Multifunctional hydrogels based on photothermal therapy: A prospective platform for the postoperative management of melanoma.

Preventing the recurrence of melanoma after surgery and accelerating wound healing are among the most challenging aspects of melanoma management. Photothermal therapy has been widely used to treat tumors and bacterial infections and promote wound healing. Owing to its efficacy and specificity, it may be used for postoperative management of tumors. However, its use is limited by the uncontrollable distribution of photosensitizers and the likelihood of damage to the surrounding normal tissue. Hydrogels provide a moist environment with strong biocompatibility and adhesion for wound healing owing to their highly hydrophilic three-dimensional network structure. In addition, these materials serve as excellent drug carriers for tumor treatment and wound healing. It is possible to combine the advantages of both of these agents through different loading modalities to provide a powerful platform for the prevention of tumor recurrence and wound healing. This review summarizes the design strategies, research progress and mechanism of action of hydrogels used in photothermal therapy and discusses their role in preventing tumor recurrence and accelerating wound healing. These findings provide valuable insights into the postoperative management of melanoma and may guide the development of promising multifunctional hydrogels for photothermal therapy.

Neuron-targeted liposomal coenzyme Q10 attenuates neuronal ferroptosis after subarachnoid hemorrhage by activating the ferroptosis suppressor protein 1/coenzyme Q10 system.

Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. SAH disrupts the blood‒brain barrier, leading to the release of iron ions from blood within the subarachnoid space, subsequently inducing neuronal ferroptosis. A recently discovered protein, known as ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10 by introducing the neuron-targeting peptide Tet1 onto the surface of liposomal CoQ10. Our objective was to determine whether this formulation could activate the FSP1 system and subsequently inhibit neuronal ferroptosis. Our findings revealed that neuron-targeted liposomal CoQ10 effectively localized to neurons at the lesion site after SAH. Furthermore, it facilitated the upregulation of FSP1, reduced the accumulation of malondialdehyde and reactive oxygen species, inhibited neuronal ferroptosis, and exerted neuroprotective effects both in vitro and in vivo. Our study provides evidence that supplementation with CoQ10 can effectively activate the FSP1 system. Additionally, we developed a neuron-targeted liposomal CoQ10 formulation that can be selectively delivered to neurons at the site of SAH. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH. STATEMENT OF SIGNIFICANCE: Subarachnoid hemorrhage (SAH) is primarily attributed to the rupture of intracranial aneurysms and is associated with a high incidence of disability and mortality. Ferroptosis suppressor protein 1 (FSP1), exerts anti-ferroptotic effects by facilitating the conversion of oxidative coenzyme Q 10 (CoQ10) to its reduced form, which effectively scavenges reactive oxygen radicals and mitigates iron-induced ferroptosis. In our investigation, we observed an increase in FSP1 levels following SAH. However, the depletion of CoQ10 caused by SAH hindered the biological function of FSP1. Therefore, we created neuron-targeted liposomal CoQ10. We find that it effectively localized to neurons at the lesion site after SAH and activated the FSP1/CoQ10 system. This innovative approach represents a promising therapeutic strategy for neuronal ferroptosis following SAH and other central nervous system diseases characterized by disruption of the blood-brain barrier.

Lipopolysaccharide binding protein resists hepatic oxidative stress by regulating lipid droplet homeostasis.

Oxidative stress-induced lipid accumulation is mediated by lipid droplets (LDs) homeostasis, which sequester vulnerable unsaturated triglycerides into LDs to prevent further peroxidation. Here we identify the upregulation of lipopolysaccharide-binding protein (LBP) and its trafficking through LDs as a mechanism for modulating LD homeostasis in response to oxidative stress. Our results suggest that LBP induces lipid accumulation by controlling lipid-redox homeostasis through its lipid-capture activity, sorting unsaturated triglycerides into LDs. N-acetyl-L-cysteine treatment reduces LBP-mediated triglycerides accumulation by phospholipid/triglycerides competition and Peroxiredoxin 4, a redox state sensor of LBP that regulates the shuttle of LBP from LDs. Furthermore, chronic stress upregulates LBP expression, leading to insulin resistance and obesity. Our findings contribute to the understanding of the role of LBP in regulating LD homeostasis and against cellular peroxidative injury. These insights could inform the development of redox-based therapies for alleviating oxidative stress-induced metabolic dysfunction.

Antioxidant, anti-inflammatory and antiseptic molecular actions of gedunin against lipopolysaccharide-induced sepsis in experimental rats.

BACKGROUND: Sepsis is a life-threatening organ dysfunction without effective therapeutic options. Lipopolysaccharide (LPS), a bacterial endotoxin, is known to induce sepsis. It is associated with oxidative stress, inflammation and multiple organ failure. Gedunin (GN) is a tetranortriterpenoid isolated from the Meliaceae family. Gedunin possesses numerous pharmacological properties, including antibacterial, anti-inflammatory, antiallergic, and anticancer activities. However, the molecular anti-inflammatory mechanism of GN in sepsis has not been established. OBJECTIVES: The aim of the study was to explore the antioxidant and anti-inflammatory molecular actions underlying the antiseptic activity of GN in an LPS-induced rat model. MATERIAL AND METHODS: Rats were randomized into 4 sets: group 1 (control) was given 1 mL of dimethyl sulfoxide (DMSO) by gavage, group 2 rats were treated with LPS (100 µg/kg body weight (BW), intraperitoneally (ip.)), group 3 rats were given LPS (100 µg/kg BW, ip.)+GN (50 mg/kg BW in DMSO), and rats in the group 4 were given GN (50 mg/kg BW in DMSO) alone. We studied hepatic markers, inflammatory cytokines and antioxidants using specific biochemical kits and analyzed their statistical significance. Histopathology of liver, lungs and kidney tissues was also explored. The mRNA levels and conducted protein investigations were performed using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot, respectively. RESULTS: Our findings revealed that GN significantly (p < 0.05) inhibited oxidative stress, lipid peroxides, toxic markers, pro-inflammatory cytokines, and histological changes, thereby preventing multi-organ impairment. Additionally, GN attenuated the HMGß1/NLRP3/NF-κB signaling pathway and prevented the degradation of Iκßα. CONCLUSIONS: Gedunin is a promising natural antiseptic agent for LPS-induced sepsis in rats.

An overview of scholarly literature on navigation hazards in Arctic shipping routes.

Maritime transport plays a crucial role in international trade. As the number and tonnage of ships continue to increase, traditional shipping routes are becoming progressively congested. The development of Arctic shipping routes has the potential to significantly improve trade efficiency and decrease reliance on traditional shipping routes. At the same time, the harsh navigation conditions in the Arctic pose a huge challenge to ships crossing the Arctic shipping routes. To address the above issues, this paper reviews the natural, navigational environment and unique navigational modes of ships in the Arctic shipping routes. Furthermore, the navigational risks caused by factors including low temperature, sea ice, poor visibility, communication, lack of infrastructure, lack of navigational experience, lack of historical data, high collision risk, and complex navigational environment are summarized and analyzed, providing a reference for researchers and policymakers to conduct research related to Arctic shipping routes.

Effects of oxycodone hydrochloride sustained-release tablets and morphine hydrochloride sustained-release tablets on peripheral blood T cell levels in advanced lung squamous cell carcinoma with moderate to severe cancer pain.

Objective: To investigate the effects of morphine hydrochloride sustained-release tablets and oxycodone hydrochloride sustained-release tablets on T-cell levels in advanced lung squamous cell carcinoma(LUSC) with moderate to severe cancer pain. Methods: A retrospective study was used, ninety-eight patients who were admitted to The First Affiliated Hospital of Hebei North University for treatment of advanced LUSC with moderate to severe cancer pain between January 2021 and December 2021 were randomized into two groups(n=49 each) using the sealed envelope system. The reference group was treated with morphine hydrochloride sustained-release tablets, while the experimental group received oxycodone hydrochloride sustained-release tablets to compare pain relief rates(PRRs), levels of T cells, pain intensity, et al. Blood samples were collected for lymphocyte levels by flow cytometry. Results: The experimental group had significantly higher level than the reference group(P<0.05). Before administration, the two groups did not differ greatly in levels of T-cell subsets or pain scores on the visual analog scale(P>0.05, respectively). At 15 days of administration, the Treg level in the experimental group was higher than in the reference group; T helper 17 and 22 cells were reduced in both groups, and the decrease was more pronounced in the experimental group. At seven and 15 days of administration, the experimental group had a VAS score significantly lower than the reference group(P<0.05). The total adverse reaction rate was significantly lower in the experimental group as compared with the reference group(P<0.05). Conclusions: Oxycodone hydrochloride sustained-release tablets demonstrate desirable efficacy and safety in advanced LUSC with moderate to severe cancer pain by modulating T-cells in the body and improving the PRR.

Lipid-hybrid cell-derived biomimetic functional materials: A state-of-the-art multifunctional weapon against tumors.

Tumors are among the leading causes of death worldwide. Cell-derived biomimetic functional materials have shown great promise in the treatment of tumors. These materials are derived from cell membranes, extracellular vesicles and bacterial outer membrane vesicles and may evade immune recognition, improve drug targeting and activate antitumor immunity. However, their use is limited owing to their low drug-loading capacity and complex preparation methods. Liposomes are artificial bionic membranes that have high drug-loading capacity and can be prepared and modified easily. Although they can overcome the disadvantages of cell-derived biomimetic functional materials, they lack natural active targeting ability. Lipids can be hybridized with cell membranes, extracellular vesicles or bacterial outer membrane vesicles to form lipid-hybrid cell-derived biomimetic functional materials. These materials negate the disadvantages of both liposomes and cell-derived components and represent a promising delivery platform in the treatment of tumors. This review focuses on the design strategies, applications and mechanisms of action of lipid-hybrid cell-derived biomimetic functional materials and summarizes the prospects of their further development and the challenges associated with it.

MemBridge: Video-Language Pre-Training With Memory-Augmented Inter-Modality Bridge.

Video-language pre-training has attracted considerable attention recently for its promising performance on various downstream tasks. Most existing methods utilize the modality-specific or modality-joint representation architectures for the cross-modality pre-training. Different from previous methods, this paper presents a novel architecture named Memory-augmented Inter-Modality Bridge (MemBridge), which uses the learnable intermediate modality representations as the bridge for the interaction between videos and language. Specifically, in the transformer-based cross-modality encoder, we introduce the learnable bridge tokens as the interaction approach, which means the video and language tokens can only perceive information from bridge tokens and themselves. Moreover, a memory bank is proposed to store abundant modality interaction information for adaptively generating bridge tokens according to different cases, enhancing the capacity and robustness of the inter-modality bridge. Through pre-training, MemBridge explicitly models the representations for more sufficient inter-modality interaction. Comprehensive experiments show that our approach achieves competitive performance with previous methods on various downstream tasks including video-text retrieval, video captioning, and video question answering on multiple datasets, demonstrating the effectiveness of the proposed method. The code has been available at https://github.com/jahhaoyang/MemBridge.

LncRNA NEAT-2 regulate the function of endothelial progenitor cells in experimental Sepsis model.

BACKGROUND: Sepsis is a life-threatening disease with a limited effectiveness and the potential mechanism remains unclear. LncRNA NEAT-2 is reported to be involved in the regulation of cardiovascular disease. This study aimed to investigate the function of NEAT-2 in sepsis. METHODS: We built sepsis animal model with Male Balb/C mice induced by cecal ligation and puncture (CLP). A total of 54 mice were randomly assigned into eight groups: sham operation group (n = 18), CLP group (n = 18), CLP plus si-control group (n = 3), CLP plus si-NEAT2 group (n = 3), CLP plus mimic control group (n = 3), CLP plus miR-320 group (n = 3), CLP plus normal saline group (n = 3), and normal control group (n = 3). The number of peripheral endothelial progenitor cells (EPCs), the expression level of NEAT-2 and miR-320 were detected during progression of sepsis, as well as the number of peripheral EPCs and level of TNF-α, IL-6, VEGF, ALT, AST and Cr. In addition, the function of EPCs was evaluated after NEAT-2 knockdown and miR-320 overexpression in vitro. RESULTS: The number of circulating EPCs increased significantly in sepsis. NEAT-2 expression was significantly increased in the progress of sepsis, accompanied with miR-320 downregulated. NEAT-2 knockdown and miR-320 overexpression attenuated hepatorenal function and increased cytokines in sepsis. Moreover, NEAT-2 knockdown and miR-320 overexpression decreased the proliferation, migration and angiogenesis of endothelial progenitor cells in vitro. CONCLUSIONS: LncRNA-NEAT2 regulated the number and function of endothelial progenitor cells via miR-320 in sepsis, which may contribute to the development of novel potential clinical therapy for sepsis.

Umbilical cord blood exosomes from very preterm infants with bronchopulmonary dysplasia aggravate lung injury in mice.

Bronchopulmonary dysplasia (BPD) is characterized by abnormal development of the blood vessels and alveoli in lungs, which largely occurs in premature infants. Exosomes (EXO) from very preterm infants (VPI) with BPD (BPD-EXO) impair angiogenic activities of human umbilical vein endothelial cells (HUVECs) via EXO-miRNAs cargo. This study aimed to determine whether and how BPD-EXO affect the development of BPD in a mouse model. We showed that treating BPD mice with BPD-EXO chronically and irreversibly aggravated lung injury. BPD-EXO up-regulated 139 and down-regulated 735 genes in the mouse lung tissue. These differentially expressed genes were enriched to the MAPK pathway (e.g., Fgf9 and Cacna2d3), which is critical to angiogenesis and vascular remodeling. BPD-EXO suppressed expression of Fgf9 and Cacna2d3 in HUVECs and inhibited migration, tube formation, and increased cell apoptosis in HUVECs. These data demonstrate that BPD-EXO aggravate lung injury in BPD mice and impair lung angiogenesis, plausibly leading to adverse outcomes of VPI with BPD. These data also suggest that BPD-EXO could serve as promising targets for predicting and treating BPD.

Relative contributions of fasting and postprandial glucose increments, glycemic variability, and non-glycemic factors to HbA1c in individuals with type 1 diabetes.

AIM: Evidence for contribution of basal and postprandial glucose increment, and glycemic variability to glycated hemoglobin (HbA1c) among adults with type 1 diabetes (T1D) is limited. This study aimed to capture glycemic fluctuation patterns and quantify contributions of these factors to HbA1c levels among adults with T1D. METHODS: HbA1c, continuous glucose monitoring (CGM), and diet diaries were collected and pooled from two clinical trials. Available data sets were divided into HbA1c quartiles: group 1 (≤6.7%), group 2 (6.7%-7.3%), group 3 (7.3%-7.8%), and group 4 (≥7.8%). Area under curve above 110 mg/dL (AUC>110mg/dL ) in 24-h profile was defined as overall hyperglycemia and stratified with postprandial hyperglycemia (PHG, AUC>110mg/dL in 3-h period after meals) and basal hyperglycemia (BHG, AUC>110mg/dL in remaining period). Linear regression analysis was used to estimate the proportion of variance in HbA1c explained by BHG, preprandial glucose, PHG, glycemic variability, and non-glycemic factors (age, body mass index, hemoglobin, and duration). RESULTS: A total of 169 550 glucose data in 2409 meals recorded from 102 patients (male/female, 34/68) were included. Age and duration were 35.2 ± 12.6 and 8.9 (2.9, 13.0) years, with 51.0% using pumps. Overall, BHG was four times higher than PHG (p all <.05) and between-group comparisons showed BHG exhibited a progressive increase (group 1 vs. 2, 3, 4, p = .053, .086, .006) with fasting contribution of 76.1%, 82.6%, 81.5%, and 84.3% from group 1 to 4. The increment was not significant among groups 2, 3, and 4 (p > .05). Factors included in analysis explained a total of 74% of the variance in HbA1c, in which BHG accounted for 32.1% of variance whereas PHG accounted for 24.4%. In group with HbA1c >7.3%, BHG accounted for a higher percentage with 33.8% of the variance in HbA1c. CONCLUSIONS: In our study, basal hyperglycemia better predicts overall glycemic control than postprandial hyperglycemia among adults with T1D. The relative contribution of basal hyperglycemia increased gradually with HbA1c increasing and predominant strategy for insulin titration among T1D is different among different levels of glycemic control.

Kosakonia radicincitans with hypervirulent lON genes causes human bloodstream infections.

Kosakonia radicincitans is a species within the new genus Kosakonia, which is typically a plant pathogen, with rare reports of human infection. The number of human infections may be underestimated because this new genus is under-represented among diagnostic tools. This report describes a case of bloodstream infection caused by K. radicincitans. The pathogen was identified by matrix-assisted laser desorption/ionization-TOF mass spectrometry and 16S rRNA gene sequencing. The hypervirulent human pathogenicity gene LON, which has not been described before, was detected in the bacterial genome by gene annotation. Thus, this discovery provides a new reference for studying the pathogenic mechanism of this rare pathogen.

Clinical Application of Metformin Use in Anhui Province, China: A Cross-Sectional Study.

Purpose: Given the importance of metformin, reasonable utilization is essential. We designed a cross-sectional survey on physicians' attitude and clinical application of metformin in Anhui Province, China. Methods: The survey was distributed via an electronic questionnaire among endocrinologists and general practitioners. Seven representative questions were used to evaluate professional levels. Results: Among the 477 valid responses, 72.75% of the respondents preferred to prescribe metformin extended-release, while only 34.38% of them would prescribe metformin extended-release at the correct frequency. More than half of the respondents thought that estimated glomerular filtration rate ˂ 45 mL/min/1.73 m² should be the contraindication of metformin prescription. Less than 10% of the physicians selected correct responses for two questions regarding metformin usage and contrast agent. Physicians with higher levels of hospital grades, education background and professional titles as well as working in general hospitals and in the Department of Endocrinology achieved high scores (P˂0.05). Logistic regression showed that department was an independent predictor for high scores. Conclusion: Physicians, especially non-endocrinologists, are not at a professional level for prescribing metformin. Physicians should be highly vigilant in terms of standardized prescription for metformin. The guidelines or consensuses about diabetes care for physicians should be promoted.

Effects of intermittently scanned continuous glucose monitoring in adult type 1 diabetes patients with suboptimal glycaemic control: A multi-centre randomized controlled trial.

AIMS: To investigate whether intermittently scanned continuous glucose monitoring without alarms (intermittently scanned CGM (isCGM)) improves glycaemic control over capillary blood glucose monitoring (BGM) among adult type 1 diabetes mellitus (T1DM) patients with suboptimal control. MATERIALS AND METHODS: Adults with T1DM and HbA1c between 7% and 10% were 1:1 randomized to use isCGM or BGM for 24 weeks. The primary outcome was the change in HbA1c levels after intervention. The secondary outcomes were the changes in sensor-derived metrics. RESULTS: A total of 104 adults with T1DM (34.2 ± 12.2 years; M/F, 38/66) were randomized to the isCGM group (n = 54) and the BGM group (n = 50). After 24 weeks, HbA1c significantly decreased in the isCGM group (8.1 ± 0.7% to 7.5 ± 1.0%) and the BGM group (8.0 ± 0.8% to 7.7 ± 1.0%) with between-group differences of 0.3% (95% coefficient intervals, 0.0%-0.6%; P = 0.04). The percentage of HbA1c reduction over 1.0% and 1.5% was significantly higher in the isCGM group with adjusted odds ratios of 2.5 (95% CI: 1.1-5.5; P = 0.03) and 3.2 (95% CI: 1.1-9.0; P = 0.03). Mean time-in-range 70-180 mg/dl (TIR) in the isCGM group significantly increased (from 58.5 ± 13.0% to 63.0 ± 12.6%), whereas mean TIR was similar in the BGM group (from 58.0 ± 14.6% to 57.5 ± 14.5%). Time spent in hyperglycemia reduced more in the isCGM group and time spent in hypoglycemia did not change significantly in both groups. CONCLUSIONS: Among adult T1DM patients with suboptimal glycaemic control, compared with BGM, isCGM use resulted in a statistically significant improvement in glycaemic control after 24-week intervention. TRIAL REGISTRATION: Clinicaltrials.gov Identifier (NCT03522870).

Biomembrane-Based Nanostructure- and Microstructure-Loaded Hydrogels for Promoting Chronic Wound Healing.

Wound healing is a complex and dynamic process, and metabolic disturbances in the microenvironment of chronic wounds and the severe symptoms they cause remain major challenges to be addressed. The inherent properties of hydrogels make them promising wound dressings. In addition, biomembrane-based nanostructures and microstructures (such as liposomes, exosomes, membrane-coated nanostructures, bacteria and algae) have significant advantages in the promotion of wound healing, including special biological activities, flexible drug loading and targeting. Therefore, biomembrane-based nanostructure- and microstructure-loaded hydrogels can compensate for their respective disadvantages and combine the advantages of both to significantly promote chronic wound healing. In this review, we outline the loading strategies, mechanisms of action and applications of different types of biomembrane-based nanostructure- and microstructure-loaded hydrogels in chronic wound healing.

Fusidic Acid and Its Major Active Metabolite Penetration into Cerebrospinal Fluid for Assessing Treatment of Intracranial Infections.

Fusidic acid (FA) had excellent antimicrobial effects due to its unique mechanism of action. Since 1962, FA has been widely used in the systemic and topical treatment of staphylococcal infections and exhibits a well-characterized potency against methicillin-susceptible Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and methicillin-resistant coagulase-negative Staphylococci. In view of the spectrum of activity, no cross-resistance with other clinically used antibiotics, and potential penetration into brain tissue, FA was used to treat possible gra-positive bacteria in 3 patients with intracranial infections in the present report. FA and its active metabolite (3-keto FA) were measured in plasma and cerebrospinal fluid (CSF) to assess the treatment of FA, and the results indicated that 1,500 mg per day of FA was sufficient to achieve therapeutic concentrations in both plasma and CSF in intracranial infection patients, while the dosage did not experience unexpected regimen-related toxicity.

The Serum Uric Acid to Serum Creatinine Ratio is an Independent Risk Factor for Diabetic Kidney Disease.

Purpose: A retrospective study was designed to evaluate whether the serum uric acid to serum creatinine ratio (SUA/SCr) can be used as an indicator of diabetic kidney disease (DKD) and macroangiopathy in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: We screened 2227 patients diagnosed with T2DM, and 450 patients were finally included. They were assigned to three groups based on the tertile of SUA/SCr (Group Tertile 1, Tertile 2, Tertile 3). Demographic information and biochemical parameters were collected from Electronic Patient Record (EPR). Results: The estimated glomerular filtration rate (eGFR) values were lowest in Group Tertile 1 and highest in Group Tertile 3 (P < 0.05). There was no significant difference in urinary albumin creatinine ratio (UACR) among the three groups (P > 0.05). Partial correlation analyses revealed that SUA/SCr levels were significantly and positively correlated with eGFR, SUA, body mass index, gamma-glutamyl transpeptidase, alanine transaminase, triglycerides, C-peptide, high-density lipoprotein cholesterol and fatty liver, while they were negatively correlated with SCr, blood urea nitrogen, cystatin-c, age, male sex, DM duration and hypertension history (P < 0.05). Logistic regression analysis revealed that SUA/SCr was an independent risk factor for eGFR < 60 mL/min/1.73 m² (P < 0.05). The ROC curve showed that the cutoff value of SUA/SCr for the identification of eGFR < 60 mL/min/1.73 m² was 3.434. In patients with normal UACR, SUA/SCr levels of patients with eGFR < 60 mL/min/1.73 m² were lower than those with eGFR ≥ 60 mL/min/1.73 m² (P < 0.05). Regression analysis did not show SUA/SCr associate to macrovascular disease after adjusting for confounding factors. Conclusion: SUA/SCr is an independent risk factor for DKD in patients with T2DM and may be helpful for identifying normoalbuminuric DKD.

Diabetic ketoacidosis induced by nivolumab in invasive mucinous adenocarcinoma of the lung: a case report and review of the literature.

Background: Nivolumab is the first programmed cell death receptor 1 (PD-1) inhibitor approved in China. Compared with chemotherapy, nivolumab has shown advantages of good efficacy and safety in the treatment of a variety of tumors. However, due to its short time of use in China and lack of safety experience, clinical understanding of its adverse reactions has not been sufficiently elucidated. In recent years, cases of diabetic ketoacidosis caused by nivolumab have been reported in the emergency department, which has aroused our concern. Case Description: Here we present a serious case of diabetic ketoacidosis in a 69-year-old woman with invasive mucinous adenocarcinoma of the lung, which occurred following therapy with the PD-1 inhibitor nivolumab and dendritic cell/cytokine-induced killer cell (DC/CIK) immunotherapy. She presented with diabetic ketoacidosis 5 days after the second cycle of nivolumab administration. The patient presented with dry mouth symptoms, a maximum blood glucose of 511.2 mg/dL, hemoglobin A1c (HbA1c) level of 7.4%, urine ketone body value of 3+, and extracellular fluid residual alkali level of -3.8 mmol/L. Normal saline and insulin was initiated. The patient had no history of obesity or family history of diabetes. She received a single dose of 3.75 mg of dexamethasone treatment during this period of time which resulted in cough improvement, but did not explain the onset of the diabetes. She was treated with insulin, sitagliptin phosphate tablets and acarbose tablets. Diabetic ketoacidosis was considered an immune-related toxicity caused by nivolumab, and consequently, treatment with nivolumab was suspended. Patient was maintained under insulin treatment with a blood glucose levels normalization. Conclusions: The incubation period of nivolumab-induced diabetic ketoacidosis is dispersive and the clinical risk is high. Patients need life-long insulin therapy. Blood glucose and HbA1c should be monitored routinely before and during nivolumab immunotherapy to avoid the occurrence of diabetic ketoacidosis. After the occurrence of diabetic ketoacidosis, insulin should be used to actively control blood glucose and do a good job in medication education to ensure long-term compliance of patients. Nivolumab should only be initiated if the patient has a clinical benefit under stable glucose control.

Revealing the Pathogenesis of Salt-Sensitive Hypertension in Dahl Salt-Sensitive Rats through Integrated Multi-Omics Analysis.

Salt-induced renal metabolism dysfunction is an important mechanism of salt-sensitive hypertension. Given that the gut-liver axis is the first hit of a high-salt diet (HSD), we aimed to identify the extra-renal mechanism from hepatic metabolism and gut microbiota, and attempted to relieve the salt-induced metabolic dysfunctions by curcumin. Untargeted metabolomics analysis was performed to identify the changes in hepatic metabolic pathways, and integrated analysis was employed to reveal the relationship between hepatic metabolic dysfunction and gut microbial composition. HSD induced significant increase in fumaric acid, l-lactic acid, creatinine, l-alanine, glycine, and l-cysteine levels, and amino acids metabolism pathways associated with glycolysis were significantly altered, including alanine, aspartate, and glutamate metabolism; glycine, serine, and threonine metabolism, which were involved in the regulation of blood pressure. Integrated multi-omics analysis revealed that changes in Paraprevotella, Erysipelotrichaceae, and genera from Clostridiales are associated with metabolic disorders. Gene functional predication analysis based on 16S Ribosomal RNA sequences showed that the dysfunction in hepatic metabolism were correlated with enhanced lipopolysaccharide (LPS) biosynthesis and apoptosis in gut microbes. Curcumin (50 mg/kg/d) might reduce gut microbes-associated LPS biosynthesis and apoptosis, partially reverse metabolic dysfunction, ameliorate renal oxidative stress, and protect against salt-sensitive hypertension.