Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity.

Oncolytic viruses (OVs) show promise as a cancer treatment by selectively replicating in tumor cells and promoting antitumor immunity. However, the current immunogenicity induced by OVs for tumor treatment is relatively weak, necessitating a thorough investigation of the mechanisms underlying its induction of antitumor immunity. Here, we show that HSV-1-based OVs (oHSVs) trigger ZBP1-mediated PANoptosis (a unique innate immune inflammatory cell death modality), resulting in augmented antitumor immune effects. Mechanistically, oHSV enhances the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA and subsequent activation of ZBP1. To further enhance the antitumor potential of oHSV, we conduct a screening and identify Fusobacterium nucleatum outer membrane vesicle (Fn-OMV) that can increase the expression of PANoptosis execution proteins. The combination of Fn-OMV and oHSV demonstrates potent antitumor immunogenicity. Taken together, our study provides a deeper understanding of oHSV-induced antitumor immunity, and demonstrates a promising strategy that combines oHSV with Fn-OMV.

HMGA1 sensitizes esophageal squamous cell carcinoma to mTOR inhibitors through the ETS1-FKBP12 axis.

Esophageal carcinoma is amongst the prevalent malignancies worldwide, characterized by unclear molecular classifications and varying clinical outcomes. The PI3K/AKT/mTOR signaling, one of the frequently perturbed dysregulated pathways in human malignancies, has instigated the development of various inhibitory agents targeting this pathway, but many ESCC patients exhibit intrinsic or adaptive resistance to these inhibitors. Here, we aim to explore the reasons for the insensitivity of ESCC patients to mTOR inhibitors. We assessed the sensitivity to rapamycin in various ESCC cell lines by determining their respective IC50 values and found that cells with a low level of HMGA1 were more tolerant to rapamycin. Subsequent experiments have supported this finding. Through a transcriptome sequencing, we identified a crucial downstream effector of HMGA1, FKBP12, and found that FKBP12 was necessary for HMGA1-induced cell sensitivity to rapamycin. HMGA1 interacted with ETS1, and facilitated the transcription of FKBP12. Finally, we validated this regulatory axis in in vivo experiments, where HMGA1 deficiency in transplanted tumors rendered them resistance to rapamycin. Therefore, we speculate that mTOR inhibitor therapy for individuals exhibiting a reduced level of HMGA1 or FKBP12 may not work. Conversely, individuals exhibiting an elevated level of HMGA1 or FKBP12 are more suitable candidates for mTOR inhibitor treatment.

Porcine kobuvirus enhances porcine epidemic diarrhea virus pathogenicity and alters the number of intestinal lymphocytes in piglets.

Recent epidemiological studies have discovered that a lot of cases of porcine epidemic diarrhea virus (PEDV) infection are frequently accompanied by porcine kobuvirus (PKV) infection, suggesting a potential relationship between the two viruses in the development of diarrhea. To investigate the impact of PKV on PEDV pathogenicity and the number of intestinal lymphocytes, piglets were infected with PKV or PEDV or co-infected with both viruses. Our findings demonstrate that co-infected piglets exhibit more severe symptoms, acute gastroenteritis, and higher PEDV replication compared to those infected with PEDV alone. Notably, PKV alone does not cause significant intestinal damage but enhances PEDV's pathogenicity and alters the number of intestinal lymphocytes. These results underscore the complexity of viral interactions in swine diseases and highlight the need for comprehensive diagnostic and treatment strategies addressing co-infections.

Selection of Peptide-Bismuth Bicycles Using Phage Display.

Cysteine conjugation is widely used to constrain phage displayed peptides for the selection of cyclic peptides against specific targets. In this study, the nontoxic Bi3+ ion was used as a cysteine conjugation reagent to cross-link peptide libraries without compromising phage infectivity. We constructed a randomized 3-cysteine peptide library and cyclized it with Bi3+, followed by a selection against the maltose-binding protein as a model target. Next-generation sequencing of selection samples revealed the enrichment of peptides containing clear consensus sequences. Chemically synthesized linear and Bi3+ cyclized peptides were used for affinity validation. The cyclized peptide showed a hundred-fold better affinity (0.31 ± 0.04 µM) than the linear form (39 ± 6 µM). Overall, our study proved the feasibility of developing Bi3+ constrained bicyclic peptides against a specific target using phage display, which would potentially accelerate the development of new peptide-bismuth bicycles for therapeutic or diagnostic applications.

PTGER3 knockdown inhibits the vulnerability of triple-negative breast cancer to ferroptosis.

Prostaglandin E receptor 3 (PTGER3) is involved in a variety of biological processes in the human body and is closely associated with the development and progression of a variety of cancer types. However, the role of PTGER3 in triple-negative breast cancer (TNBC) remains unclear. In the present study, low PTGER3 expression was found to be associated with poor prognosis in TNBC patients. PTGER3 plays a crucial role in regulating TNBC cell invasion, migration, and proliferation. Upregulation of PTGER3 weakens the epithelial-mesenchymal phenotype in TNBC and promotes ferroptosis both in vitro and in vivo by repressing glutathione peroxidase 4 (GPX4) expression. On the other hand, downregulation of PTGER3 inhibits ferroptosis by increasing GPX4 expression and activating the PI3K-AKT pathway. Upregulation of PTGER3 also enhances the sensitivity of TNBC cells to paclitaxel. Overall, this study has elucidated critical pathways in which low PTGER3 expression protects TNBC cells from undergoing ferroptosis, thereby promoting its progression. PTGER3 may thus serve as a novel and promising biomarker and therapeutic target for TNBC.

Efficacy and safety of minimally invasive laparoscopic surgery under general anesthesia for ovarian cancer.

BACKGROUND: Ovarian cancer is one of the most common malignant tumors in female reproductive system in the world, and the choice of its treatment is very important for the survival rate and prognosis of patients. Traditional open surgery is the main treatment for ovarian cancer, but it has the disadvantages of big trauma and slow recovery. With the continuous development of minimally invasive technology, minimally invasive laparoscopic surgery under general anesthesia has been gradually applied to the treatment of ovarian cancer because of its advantages of less trauma and quick recovery. However, the efficacy and safety of minimally invasive laparoscopic surgery under general anesthesia in the treatment of ovarian cancer are still controversial. AIM: To explore the efficacy and safety of general anesthesia minimally invasive surgery in the treatment of ovarian cancer. METHODS: The clinical data of 90 patients with early ovarian cancer in our hospital were analyzed retrospectively. According to the different surgical treatment methods, patients were divided into study group and control group (45 cases in each group). The study group received minimally invasive laparoscopic surgery under general anesthesia for ovarian cancer, while the control group received traditional open surgery for ovarian cancer. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), clinical efficacy and safety of the two groups were compared. RESULTS: The intraoperative blood loss, length of hospital stay, postoperative gas evacuation time, and postoperative EORTC QLQ-C30 score of the study group were significantly better than those of the control group (P < 0.05). The incidence of postoperative complications in the study group was significantly lower than in the control group (P < 0.05). The two groups had no significant differences in the preoperative adrenocorticotropic hormone (ACTH), androstenedione (AD), cortisol (Cor), cluster of differentiation 3 positive (CD3+), and cluster of differentiation 4 positive (CD4+) indexes (P > 0.05). In contrast, postoperatively, the study group's ACTH, AD, and Cor indexes were lower, and the CD3+ and CD4+ indexes were higher than those in the control group (P < 0.05). CONCLUSION: Minimally invasive laparoscopic surgery under general anesthesia in patients with early ovarian cancer can significantly improve the efficacy and safety, improve the short-term prognosis and quality of life of patients, and is worth popularizing.

One-step flow synthesis of size-controlled polymer nanogels in a fluorocarbon microfluidic chip.

Synthetic polymer nanoparticles (NPs) with biomimetic properties are ideally suited for different biomedical applications such as drug delivery and direct therapy. However, bulk synthetic approaches can suffer from poor reproducibility and scalability when precise size control or multi-step procedures are required. Herein, we report an integrated microfluidic chip for the synthesis of polymer NPs. The chip could sequentially perform homopolymer synthesis and subsequent crosslinking into NPs without intermediate purification. This was made possible by fabrication of the chip with a fluorinated elastomer and incorporation of two microfluidic mixers. The first was a long channel with passive mixing features for the aqueous RAFT synthesis of stimuli-responsive polymers in ambient conditions. The polymers were then directly fed into a hydrodynamic flow focusing (HFF) junction that rapidly mixed them with a crosslinker solution to produce NPs. Compared to microfluidic systems made of PDMS or glass, our chip had better compatibility and facile fabrication. The polymers were synthesized with high monomer conversion and the NP size was found to be influenced by the flow rate ratio between the crosslinker solution and polymer solution. This allowed for the size to be predictably controlled by careful adjustment of the fluid flow rates. The size of the NPs and their stimuli-responses were studied using DLS and SEM imaging. This microfluidic chip design can potentially streamline and provide some automation for the bottom-up synthesis of polymer NPs while offering on-demand size control.

Effects of ant nests on soil CH4 emissions from Syzygium oblatum communities of a secondary tropical forest.

Exploring the effects of ant nests on soil CH4 emissions in the secondary tropical forests is of great scientific significance to understand the contribution of soil faunal activities to greenhouse gas emissions. With static chamber-gas chromatography method, we measured the dry-wet seasonal dynamics of CH4 emissions from ant nests and control soils in the secondary forest of Syzygium oblatum communities in Xishuangbanna. We also examined the linkages of ant-mediated changes in functional microbial diversity and soil physicochemical properties with CH4 emissions. The results showed that: 1) Ant nests significantly accelerated soil CH4 emissions, with average CH4 emissions in the ant nests being 2.6-fold of that in the control soils. 2) The CH4 emissions had significant dry-wet seasonal variations, which was a carbon sink in the dry seasons (from -0.29±0.03 to -0.53±0.02 µg·m-2·h-1) and a carbon source in the wet seasons (from 0.098±0.02 to 0.041±0.009 µg·m-2·h-1). The CH4 emissions were significantly higher in ant nests than in control soils. The CH4 emissions from the ant nests had smaller dry-wet seasonal variation (from -0.38±0.01 to 0.12±0.02 µg·m-2·h-1) than those in the control soils (from -0.65±0.04 to 0.058±0.006 µg·m-2·h-1). 3) Ant nests significantly increased the values (6.2%-37.8%) of soil methanogen diversity (i.e., Ace and Shannon indices), temperature and humidity, carbon pools (i.e., total, easily oxidizable, and microbial carbon), and nitrogen pools (i.e., total, hydrolyzed, ammonium, and microbial biomass nitrogen), but decreased the diversity (i.e., Ace and Chao1 indices) of methane-oxidizing bacteria by 21.9%-23.8%. 4) Results of the structural equation modeling showed that CH4 emissions were promoted by soil methanogen diversity, temperature and humidity, and C and N pools, but inhibited by soil methane-oxidizing bacterial diversity. The explained extents of soil temperature, humidity, carbon pool, nitrogen pool, methanogen diversity, and methane-oxidizing bacterial diversity for the CH4 emission changes were 6.9%, 21.6%, 18.4%, 15.2%, 14.0%, and 10.8%, respectively. Therefore, ant nests regulated soil CH4 emission dynamics through altering soil functional bacterial diversities, micro-habitat, and carbon and nitrogen pools in the secondary tropical forests.

Photocatalytic Z/E isomerization unlocking the stereodivergent construction of axially chiral alkene frameworks.

The past century has witnessed a large number of reports on the Z/E isomerization of alkenes. However, the vast majority of them are still limited to the isomerization of di- and tri-substituted alkenes. The stereospecific Z/E isomerization of tetrasubstituted alkenes remains to be an underdeveloped area, thus lacking in a stereodivergent synthesis of axially chiral alkenes. Herein we report the atroposelective synthesis of tetrasubstituted alkene analogues by asymmetric allylic substitution-isomerization, followed by their Z/E isomerization via triplet energy transfer photocatalysis. In this regard, the stereodivergent synthesis of axially chiral N-vinylquinolinones is achieved efficiently. Mechanistic studies indicate that the benzylic radical generation and distribution are two key factors for preserving the enantioselectivities of axially chiral compounds.

Sildenafil improves hemodynamic changes caused by acute pulmonary embolism by inhibiting Rho kinase activity.

OBJECTIVE: This study examined the effects of sildenafil on acute pulmonary embolism (APE) using a rat model. METHODS: Sprague-Dawley rats were randomly divided into the sham, pulmonary thromboembolism (PTE), and sildenafil groups. The sham and PTE groups received normal saline once daily via gavage for 14 consecutive days, whereas the sildenafil group received sildenafil (0.5 mg/kg/day) once daily via gavage for 14 consecutive days. Autologous emboli were prepared from blood samples collected from the left femoral artery of rats in each group on day 13, and autologous emboli were injected into the jugular vein cannula of rats in the PTE and sildenafil groups on day 14. Sham-treated rats received the same volume of saline. Right systolic ventricular pressure (RVSP) and mean pulmonary arterial pressure (MPAP) were used to assess pulmonary embolism, and western blotting and enzyme-linked immunosorbent assay were used to detect relevant markers. RESULTS: The Rho kinase signaling pathway was significantly activated in rats with APE, and sildenafil significantly inhibited this activation. CONCLUSIONS: Sildenafil protected against APE through inhibiting Rho kinase activity, thereby reducing pulmonary vasoconstriction and decreasing elevated pulmonary arterial pressure. These findings might provide new ideas for the clinical treatment of acute pulmonary thromboembolism.

Macrocycle-Based Charge Transfer Cocrystals with Dynamically Reversible Chiral Self-Sorting Display Chain Length-Selective Vapochromism to Alkyl Ketones.

Chirality-driven self-sorting plays an essential role in controlling the biofunction of biosystems, such as the chiral double-helix structure of DNA from self-recognition by hydrogen bonding. However, achieving precise control over the chiral self-sorted structures and their functional properties for the bioinspired supramolecular systems still remains a challenge, not to mention realizing dynamically reversible regulation. Herein, we report an unprecedented saucer[4]arene-based charge transfer (CT) cocrystal system with dynamically reversible chiral self-sorting synergistically induced by chiral triangular macrocycle and organic vapors. It displays efficient chain length-selective vapochromism toward alkyl ketones due to precise modulation of optical properties by vapor-induced diverse structural transformations. Experimental and theoretical studies reveal that the unique vapochromic behavior is mainly attributed to the formation of homo- or heterochiral self-sorted assemblies with different alkyl ketone guests, which differ dramatically in solid-state superstructures and CT interactions, thus influencing their optical properties. This work highlights the essential role of chiral self-sorting in controlling the functional properties of synthetic supramolecular systems, and the rarely seen controllable chiral self-sorting at the solid-vapor interface deepens the understanding of efficient vapochromic sensors.

DNA Damage-driven Inflammatory Cytokines: Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy.

DNA damage occurs across tumorigenesis and tumor development. Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment (TIME) and dominate tumor progression. Accumulating evidence documents that multiple signaling pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein (ATM/ATR), are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines. These cytokines possess multifaced functions in the anti-tumor immune response. Thus, it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines, critical for the development of effective tumor therapies. This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines. We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.

Design, Synthesis, and Biological Evaluation of Novel Cinnamide Derivatives as Neuroprotective Agents for the Treatment of Cerebral Ischemia.

BACKGROUND: Ischemic stroke, the most common type of cerebrovascular accident, is a major cause of severe disability among adults worldwide. Although there has been progress in interventions for ischemic stroke in the past decades, there is no effective treatment to prevent brain damage in acute ischemic stroke. Therefore, it is urgent to develop novel neuroprotective agents with a wide therapeutic time window to provide a better prognosis for ischemic stroke patients. OBJECTIVE: The current study aimed to synthesize novel derivatives with substituent cinnamide scaffolds, evaluate biological activity, and obtain neuroprotective agents. METHODS: The target compounds were synthesized using classical methods of medicinal chemistry. The neuroprotective effects in vitro against Glu-induced neurotoxicity injury were evaluated in PC12 cells by MTT assay. The cell apoptosis was analyzed by flow cytometer. The proteins were detected by western blotting. The neuroprotective activities in vivo were determined in two in vivo models of global and focal cerebral ischemia. RESULTS: Among the title compounds, 9t, 9u, 9y, and 9z exhibited good neuroprotection in vivo and in vitro, which were selected and further studied to determine their mechanism of action. 9t, 9u, 9y and 9z protected PC12 cells against glutamate-induced apoptosis in a dose-dependent manner via caspase-3 pathway. Moreover, the four compounds significantly reduced brain infarct area and exhibited excellent neuroprotective activities in the in vivo MCAO model. CONCLUSION: Compounds 9t, 9u, 9y, and 9z, as potent neuroprotective agents with anti- neurotoxicity activity in vitro and anticerebral infarction efficacy in vivo, might serve as a useful molecular tool for further physiology and pathophysiology function studies, leading to potential clinical therapeutic agents for ischemic injury.

Ethylene controls three-dimensional growth involving reduced auxin levels in the moss Physcomitrium patens.

The conquest of land by plants was concomitant with, and possibly enabled by, the evolution of three-dimensional (3D) growth. The moss Physcomitrium patens provides a model system for elucidating molecular mechanisms in the initiation of 3D growth. Here, we investigate whether the phytohormone ethylene, which is believed to have been a signal before land plant emergence, plays a role in 3D growth regulation in P. patens. We report ethylene controls 3D gametophore formation, based on results from exogenously applied ethylene and genetic manipulation of PpEIN2, which is a central component in the ethylene signaling pathway. Overexpression (OE) of PpEIN2 activates ethylene responses and leads to earlier formation of gametophores with fewer gametophores produced thereafter, phenocopying ethylene-treated wild-type. Conversely, Ppein2 knockout mutants, which are ethylene insensitive, show initially delayed gametophore formation with more gametophores produced later. Furthermore, pharmacological and biochemical analyses reveal auxin levels are decreased in the OE lines but increased in the knockout mutants. Our results suggest that evolutionarily, ethylene and auxin molecular networks were recruited to build the plant body plan in ancestral land plants. This might have played a role in enabling ancient plants to acclimate to the continental surfaces of the planet.

Exploring microbiome and plankton responses and interactions in the mangrove ecosystem through eDNA and network analysis.

The comprehensive analysis of multiple biological communities is essential for assessing diversities within mangrove ecosystems, yet such studies are infrequent. Environmental DNA (eDNA) facilitates the simultaneous exploration of organisms across various levels within a single ecosystem. In this investigation, 16S rRNA, cytochrome C oxidase I (COI), and Mito-fish primers were employed to characterize the microbiome, eukaryotic plankton, and fish communities, along with their intricate interactions, across 24 samples from three Chinese mangrove reservoirs. The resulting dataset encompasses 3779 taxonomic groups (genus level), spanning from the microbiome to vertebrates. Diversity analysis unveiled a higher level of stability in the microbiome community compared to plankton, underscoring the superior site-specificity of plankton. The association analysis revealed that biodiversity was primarily affected by temperature, turbidity, and fluorescent dissolved organic matter (fDOM). Notably, the physicochemical factors, turbidity, and fDOM had a more pronounced impact on the microbiome than on plankton, explaining their distinct sensitivities to site-specific conditions. Network analysis constructed 15 biological interaction subnetworks representing various community connections. The most connected genera in each subnetwork, highly responsive to different environmental factors, could serve as potential indicators of distinct ecosystem states. In summary, our findings represent the first comparison of the response sensitivities of different communities and the construction of their interaction networks in mangrove environments. These results contribute valuable insights into marine ecosystem dynamics and the role of environmental factors in shaping biodiversity.

Pazopanib stimulates senescence of renal carcinoma cells through targeting nuclear factor E2-related factor 2 (Nrf2).

Renal cell carcinoma (RCC) is the most common kidney cancer with high mortality rate. Pazopanib has been approved for the treatment of RCC. However, the underlying mechanism is not clear. Here, we report a novel finding by showing that treatment with Pazopanib could promote cellular senescence of the human RCC cell line ACHN. Cells were stimulated with 5, 10, and 20 µM Pazopanib, respectively. Cellular senescence was measured using senescence-associated ß-galactosidase (SA-ß-Gal) staining. Western blot analysis and real-time polymerase chain reaction were used to measure the mRNA and protein expression of nuclear factor E2-related factor 2 (Nrf2), γH2AX, human telomerase reverse transcriptase (hTERT), telomeric repeat binding factor 2 (TERF2), p53 and plasminogen activator inhibitor (PAI). First, we found that exposure to Pazopanib reduced the cell viability of ACHN cells. Additionally, Pazopanib induced oxidative stress  by increasing the production of reactive oxygen species, reducing the levels of glutathione peroxidase, and promoting nuclear translocation of Nrf2. Interestingly, Pazopanib exposure resulted in DNA damage by increasing the expression of γH2AX. Importantly, Pazopanib increased cellular senescence and reduced telomerase activity. Pazopanib also reduced the gene expression of hTERT but increased the gene expression of TERF2. Correspondingly, we found that Pazopanib increased the expression of p53 and PAI at both the mRNA and protein levels. To elucidate the underlying mechanism, the expression of Nrf2 was knocked down by transduction with Ad- Nrf2 shRNA. Results indicate that silencing of Nrf2 in ACHN cells abolished the effects of Pazopanib in stimulating cellular senescence and reducing telomerase activity. Consistently, knockdown of Nrf2 restored the expression of p53 and PAI in ACHN cells. Based on these results, we explored a novel mechanism whereby which Pazopanib displays a cytotoxicity effect in RCC cells through promoting cellular senescence mediated by Nrf2.

OCTN2- and ATB0,+-targeted nanoemulsions for improving ocular drug delivery.

Traditional eye drops are administered via topical instillation. However, frequent dosing is needed due to their relatively rapid precorneal removal and low ocular bioavailability. To address these issues, stearoyl L-carnitine-modified nanoemulsions (SC-NEs) were fabricated. The physicochemical properties of SC-NEs in terms of size, morphology, zeta potential, encapsulation efficiency, and in vitro drug release behavior were characterized. The cellular uptake and mechanisms of SC-NEs were comprehensively studied in human corneal epithelial cells and the stearoyl L-carnitine ratio in SC-NEs was optimized. The optimized SC-NEs could target the novel organic cation/carnitine transporter 2 (OCTN2) and amino acid transporter B (0 +) (ATB0,+) on the corneal epithelium, which led to superior corneal permeation, ocular surface retention ability, ocular bioavailability. Furthermore, SC-NEs showed excellent in vivo anti-inflammatory efficacy in a rabbit model of endotoxin-induced uveitis. The ocular safety test indicated that the SC-NEs were biocompatible. In general, the current study demonstrated that OCTN2 and ATB0,+-targeted nanoemulsions were promising ophthalmologic drug delivery systems that can improve ocular drug bioavailability and boost the therapeutic effects of drugs for eye diseases.

Nonadiabatic Charge Transfer within Photoexcited Nickel Porphyrins.

Metalloporphyrins with open d-shell ions can drive biochemical energy cycles. However, their utilization in photoconversion is hampered by rapid deactivation. Mapping the relaxation pathways is essential for elaborating strategies that can favorably alter the charge dynamics through chemical design and photoexcitation conditions. Here, we combine transient optical absorption spectroscopy and transient X-ray emission spectroscopy with femtosecond resolution to probe directly the coupled electronic and spin dynamics within a photoexcited nickel porphyrin in solution. Measurements and calculations reveal that a state with charge-transfer character mediates the formation of the thermalized excited state, thereby advancing the description of the photocycle for this important representative molecule. More generally, establishing that intramolecular charge-transfer steps play a role in the photoinduced dynamics of metalloporphyrins with open d-shell sets a conceptual ground for their development as building blocks capable of boosting nonadiabatic photoconversion in functional architectures through "hot" charge transfer down to the attosecond time scale.

Red ginseng ameliorates lipotoxicity-induced renal fibrosis in hyperuricemia mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic kidney disease can be caused by numerous diseases including obesity and hyperuricemia (HUA). Obesity may exacerbate the renal injury caused by HUA. Red ginseng, a steamed products of Panax ginseng Meyer root, is known for its remarkable efficacy in improving metabolic syndrome, such as maintaining lipid metabolic balance. However, the role of red ginseng on hyperuricemia-induced renal injury in obese cases remains unclear. AIM OF THE STUDY: This study aimed to investigate the action of red ginseng extract (RGE) on lipotoxicity-induced renal injury in HUA mice. MATERIALS AND METHODS: A high-fat diet (HFD)-induced obesity model was employed to initially investigate the effects of RGE on body weight, TC, OGTT, renal lipid droplets, and renal function indices such as uric acid, creatinine, and urea nitrogen. Renal structural improvement was demonstrated by H&E staining. Subsequently, an animal model combining obesity and HUA was established to further study the impact of RGE on OAT1 and ACC1 expression levels. The mechanisms underlying renal injury regulation by RGE were postulated on the basis of RNA sequencing, which was verified by immunohistochemical (including F4/80, Ki67, TGF-ß1, α-SMA, and E-cadherin), Masson, and Sirius red staining. RESULTS: RGE modulated HFD-induced weight gain, glucose metabolism, and abnormalities of uric acid, urea nitrogen, and creatinine. RGE alleviated the more severe renal histopathological changes induced by obesity combined with HUA, with down-regulated the protein levels of ACC1, F4/80, Ki67, TGF-ß1, and α-SMA, and up-regulated OAT1 and E-cadherin. CONCLUSIONS: RGE has ameliorative effects on chronic kidney disease caused by obesity combined with HUA by maintaining lipid balance and reducing renal inflammation and fibrosis.

Clinical Management of Patients with Non-Small Cell Lung Cancer, Brain Metastases, and Actionable Genomic Alterations: A Systematic Literature Review.

INTRODUCTION: Nearly 60% of patients with non-small cell lung cancer (NSCLC) present with metastatic disease, and approximately 20% have brain metastases (BrMs) at diagnosis. During the disease course, 25-50% of patients will develop BrMs. Despite available treatments, survival rates for patients with NSCLC and BrMs remain low, and their overall prognosis is poor. Even with newer agents for NSCLC, options for treating BrMs can be limited by their ineffective transport across the blood-brain barrier (BBB) and the unique brain tumor microenvironment. The presence of actionable genomic alterations (AGAs) is a key determinant of optimal treatment selection, which aims to maximize responses and minimize toxicities. The objective of this systematic literature review (SLR) was to understand the current landscape of the clinical management of patients with NSCLC and BrMs, particularly those with AGAs. METHOD: A Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-compliant SLR was conducted to identify studies in patients with BrMs in NSCLC. Searches used the EMBASE and MEDLINE® databases, and articles published between January 1, 2017 and September 26, 2022 were reviewed. RESULTS: Overall, 179 studies were included in the SLR. This subset review focused on 80 studies that included patients with NSCLC, BrMs, and AGAs (19 randomized controlled trials [RCTs], two single-arm studies, and 59 observational studies). Sixty-four of the 80 studies reported on epidermal growth factor receptor (EGFR) mutations, 14 on anaplastic lymphoma kinase (ALK) alterations, and two on both alterations. Ninety-five percent of studies evaluated targeted therapy. All RCTs allowed patients with previously treated, asymptomatic, or neurologically stable BrMs; the percentage of asymptomatic BrMs varied across observational studies. CONCLUSIONS: Although targeted therapies demonstrate systemic benefits for patients with NSCLC, BrMs, and AGAs, there remains a continued need for effective therapies to treat and prevent BrMs in this population. Increased BBB permeability of emerging therapies may improve outcomes for this population.