based on non-genetic predictors in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is a systemic hematological malignancy usually incurable. The value of some important prognostic factors may gradually decrease. OBJECTIVE: We aimed to explore the non-genetic indexes, prognostic models, and significance of clinical staging systems of MM. METHODS: A retrospective analysis was conducted on clinical data from 110 patients with MM who first visit the First Affiliated Hospital of Guangzhou Medical University between September 2005 to December 2018. RESULTS: Bone marrow plasma cell percentage (BMPC%), cystatin C (CysC), and ß2 microglobulin (ß2-MG) were positively correlated with Durie-Salmon (D-S) and international staging system (ISS) stages, while red blood cell count (RBC) and hemoglobin volume (HGB) were negatively correlated (P< 0.05). Univariate analysis showed that ISS stage, treatment protocol, immunofixation electrophoresis (IFE), ratio of red cell distribution width to platelet count (RPR), monocyte count (MONO), lactate dehydrogenase, and immunoglobulin G were significantly associated with the three-year overall survival (OS). IFE, treatment protocol, and ß2-MG significantly affected progression-free survival (P< 0.05). Multivariate analysis showed that the treatment protocol, ISS stage, RPR, MONO, and IFE were independent prognostic factors for three-year OS (P< 0.05). CONCLUSIONS: BMPC%, CysC, and ß2-MG were positively correlated with both clinical staging systems and RBC and HGB were negatively correlated. RPR and MONO affect MM prognosis and the established prognostic model can guide patient prognosis.

Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy.

Unprecedented breakthroughs have been made in cancer immunotherapy in recent years. Particularly immune checkpoint inhibitors have fostered hope for patients with cancer. However, immunotherapy still exhibits certain limitations, such as a low response rate, limited efficacy in certain populations, and adverse events in certain tumors. Therefore, exploring strategies that can improve clinical response rates in patients is crucial. Tumor-associated macrophages (TAMs) are the predominant immune cells that infiltrate the tumor microenvironment and express a variety of immune checkpoints that impact immune functions. Mounting evidence indicates that immune checkpoints in TAMs are closely associated with the prognosis of patients with tumors receiving immunotherapy. This review centers on the regulatory mechanisms governing immune checkpoint expression in macrophages and strategies aimed at improving immune checkpoint therapies. Our review provides insights into potential therapeutic targets to improve the efficacy of immune checkpoint blockade and key clues to developing novel tumor immunotherapies.

Design and Synthesis of Bouchardatine Derivatives as a Novel AMP-Activated Protein Kinase Activator for the Treatment of Colorectal Cancer.

Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine, modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.