Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

Intracranial seminoma is a rare malignant tumor originating from the germ cells,usually occurring in the pineal gland or pituitary gland.In June 2020,the Department of Endocrinology at the First Affiliated Hospital of Army Military Medical University admitted a 20-year-old male patient with an intracranial germ cell tumor and spinal metastases.The patient presented with headache,dizziness,and visual impairment.Enhanced magnetic resonance imaging(MRI)of the head indicated thickening of the pituitary stalk.After multidisciplinary consultation,the patient underwent endonasal transsphenoidal resection of the tumor,with the pathological diagnosis confirming germ cell tumor.The patient received regular radiotherapy postoperatively.One year later,the tumor recurred and metastasized,leading to a second surgery for tumor resection in the thoracic spinal canal,followed by continued chemotherapy.The patient's clinical symptoms,such as headache and visual disturbances,improved,but he continued to experience panhypopituitarism and required long-term hormone replacement therapy.Early diagnosis of intracranial germ cell tumors is challenging,and they are prone to metastasis and highly sensitive to radiotherapy and chemotherapy.Early diagnosis and multidisciplinary comprehensive treatment can help improve the quality of life and prognosis for patients.

Phytoremediation plays an important role in the treatment of heavy metal pollution in soil. In order to elucidate the mechanism of salicylic acid (SA) on copper absorption, seedlings from Xuzhou (with strong Cu-tolerance) and Weifang Helianthus tuberosus cultivars (with weak Cu-tolerance) were selected for pot culture experiments. 1 mmol/L SA was sprayed upon 300 mg/kg soil copper stress, and the photosynthesis, leaf antioxidant system, several essential mineral nutrients and the changes of root upon copper stress were analyzed to explore the mechanism of copper resistance. The results showed that Pn, Tr, Gs and Ci upon copper stress decreased significantly compared to the control group. Meanwhile, chlorophyll a, chlorophyll b and carotenoid decreased with significant increase in initial fluorescence (F₀), maximum photochemical quantum yield of PSⅡ (Fv/Fm), electron transfer rate (ETR) and photochemical quenching coefficient (qP) content all decreased. The ascorbic acid (AsA) content was decreased, the glutathione (GSH) value was increased, the superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX) activity in the leaves were decreased, and the peroxidase (POD) activity was significantly increased. SA increased the Cu content in the ground and root system, and weakened the nutrient uptake capacity of K, Ca, Mg, and Zn in the root stem and leaves. Spray of exogenous SA can maintain the opening of leaf stomata, improve the adverse effect of copper on photosynthetic pigment and PSⅡ reaction center. Mediating the SOD and APX activity started the AsA-GSH cycle process, effectively regulated the antioxidant enzyme system in chrysanthemum taro, significantly reduced the copper content of all parts of the plant, and improved the ion exchange capacity in the body. External SA increased the content of the negative electric group on the root by changing the proportion of components in the root, promoted the absorption of mineral nutrient elements and the accumulation of osmoregulatory substances, strengthened the fixation effect of the root on metal copper, and avoided its massive accumulation in the H. tuberosus body, so as to alleviate the inhibitory effect of copper on plant growth. The study revealed the physiological regulation of SA upon copper stress, and provided a theoretical basis for planting H. tuberosus to repair soil copper pollution.
Antioxidants ; Copper ; Helianthus/metabolism* ; Salicylic Acid/pharmacology* ; Chlorophyll A/pharmacology* ; Spectroscopy, Fourier Transform Infrared ; Chlorophyll/pharmacology* ; Ascorbic Acid ; Superoxide Dismutase/metabolism* ; Photosynthesis ; Glutathione ; Plant Leaves ; Stress, Physiological ; Seedlings

Objective To study on the relationship between the serum level of highsensitivity c-reaction protein (hs-CR),matrix metalloproteinase 9 (MMT-9),tissue inhibitor of metalloproteinase 1 (TIMP-1) and carotid plaque stability in elderly people.Methods According to the carotid ultrasonography examination,120 old people were divided into vulnerable plaque group (group A,n =45),stable plaque group (group B,n =41) and no plaque group (group C,n =34),and serum levels of hs-CRP,MMP-9,TIMP-1 in each group were also detected.Results The serum levels of hs-CRP and MMP-9 of unstable plaque group and stable plaque group were higher than those of non-plaque group (P ＜ 0.05).hsCRP and MMP-9 were positively correlated with carotid plaque unstability,while TIMP-1 was negatively correlated with carotid plaque unstability,hs-CRP,MMP-9 and TIMP-1 were independent risk factors for carotid plaque stability.Conclusions Serum levels of hs-CRP,MMP-9 and TIMP-1 are closely related to the stability of carotid plaque.Elevated levels of hs-CRP and MMP-9 increase the risk of carotid plaque,and elevated levels of TIMP-1 decrease the risk of carotid plaque.

BACKGROUND: Insulin like growth factor 2 (IGF2) is an important embryonic mitosis growth promoting factor, whichplays a critical role in the process of maintaining normal cell growth. The gene expression of IGF2 is under epigeneticregulation in the way of genomic imprinting. Imprinting loss of IGF2 is likely to be associated with the abnormaldevelopment of the individual and tumorigenesis.OBJECTIVE: To investigate the effect of imprinting loss of IGF2 gene on the differentiation of mouse embryonic stemcells into islet-like cells.METHODS: Two kinds of mouse embryonic stem cells (SF1-G and SF1-1) were induced to differentiate into islet-likecells in vitro. The expression of Insulin gene was detected by real-time PCR and cell immunofluorescence. Theexpression of IGF2 was detected by the polymerase chain reaction-restriction fragment length polymorphism in the cellsbefore and after induced differentiation. The level of insulin released at terminal differentiation stage was tested by insulinrelease assay in vitro.RESULTS AND CONCLUSION: (1) There was no change in the imprinting state of the two kinds of mouse embryonicstem cells with normal and imprinted IGF-2 gene before and after differentiation. (2) In the induced cells, the expressionlevel of insulin in the SF1-1 group was higher than that in the SF1-G group, although there was no significant differencein the insulin release between the two kinds of cells. (3)The imprinting loss of IGF-2 gene may be related to theup-regulation of insulin mRNA expression in terminal cells during induced differentiation.

A series of novel N-phenylbenzamide and N-phenylacetophenone compounds were synthesized and evaluated for their antiviral activity against HCV and EV71 (strain SZ-98). The biological results showed that three compounds (23, 25 and 41) exhibited considerable anti-HCV activity (IC50=0.57-7.12 μmol/L) and several compounds (23, 28, 29, 30, 31 and 42) displayed potent activity against EV71 with the IC50 values lower than 5.00 μmol/L. The potency of compound 23 (IC50=0.57 μmol/L) was superior to that of reported compounds IMB-1f (IC50=1.90 μmol/L) and IMB-1g (IC50=1.00 μmol/L) as anti-HCV agents, and compound 29 possessed the highest anti-EV71 activity, comparable to the comparator drug pirodavir. The efficacy in vivo and antiviral mechanism of these compounds warrant further investigations.

Antibodies, Monoclonal, Murine-Derived ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Humans ; Lymphoma, Follicular ; drug therapy ; Rituximab

OBJECTIVEA prospective, multicenter and non-interventional prospective study was conducted to evaluate the clinical features of rituximab combined with chemotherapy (R-Chemo) as first-line treatment on newly diagnosed Chinese patients with diffuse large B-cell lymphoma (DLBCL).

METHODSThis was a single arm, prospective, observational multicenter and phase IV clinical trial for 279 patients, who were newly diagnosed as CD20-positive DLBCL from 24 medical centers in China 2011 and 2012, no special exclusion criteria were used. All patients received rituximab based R-Chemo regimes, such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisolone) and other regimes as the first-line treatment. The treatment strategies were determined by physicians and patients without detailed description for treatment course, dose, interval time and examination. Clinical response and safety of all patients were investigated in 120 days after completion of last dose of rituximab.

RESULTSOf 279 patients, 258 with stage I-IV who received at least 1 cycle of rituximab treatment and completed at least one time of tumor assessment were enrolled into intention-to-treat analysis, including 148 male and 110 female. The median age of all patients was 57.2(12.8-88.4) years. ECOG performance statuses of 0 or 1 were observed in 91.1% of patients, international prognostic index levels in the low-risk and low-middle-risk groups in 76.4% of patients, the tumor diameters smaller than 7.5 cm in 69.0% of patients. All patients received 6 median cycles of R-Chemo treatment every 24.4 days. R-CHOP treatment was shown to improve the clinical response with overall response rates of 94.2%. Common adverse events included anemia, marrow failure, leukopenia, thrombocytopenia, digestive diseases, infection and liver toxicity. All adverse events are manageable.

CONCLUSIONNon-interventional clinical trial of R-Chemo remains the standard first-line treatment for newly diagnosed patients with DLBCL in real clinical practice, which is consistent with international treatment recommendations for DLBCL patients. R-Chemo can provide the clinical evidence and benefit as the first-line standard treatment for Chinese patients with DLBCL.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal, Murine-Derived ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Child ; Female ; Humans ; Lymphoma, Large B-Cell, Diffuse ; drug therapy ; Male ; Middle Aged ; Prospective Studies ; Rituximab ; Treatment Outcome

Objective To investigate the correlation between serum level of visfatin and type 2 diabetes mellitus (T2DM). Methods Impaired glucose regulation (IGR) group consisted of 40 patients,T2DM group consisted of 106 patients, while control group consisted of 86 subjects. The serum visfatin levels of all groups were detected by enzyme linked immunosorbent assay (ELISA). Results Fasting serum visfatin levels in IGR group and T2DM group were significantly higher than those in control group [(19.93 ±6.89) μg/L and (29.53 ± 11.33) μg/L vs. (16.12 ± 5.24) μ g/L, P ＜ 0.01]. Fasting serum visfatin levels positively correlated with waist-to-hipratio (WHR) (r = 0.161, P ＜ 0.05); significantly positively correlated with triacylglycerol (TG), low density lipoprotein cholesterol (LDL-C), glycosylated hemoglobin (HbA1c),fasting plasma glucose (FPG), fasting insulin (FINS), lg Homeostasis model assessment-insulin resistance index (HOMA-IR) (r = 0.189,0.266,0.643,0.574,0.285,0.526,P ＜ 0.01), and significantly negatively correlated with high density lipoprotein cholesterol (HDL-C)(r =-0.377,P ＜0.01). When visfatin was analyzed as a dependent variable in multiple linear regression, HbA1c (β = 0.512, P = 0.000), lg HOMA-IR (β= 0.172, P = 0.026), WHR (β = 0.119, P = 0.036) were into the equation. Conclusion Visfatin may be involved in glucose and lipid metabolism regulation, and closely related with insulin resistance; visfatin may be a risk factor for T2DM.

Objective To explore the possible mechanism of sex hormone-binding globulin (SHBG) in diabetes mellitus by detecting the level of serum SHBG in patients with newly diagnosed type 2 diabetes mellitus (T2DM),and analyze the correlation between serum SHBG and insulin resistance.Methods SHBG levels were determined by enzyme linked immunosorbent assay (ELISA) in 30 normal controls (control group) and 60 newly diagnosed T2DM patients(T2DM group).HOMA-IR was calculated.Results The levels of serum SHBG in T2DM group were significantly lower than those in control group [(22.6 ±9.7)mmol/L vs.43.1 ±11.9) mmol/L,P <0.05]; SHBG level was negatively correlated with triglyceride(TG),low density hpoprotein cholesterol(LDL-C),fasting insulin(FINS),hemoglobintHbA1c) and lgHOMA-IR (r =-0.351,-0.361,-0.426,-0.645,-0.483,P <0.05),and positively correlated with high density lipoprotein cholesterol (HDL-C) (r =0.453,P <0.01).When SHBG was analyzed as a dependent variable by multiple linear regression,HbA1c (β =-0.614,P =0.000),lgHOMA-IR (β =-0.473,P = 0.014) and HDL-C (β = 0.234,P= 0.048) were into the equation.Conclusions Patients who have diagnosed T2DM show low level of serum SHBG.HOMA-IR and HbA1c are key indicators of SHBG,suggesting that SHBG may be closely related with T2DM.