Rational Design of Diatomic Active Sites for Elucidating Oxygen Evolution Reaction Performance Trends.

Diatomic catalysts, especially those with heteronuclear active sites, have recently attracted significant attention for their advantages over single-atom catalysts in reactions with relatively high energy barrier, e.g. oxygen evolution reaction. Rational design and synthesis of heteronuclear diatomic catalysts are of immense significance but have so far been plagued by the lack of a definitive correlation between structure and catalytic properties. Here, we report macrocyclic precursor constrained strategy to fabricate series of transition metal (MT, Ni, Co, Fe, Mn, or Cu)-noble (MN, Ir or Ru) centers in carbon material. One notable performance trend is observed in the order of Cu-MN < Mn-MN < Fe-MN < MN < Co-MN < Ni-MN. However, the pathway has been not altered, still following the traditional adsorption reaction mechanism. The effect of the MT atoms on the performances could possibly originate from the distinct adsorption/desorption behaviors of key intermediates (i.e. *OH, *O and/or *OOH), strongly implying that ΔG*OOH-ΔG*OH could be used as the performance descriptor. We believe that our work provides useful strategy for synthesis of diatomic active sites with sole coordination configuration and varied composition, and in-depth insight to their catalytic mechanism, which could be used for further optimization of diatomic catalysts towards oxygen electrocatalysis.

Alendronate-functionalized polymeric micelles target icaritin to bone for mitigating osteoporosis in a rat model.

Formulating drugs into nanoparticles that target sites of disease can lead to strong therapeutic effects with lower doses of drugs and lower rates of off-target adverse effects. Few ways to target drugs to bone have been described, hampering the treatment of osteoporosis. Here we exploit the ability of alendronate to bind tightly to hydroxyapatite in bone as a tactic to target polymeric micelles loaded with the plant flavonoid icaritin to osteoporotic lesions. The traditional Chinese medicine icaritin, from Herba Epimedii, has previously been shown to inhibit adipogenesis and enhance osteogenesis by bone mesenchymal stem cells, but the compound on its own persists only briefly in the bloodstream. Our delivery system led to stronger inhibition of adipogenesis and activation of osteogenesis in a rat model of osteoporosis than when the icaritin-loaded micelles lacked alendronate. These results establish the feasibility of using alendronate to target osteogenic phytomolecules to sites of bone injury, which may guide the development of effective therapies against osteoporosis and, by extension, other bone disorders.

Recurrent multisystem Langerhans cell histiocytosis involving the female genitalia: A case report.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a histiocytic proliferative disease caused by clonal proliferation of Langerhans cells, which is currently defined as an inflammatory myeloid tumor. It is rare in adults, with an incidence of 1-2 per million, and is highly heterogeneous in clinical presentation, with unpredictable disease progression and outcome. CASE SUMMARY: A 52-year-old postmenopausal female patient presented to the gynecology department in July 2023 with bilateral vulvar masses. She was diagnosed with recurrent multisystem LCH. The patient had previously been diagnosed with a single-system and single-focal LCH in October 2021 due to a right maxillofacial mass, which resolved after surgical treatment. A chemotherapy regimen was developed after multidisciplinary consultation. Six cycles of chemotherapy resulted in partial remission, and maintenance chemotherapy is currently being administered. CONCLUSION: Recurrent LCH involving the bilateral vulva has been poorly reported. Comprehensive imaging and pathological evaluation is important for diagnosis. The model of joint multidisciplinary specialist diagnosis and treatment is worthy of clinical application.

Optimizing electric load forecasting with support vector regression/LSTM optimized by flexible Gorilla troops algorithm and neural networks a case study.

This research work focuses on addressing the challenges of electric load forecasting through the combination of Support Vector Regression and Long Short-Term Memory (SVR/LSTM) methodology. The model has been modified by a flexible version of the Gorilla Troops optimization algorithm. The objective of this study is to enhance the precision and effectiveness of load forecasting models by integrating the adaptive functionalities of the Gorilla Troops algorithm within the SVR/LSTM framework. To assess the efficacy of the proposed methodology, a comprehensive series of experiments and evaluations have been undertaken, utilizing authentic data obtained from 200 residential properties located in Texas, United States of America. The dataset comprises historical records of electricity consumption, meteorological data, and other pertinent variables that exert an impact on energy demand. The presence of this general dataset enhances the dependability and inclusiveness of the empirical findings. The proposed methodology was evaluated against various contemporary load forecasting techniques that are widely employed in the industry. The results of a comprehensive evaluation and performance analysis indicate that the modified SVR/LSTM model exhibits superior performance compared to the existing methods in terms of accuracy and robustness. The comparison results unequivocally demonstrate the superiority of the proposed method in accurately forecasting electric load demand.

When anaphylactic shock meets epinephrine and blood lactate increases: A case report.

RATIONALE: Anaphylactic shock, a severe and rapid systemic allergic reaction, poses significant treatment challenges. Epinephrine, the first-line treatment, effectively reverses symptoms but can complicate the clinical picture by elevating lactate levels, blurring the distinction between shock-induced hypoperfusion and drug-induced metabolic effects. PATIENT CONCERNS: A 26-year-old female presented with anaphylactic shock following an antibiotic infusion, experiencing chest tightness, hypotension, and pulmonary edema, without significant past medical history apart from a noted allergy to fish and shrimp. DIAGNOSES: Anaphylaxis was diagnosed based on clinical presentation and supported by imaging that revealed pulmonary edema, despite normal troponin levels and electrocardiogram. INTERVENTIONS: Treatment included 0.5 mg of intramuscular epinephrine and 5 mg of intravenous dexamethasone, with subsequent intubation and mechanical ventilation in the intensive care unit. An intravenous epinephrine infusion was also administered for hemodynamic support. OUTCOMES: While epinephrine resolved the pulmonary edema and stabilized circulation, it led to a significant, albeit transient, increase in lactate levels, which normalized following discontinuation of epinephrine, indicating the metabolic effect of the drug rather than ongoing tissue hypoperfusion. LESSONS: This case illustrates the importance of recognizing epinephrine-induced lactate elevation in anaphylactic shock, necessitating a nuanced interpretation of lactate dynamics. Clinicians must differentiate between lactate elevations due to tissue hypoperfusion and those arising from epinephrine's pharmacologic effects to optimize patient care.

Plastid phylogenomics provides new insights into the systematics, diversification, and biogeography of Cymbidium (Orchidaceae).

Cymbidium (Orchidaceae: Epidendroideae), with around 60 species, is widely-distributed across Southeast Asia, providing a nice system for studying the processes that underlie patterns of biodiversity in the region. However, phylogenetic relationships of Cymbidium have not been well resolved, hampering investigations of species diversification and the biogeographical history of this genus. In this study, we construct a plastome phylogeny of 56 Cymbidium species, with four well-resolved major clades, which provides a framework for biogeographical and diversification rate analyses. Molecular dating and biogeographical analyses show that Cymbidium likely originated in the region spanning northern Indo-Burma to the eastern Himalayas during the early Miocene (∼21.10 Ma). It then rapidly diversified into four major clades in East Asia within approximately a million years during the middle Miocene. Cymbidium spp. migration to the adjacent regions (Borneo, Philippines, and Sulawesi) primarily occurred during the Pliocene-Pleistocene period. Our analyses indicate that the net diversification rate of Cymbidium has decreased since its origin, and is positively associated with changes in temperature and monsoon intensity. Favorable hydrothermal conditions brought by monsoon intensification in the early Miocene possibly contributed to the initial rapid diversification, after which the net diversification rate was reduced with the cooling climate after the middle Miocene. The transition from epiphytic to terrestrial habits may have enabled adaptation to cooler environments and colonization of northern niches, yet without a significant effect on diversification rates. This study provides new insights into how monsoon activity and temperature changes affected the diversification dynamics of plants in Southeast Asia.

Renal-Targeted Drug Delivery by Chitosan Oligosaccharide Micelles with HSA-Enriched Protein Corona for the Treatment of Ischemia/Reperfusion-Induced Acute Kidney Injury.

Renal-specific nanoparticulate drug delivery systems have shown great potential in reducing systemic side effects and improving the safety and efficacy of treatments for renal diseases. Here, stearic acid-grafted chitosan oligosaccharide (COS-SA) was synthesized as a renal-targeted carrier due to the high affinity of the 2-glucosamine moiety on COS to the megalin receptor expressed on renal proximal tubular epithelial cells. Specifically, COS-SA/CLT micelles were prepared by encapsulating celastrol (CLT) with COS-SA, and different proportions of human serum albumin (HSA) were then adsorbed onto its surface to explore the interaction between the protein corona and cationic polymeric micelles. Our results showed that a multilayered protein corona, consisting of an inner "hard" corona and an outer "soft" corona, was formed on the surface of COS-SA/CLT@HSA8, which was beneficial in preventing its recognition and phagocytosis by macrophages. The formation of HSA protein corona on COS-SA/CLT micelles also increased its accumulation in the renal tubules. Furthermore, the electropositivity of COS-SA/CLT micelles affected the conformation of adsorbed proteins to various degrees. During the adsorption process, the protein corona on the surface of COS-SA/CLT@HSA1 was partially denatured. Overall, COS-SA/CLT and COS-SA/CLT@HSA micelles demonstrated sufficient safety with renal targeting potential, providing a viable strategy for the management of ischemia/reperfusion-induced acute kidney injury.

Host-guest strategy improves rheological properties, conformational stability and oil displacement efficiency of xanthan gum.

The low cost and environmental advantages of Xanthan gum make its production and application scale exceed that of other polysaccharides. However, the temperature resistance of Xanthan gum limits its application. In this study, polysaccharide supramolecular Xanthan gum network (XG-ß-CD/AD) based on ß-cyclodextrin and adamantane was prepared for enhanced oil recovery. The structure of Xanthan gum was characterized by Fourier infrared spectroscopy, nuclear magnetic resonance spectroscopy and thermogravimetric analysis. The rheological properties of the modified polysaccharide network in aqueous solution were systematically studied. The results showed that physical cross-linking of host-guest interacion enhanced the thickening ability of the polymer. Shear rheology, extensional rheology and dynamic modulus test proved that XG-ß-CD/AD had excellent rheological properties. The micromorphology, dynamic light scattering and circular dichroism clarified the molecular conformation, the host-guest interaction can improve conformational transition temperature (Tm) and inorganic salt tolerance of Xanthan gum. Under harsh environment (90 °C, 30000 mg/L brine), the oil recovery of XG-ß-CD/AD is 6 %-11 % higher than that of XG at the same conditions, showing a better ability to improve the recovery rate. This study provides a research idea for the selection, development and application of biomacromolecular materials.

The Activity Patterns and Grouping Characteristics of the Remaining Goitered Gazelle (Gazella subgutturosa) in an Isolated Habitat of Western China.

Wildlife activity patterns, which reveal the daily allocation of time and energy, are crucial for understanding survival pressures, adaptive strategies, and behavioral characteristics in different environments. Among ungulates, grouping behavior is a prevalent adaptive trait that reflects the population structure, mating systems, and life history strategies formed over long-term evolutionary processes. This study aimed to elucidate the daily activity patterns and grouping characteristics of the rare goitered gazelle (Gazella subgutturosa) in the Helan Mountains of western China from 2022 to 2023 using camera trap monitoring. With a total of 3869 camera days of effective trapping, we recorded 442 independent detections of goitered gazelles. The results revealed the following: (1) Goitered gazelle is primarily active during the day, showing an activity pattern similar to crepuscular animals, with two activity peaks occurring after dawn and before dusk. (2) Daily activity patterns showed both seasonal and sex differences. In the warm season, morning activity peaks occurred earlier, and afternoon peaks occurred later compared to the cold season. The overlap in daily activity patterns between females and males in the warm season was lower than that in the cold season, and this trend persisted throughout the year. (3) The number of times different types of groups were observed varied significantly, with single males and single females accounting for a larger proportion of all observed groups. There was no significant difference in group size across seasons, with groups typically consisting of 1-2 individuals. Our study provides detailed insights into the temporal ecology and population structure of goitered gazelles in arid and semi-arid ecosystems. This information will guide the identification of future conservation priorities and the development of management plans for the reserve.

A new long-acting analgesic formulation for postoperative pain management.

Local anesthetics (LA), as part of multimodal analgesia, have garnered significant interest for their role in delaying the initiation of opioid therapy, reducing postoperative opioid usage, and mitigating both hospitalization duration and related expenses. Despite numerous endeavors to extend the duration of local anesthetic effects, achieving truly satisfactory long-acting analgesia remains elusive. Drawing upon prior investigations, vesicular phospholipid gels (VPGs) emerge as promising candidates for extended-release modalities in small-molecule drug delivery systems. Therefore, we tried to use the amphiphilicity of phospholipids to co-encapsulate levobupivacaine hydrochloride and meloxicam, two drugs with different hydrophilicity, to obtain a long-term synergistic analgesic effect. Initially, the physicochemical attributes of the formulation were characterized, followed by an examination of its in vitro release kinetics, substantiating the viability of extending the release duration of the dual drugs. Sequentially, in vivo investigations encompassing pharmacokinetic profiling and assessment of analgesic efficacy were undertaken, revealing a prolonged release duration of up to 120 h and attainment of optimal postoperative analgesia. Subsequently, inquiries into the mechanism underlying synergistic analgesic effects and safety evaluations pertinent to the delivery strategy were pursued. In summation, we successfully developed a promising formulation to achieve long-acting analgesia.

Sialic acid-modified docetaxel cationic liposomes: double targeting of tumor-associated macrophages and tumor endothelial cells.

Taxane drugs are clinically used for the treatment of many types of cancers due to their excellent antitumor effects. However, the surfactants contained in the injections currently used in the clinic may have serious toxic side effects on the organism, making it necessary to develop new dosage forms. Cationic liposomes have been widely used in antitumor research because of their advantage of preferentially targeting tumor neovascularization, but antitumor by targeting tumor vasculature alone does not necessarily provide good results. Malignant tumors represent complex ecosystems, tumor-associated macrophages (TAMs) and tumor endothelial cells (TECs) in the tumor microenvironment play crucial roles in tumor growth. Therefore, given the ability to achieve active targeting of TAMs and TECs by using sialic acid (SA) as a targeting material, the potential of cationic nanoformulations to preferentially target neovascularization at the tumor site, and the excellent antitumor effects of the taxane drugs docetaxel (DOC), in the present study, sialic acid-cholesterol coupling (SA-CH) was selected as a targeting material to prepare a DOC cationic liposome (DOC-SAL) for tumor therapy. The results of the study showed that DOC-SAL had the strongest drug accumulation in tumor tissues compared with the common DOC formulations, and was able to effectively reduce the colonization of TAMs, inhibit the proliferation of tumor cells, and have the best tumor-suppressing effect. In addition, DOC-SAL was able to improve the internal microenvironment of tumors by modulating cytokines. In summary, this drug delivery system has good anti-tumor effects and provides a new option for tumor therapy.

Dexamethasone Palmitate Encapsulated in Palmitic Acid Modified Human Serum Albumin Nanoparticles for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory joint condition characterized by symmetric, erosive synovitis leading to cartilage erosion and significant disability. Macrophages, pivotal in disease progression, release pro-inflammatory factors upon activation. We developed a nanoparticle delivery system (DXP-PSA NPs), based on palmitic acid modified human serum albumin (PSA), to deliver dexamethasone palmitate (DXP) directly to sites of inflammation, enhancing treatment effectiveness and minimizing possible side effects. The system actively targets scavenger receptor-A on activated macrophages, achieving selective accumulation at inflamed joints. In vitro effect and preliminary targeting abilities were investigated on LPS-activated RAW264.7 cells. The in vivo efficacy and safety were evaluated and compared side to side with commercially available lipid emulsion Limethason® in an advanced adjuvant-induced arthritis rat model. DXP-PSA NPs offer a novel approach to RA treatment and presents promising prospects for clinical translation.

Cascade Synthesis of Fe-N2-Fe Dual-Atom Catalysts for Superior Oxygen Catalysis.

Dual-atom catalysts (DACs) have been proposed to break the limitation of single-atom catalysts (SACs) in the synergistic activation of multiple molecules and intermediates, offering an additional degree of freedom for catalytic regulation. However, it remains a challenge to synthesize DACs with high uniformity, atomic accuracy, and satisfactory loadings. Herein, we report a facile cascade synthetic strategy for DAC via precise electrostatic interaction control and neighboring vacancy construction. We synthesized well-defined, uniformly dispersed dual Fe sites which were connected by two nitrogen bonds (denoted as Fe-N2-Fe). The as-synthesized DAC exhibited superior catalytic performances towards oxygen reduction reaction, including good half-wave potential (0.91 V), high kinetic current density (21.66 mA cm-2), and perfect durability. Theoretical calculation revealed that the DAC structure effectively tunes the oxygen adsorption configuration and decreases the cleavage barrier, thereby improving the catalytic kinetics. The DAC-based zinc-air batteries exhibited impressive power densities of 169.8 and 52.18 mW cm-2 at 25 °C and -40 °C, which is 1.7 and 2.0 times higher than those based on Pt/C+Ir/C, respectively. We also demonstrated the universality of our strategy in synthesizing other M-N2-M DACs (M=Co, Cu, Ru, Pd, Pt, and Au), facilitating the construction of a DAC library for different catalytic applications.

Quantitative Characterization of Adhesion Work on Shale Surfaces and Discussion on the Influence of Roughness Based on Atomic Force Microscopy (AFM).

Adhesion is an intrinsic property of rocks and liquids. Investigating the factors contributing to its formation and the mechanisms governing its action is crucial for elucidating the adhesion work between solids and liquids. The adhesion work, serving as a parameter that characterizes the energy changes during the solid-liquid contact process, is a vital tool for probing this phenomenon. However, conventional measurements of the adhesion work are significantly influenced by surface roughness and fail to differentiate local variations in the adhesion performance. This limitation obscures our understanding of the primary adsorption sites and mechanisms between solids and liquids, posing significant challenges to the study of rock surface properties. In this study, in conjunction with scanning electron microscopy and contact angle analyses, we elucidated for the first time the locations where voids form during the solid-liquid contact process, the lithological composition of rough areas, and their impact on the adhesion work between water/oil and the surfaces. Additionally, employing atomic force microscopy (AFM), we examined the variations in water/oil-solid adhesion work across different characteristic regions, thereby characterizing the overall hydrophilic/hydrophobic properties of the rock core. Specific conclusions are as follows: (1) A negative correlation exists between roughness and the contact angle adhesion work, with heterogeneity impeding liquid-rock contact; (2) By comparing the strength of water-solid/oil-solid adhesion work within localized areas, we delineated the adhesion work characteristics of samples and their primary generation sites, with oil-solid adhesion work in target blocks predominantly originating from quartz, clay minerals, and organic matter; (3) The influence of pore throat development on the overall adhesion work of samples was clarified, demonstrating that an increase in the proportion of internal rock pores enhances the surface oil-solid adhesion work; (4) A dimensionless wetting index I was established to mitigate the impact of roughness on the expression of adhesion work, exhibiting a strong correlation with traditional evaluation methods.

Inhibiting HMGCR represses stemness and metastasis of hepatocellular carcinoma via Hedgehog signaling.

Cancer stem cells (CSCs) play a crucial role in tumor initiation, recurrence, metastasis, and drug resistance. However, the current understanding of CSCs in hepatocellular carcinoma (HCC) remains incomplete. Through a comprehensive analysis of the database, it has been observed that 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a critical enzyme involved in cholesterol synthesis, is up-regulated in HCC tissues and liver CSCs. Moreover, high expression of HMGCR is associated with a poor prognosis in patients with HCC. Functionally, HMGCR promotes the stemness and metastasis of HCC both in vitro and in vivo. By screening various signaling pathway inhibitors, we have determined that HMGCR regulates stemness and metastasis by activating the Hedgehog signaling in HCC. Mechanistically, HMGCR positively correlates with the expression of the Smoothened receptor and facilitates the nuclear translocation of the transcriptional activator GLI family zinc finger 1. Inhibition of the Hedgehog pathway can reverse the stimulatory effects of HMGCR on stemness and metastasis in HCC. Notably, simvastatin, an FDA-approved cholesterol-lowering drug, has been shown to inhibit stemness and metastasis of HCC by targeting HMGCR. Taken together, our findings suggest that HMGCR promotes the regeneration and metastasis of HCC through the activation of Hedgehog signaling, and simvastatin holds the potential for clinical suppression of HCC metastasis.

Exploring depressive symptoms and coping strategies in Chinese women facing infertility: A cross-sectional observational study.

Infertility can lead to significant psychological distress among women, yet the roles of hope and resilience in mitigating depressive symptoms remain inadequately explored, particularly within the Chinese context. We performed a cross-sectional observational study to investigate the psychological impacts of infertility among Chinese women as well as to discern whether hope and resilience can influence their depressive symptoms. We recruited 364 Chinese women seeking infertility treatment in the Shandong region. Participants completed validated assessments including the Hospital Anxiety and Depression Scale, Connor-Davidson Resilience Scale, and Herth Hope Index. Demographic and clinical data were also collected. We observed elevated levels of depressive symptoms and anxiety among women with infertility. Particularly, demographic factors such as an older age, rural residence, lower income, lower education, adverse life events, and longer infertility duration were associated with increased depressive symptoms. Individuals who experienced adverse life events were at a 2.42-fold increased risk of developing depressive symptoms (P = .04). Depressive symptoms were inversely correlated with both hope levels (r = -0.25; P < .05) and resilience levels (r = -0.32; P < .05). Hope levels were positively correlated with resilience (R = 0.67; P < .05). After controlling for the interaction of hope and resilience, we found that only depressive symptoms and resilience were negatively correlated. The psychological burden of infertility among Chinese women is widespread and affects many individuals from different demographic backgrounds. Interventions aimed at increasing resilience may be helpful to mitigate depressive symptoms.

Intra-Articular Delivery of an AAV-Anti-TNF-α Vector Alleviates the Progress of Arthritis in a RA Mouse Model.

Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disease marked by joint destruction and functional impairment. Tumor necrosis factor (TNF) plays a critical role in RA pathogenesis. Although TNF-targeting drugs are clinically effective, their need for frequent and long-term administration often results in poor patient adherence and suboptimal outcomes. This study developed a gene therapy approach using engineered adeno-associated virus (AAV) vectors to deliver an anti-TNF agent directly into the joint cavity of RA animal models. Animals receiving this therapy demonstrated sustained improvement in clinical scores, inflammatory markers, and joint tissue health. Immunofluorescence staining revealed that AAV vectors could transduce various cell types, including T cells, type A synoviocytes, and dendritic cells. Our results indicate that a single administration of this gene therapy provided long-term efficacy. This suggests that AAV-mediated anti-TNF gene therapy can offer prolonged relief from clinical symptoms and reduce inflammatory damage in a mouse model of RA. This innovative approach presents a promising new therapy with significant clinical prospects to treat patients with RA.

Optimizing the Intermediates Adsorption by Manipulating the Second Coordination Shell of Ir Single Atoms for Efficient Water Oxidation.

The precise regulation of single-atom catalysts (SACs) with the desired local chemical environment is vital to elucidate the relationship between the SACs structure and the catalytic performance. The debate on the effect of the local coordination environment is quite complicated even for the SACs with the same composition and chemical nature, calling for increased attention on the regulation of second coordination shell. For oxide-supported SACs, it remains a significant challenge to precisely manipulate the second coordination shell of single atoms supported on oxides due to the structural robustness of oxides. Here, Ir single atoms are anchored on NiO supports via different bonding strategies, resulting in the diverse Ir-O-Ni coordination numbers for Ir sites. Specifically, Ir1/NiO, Ir1-NiO, and Ir1@NiO SACs with increasing Ir-O-Ni coordination numbers of 3, 4, and 5 were synthesized, respectively. We found that the activity of the three samples towards oxygen evolution reaction (OER) exhibited a volcano-shaped relationship with the Ir-O-Ni coordination number, with Ir1-NiO showing the lowest overpotential of 225 mV at 10 mA cm-2. Mechanism investigations indicate that the moderate coordination number of Ir-O-Ni in Ir1-NiO creates the higher occupied Ir dz2 orbital, weakening the adsorption strength for *OOH intermediates and thereby enhancing the OER activity.

Cystatin SN (CST1) Is a Poor Independent Prognostic Biomarker for Gastrointestinal Diffuse Large B-Cell Lymphoma.

BACKGROUND Gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common histological subtype of extra-nodal DLBCL, but the risk factors, prognostic biomarkers, histopathological classifications, and treatment strategies have not had significant progress. Emerging evidence shows that cystatin SN (CST1) is involved in tumor progression in several cancer types, but its role in GI-DLBCL has not been revealed. MATERIAL AND METHODS We established a cohort consisting of 84 patients with GI-DLBCL who underwent surgical resection. The expression of CST1 in the cohort was investigated by immunohistochemistry, which divided the patients into subgroups with low or high expression of CST1. Moreover, the CST1 expression in GI-DLBCL tissues or adjacent GI tissues were compared with RT-qPCR. The correlation between CST1 expression and clinicopathological factors was analyzed with the chi-square test. The prognostic significance of CST1 was estimated by univariate and multivariate analysis, and statistical significance was analyzed with the log-rank test. RESULTS CST1 was aberrantly upregulated in GI-DLBCL tissues compared with in non-tumor GI tissues. High expression of CST1 indicated poor prognosis of GI-DLBCL (P=0.012), and CST1 can be regarded as an independent prognostic biomarker of GI-DLBCL (hazard ratio=3.07). In our study, serum lactate dehydrogenase (P=0.002), performance status (P=0.003), Lugano stage (P=0.002), and International Prognostic Index (P=0.001) were also prognostic factors of GI-DLBCL. CONCLUSIONS CST1 is an independent prognostic biomarker of GI-DLBCL, indicating unfavorable prognosis. Our results suggested that CST1 detection can be a promising method to stratify high-risk patients and guide individual treatment.

Adipocyte-targeted celastrol delivery via biguanide-modified micelles improves treatment of obesity in DIO mice.

Obesity has emerged as a significant global health burden, exacerbated by serious side effects associated with existing anti-obesity medications. Celastrol (CLT) holds promise for weight loss but encounters challenges related to poor solubility and systemic toxicity. Here, we present chondroitin sulfate (CS)-derived micelles engineered for adipocyte-specific targeting, aiming to enhance the therapeutic potential of CLT while minimizing its systemic toxicity. To further enhance adipocyte affinity, we introduced a biguanide moiety into a micellar vehicle. CS is sequentially modified with hydrophilic metformin and hydrophobic 4-aminophenylboronic acid pinacol ester (PBE), resulting in the self-assembly of CLT-encapsulated micelles (MET-CS-PBE@CLT). This innovative design imparts amphiphilicity via the PBE moieties while ensuring the outward exposure of hydrophilic metformin moieties, facilitating active interactions with adipocytes. In vitro studies confirmed the enhanced uptake of MET-CS-PBE@CLT micelles by adipocytes, while in vivo studies demonstrated increased distribution within adipose tissues. In a diet-induced obese mouse model, MET-CS-PBE@CLT exhibited remarkable efficacy in weight loss without affecting food intake. This pioneering strategy offers a promising, low-risk, and highly effective solution to address the global obesity epidemic.