Peptides are a particular molecule class with inherent attributes of some small-molecule drugs and macromolecular biologics, thereby inspiring continuous searches for peptides with therapeutic and/or agrochemical potentials. However, the success rate is decreasing, presumably because many interesting but less-abundant peptides are so scarce or labile that they are likely 'overlooked' during the characterization effort. Here, we present the biochemical characterization and druggability improvement of an unprecedented minor fungal RiPP (ribosomally synthesized and post-translationally modified peptide), named acalitide, by taking the relevant advantages of metabolomics approach and disulfide-bridged substructure which is more frequently imprinted in the marketed peptide drug molecules. Acalitide is biosynthetically unique in the macrotricyclization via two disulfide bridges and a protease (AcaB)-catalyzed lactamization of AcaA, an unprecedented precursor peptide. Such a biosynthetic logic was successfully re-edited for its sample supply renewal to facilitate the identification of the in vitro and in vivo antiparkinsonian efficacy of acalitide which was further confirmed safe and rendered brain-targetable by the liposome encapsulation strategy. Taken together, the work updates the mining strategy and biosynthetic complexity of RiPPs to unravel an antiparkinsonian drug candidate valuable for combating Parkinson's disease that is globally prevailing in an alarming manner.

Screening and evaluating the diseases responding specifically to traditional Chinese medicine （TCM） will help to highlight the advantages of TCM treatment， and the evaluation method should be standardized with consideration to the unique characteristics of the diseases. The incidence of Sjögren's Syndrome （SS） is increasing year by year， while the pathogenesis of this disease remains unclear. Modern therapies for this disease include biological agents and immunosuppressants， which generally have unsatisfactory efficacy. The TCM treatment of SS focuses on the harmony of the physical and mental health. The Rheumatology Branch of the China Association of Chinese Medicine organizes experts in TCM， Western medicine， and evidence-based medicine to form working groups. Delphi method and bibliometric method were used for analysis， and SS was selected as a disease responding specifically to TCM. Furthermore， the evaluation system was established for this disease， and the consensus regarding this disease was reached after seminar discussion. This paper summarized the whole process of the evaluation of the advantages of TCM treatment of SS. First， because TCM atomization is widely used in clinical practice and enriches TCM administration methods， this therapy is included after other non-drug therapies were taken as characteristic therapies. Second， the evaluation indicators of therapeutic effect should be determined with consideration to international acceptance and the current research status. Third， the expression method should be accurate， standardized， and objective， highlight the natural advantages of TCM， and avoid arbitrary extension. This paper provides a reference for clinicians to explore other diseases responding specifically to TCM.

Objective:To compare and analyze the clinical characteristics of acute myeloid leukemia (AML) related to the treatment of hematological tumors and solid tumors.Methods:The laboratory and clinical data of 41 patients with treatment-related AML (t-AML) in the Department of Hematology, Henan Cancer Hospital from January 2014 to December 2021 were retrospectively analyzed, and they were divided into hematological tumor group and solid tumor group. Survival analysis was performed using the Kaplan-Meier method and Log rank test.Results:The median interval from the first tumor diagnosis to t-AML in 41 patients was 21.0 (16.5-46.0) months; 24 (58.5%) had abnormal expression of lymphoid antigen, 28 (68.3%) had abnormal karyotype, 18 cases (43.9%) were positive for fusion gene, and 28 cases (68.3%) were positive for gene mutation; the median recurrence-free survival (RFS) was 11.0 months, and the median overall survival (OS) was 11.5 months. The proportion of acute promyelocytic leukemia ([APL], 0.0, 0/13), complete response ([CR],18.2%, 2/11), median OS (4.5 months) and median RFS (2.5 months) of t-AML patients in the hematological tumor group were significantly lower than those in the solid tumor group (35.7%, 10/28; 68.0%, 17/25; not reach; not reach), but the proportion of M4 /M5 (93.2%,12/13) was significantly higher than that in the solid tumor group (53.6%,15/18; all P values<0.05). Through subgroup analysis, the proportion of patients with positive PML-RARa and good prognosis karyotypes in the solid tumor group (35.7%, 10/28; 46.4%, 13/28) was significantly higher than that in the hematological tumor group (0.0, 0/13; 0.0, 0/13; P<0.05), while the proportion of patients with intermediate karyotypes (42.9%, 12/28) was significantly lower than that in the hematological tumor group (84.6%, 11/13; P<0.05), the difference was statistically significant. The CR rate (90.0%, 9/10), median OS (not reach) and median RFS (not reach) in the t-APL group were higher than those in the t-AML (without t-APL) group (38.5%, 10/26; 6 months; 8 months; P<0.05). After excluding the effect of t-APL patients, there was no significant difference in the CR rate, median OS and median RFS between the solid tumor group (8; 9 months; not reach) and the hematological tumor group (2; 4 months; 2 months; P>0.05). Univariate analysis showed that the primary tumor belongs to hematological tumor was a common risk factor for OS and RFS in t-AML patients ( P<0.10). Conclusions:Compared with patients with t-AML secondary to solid tumors, patients with t-AML secondary to hematological tumors have poorer treatment effects and poorer prognosis. After excluding the effect of t-APL patients, there are no significant differences in the treatment efficacy and prognosis between the two types of t-AML patients.

Objective To summarise a clinical experience of nursing care for 3 children who were treated with ECMO for sepsis and complicated with fulminant myocarditis.Methods Clinical data in nursing cares for 3 children treated with ECMO for sepsis and complicated with fulminant myocarditis were collected and analysed,with the spotted difficulties in nursing care and proposed coping strategies.Results The 3 children survived and were transferred out of the(pediatric intensive care unit,PICU)with stable vital signs and haemodynamics after emergency treatment with ECMO and continuous renal replacement therapy(CRRT).Conclusion Children with sepsis leading to myocardial depression and subsequent heart failure require close observation of the changes and consequently specialised cares after having initiated an ECMO in emergency treatment.This includes ensuring proper fixation of the cannulas,managing anticoagulation,monitoring the speed,flow rate and pressure of ECMO,management of body temperature,skin care,sedation and pain,as well as prevention of complications.These nursing care measures would improve the survival rate after the treatment of ECMO.

Drimane-type sesquiterpenoids are widely distributed in fungi. From the ethyl acetate extract of the earwig-derived Aspergillus sp. NF2396, seven new drimane-type sesquiterpenoids, named drimanenoids A-G (1-7), were isolated. Their structures were elucidated by diverse spectroscopic analysis including high-resolution ESI-MS, one- and two-dimensional NMR spectroscopy. Drimanenoids A-F (1-6) are new members of drimane-type sesquiterpenoid esterified with unsaturated fatty acid side chain at C-6. Drimanenoids C (3), D (4) and F (6) showed antibacterial activity against five types of bacteria with different inhibition diameters. Drimanenoid D (4) exhibited moderate cytotoxicity against human myelogenous leukemia cell line K562 with an IC₅₀ value of 12.88 ± 0.11 μmol·L^-1.
Humans ; Polycyclic Sesquiterpenes ; Sesquiterpenes/chemistry* ; Aspergillus/chemistry* ; Magnetic Resonance Spectroscopy ; Molecular Structure

Objective: To establish a novel stress-induced depression model by changing the lighting conditions and continuously damping cushion (L-D). Methods: The L-D stress depression animal model was established in C57BL / 6 mice with body weight of 18-22 g. Seventy-five mice with the horizontal and vertical scores higher than 30 and less than 120 in open field test were employed.In the research of model construction, mice were randomly divided into three groups: control group (n=9), chronic unpredictable mild stress(CUMS) model group (n=10) and L-D model group (n=9). In the drug intervention experiments, mice were randomly divided into five groups: control group (n=9), chronic unpredictable mild stress(CUMS) model group (n=10), L-D model group (n=9), CUMS+ fluoxetine group (n=10) and L-D model+ fluoxetine group (n=9). Open field test, forced swimming test and sucrose preference test were used to evaluate the degree of depression in animals. Results: (1) In the open field test, the horizontal score of CUMS model group (67.20±5.81) and the L-D model group (52.56±19.05) were significantly lower than that of the control group (76.44±9.22) (t=2.645, t=3.387, both P<0.05). And horizontal score of the L-D model was significantly lower than that of the CUMS model (t=2.321, both P<0.05). In forced swimming experiment, compared with the control group ((39.67±21.12)s), the immobility time of the CUMS model group ((60.90±10.34)s) and the L-D model group ((74.89±16.10)s) were significantly prolonged (t=2.831, 3.979, both P<0.05). The immobility time of the L-D model group was also significantly higher than that of the CUMS model group (t=2.278, P<0.05). In the sucrose preference experiment, the percentage of sucrose preference in CUMS model group ((72±7)%) and L-D model group ((65±5)%) was lower than that in the control group ((81±12)%) (t=2.195, 3.875, both P<0.05). The percentage of sucrose preference of L-D model group was significantly higher than that of CUMS model group (t=2.286, P<0.05). (2) After intervention with antidepressants, the horizontal scores of the CUMS model group (65.60±6.43) and the L-D model group (54.33±14.67) were significantly lower than that of the control group (75.78±8.27) in open field test (t=3.011, t=3.861, both P<0.05), and the score of L-D group was lower than that of CUMS group(t=2.235, P<0.05). The vertical score of the L-D model group (33.44±4.54) was significantly lower than that of the control group (39.22±5.56) (t=2.553, P<0.05). There was significant increase in the level score and vertical score of CUMS model and L-D model after fluoxetine intervention (t=3.090, t=2.692, both P<0.05), and significant twist in the vertical score of CUMS model and L-D model (t=2.681, t=2.354; both P<0.05). In the forced swimming experiment, the immobility time of the L-D model((64.11±13.06)s) was significantly longer than that of the control group ((42.00±13.77)s) (t=3.494, P<0.05). The immobility time of CUMS model and L-D model mice was significantly longer than that of non-intervention group (t=2.137, 2.940, both P<0.05). After the intervention of fluoxetine, there was no significant difference between the CUMS group, L-D group, the control group(all P>0.05). Conclusion Changing the lighting conditions and continuously damping cushion is a new method to establish mice model with depression behavior.Shorter modeling duration and simple operation are the main advantages of this model.

Objective: To evaluate the feasibility of two types of segmented biodegradable esophageal stents in treatment of refractory benign esophagus strictures. Methods: Uncovered biodegradable segmented stent and fully-covered biodegradable segmented stent were implanted into the porcine esophagus (6 for each). Data on biodegradation, complications, and tissue reactions were compared between two groups. Results: All animals kept good general conditions; no death, decreased food intake, weight loss and malnutrition were observed. No perforation, ulcer, hemorrhage, stent migration and severe complications occurred. Stents degradation commenced at week 3. Stents structure breakage and complete stents absorption occurred at week 7-8 and week 9-10 in uncovered stents. While in fully-covered stents, stents structure breakage and complete stents absorption occurred at week 8-9 and week 10-11. Hyperplasia was prominent at week 1-3 and ameliorated at week 6 after stent implantation. A longer degradation period was present in fully-covered stents than in uncovered stents, while fully-covered stents induced tissue reactions at early stage were mild. Conclusions: The application of biodegradable esophageal stents with a segmented trunk in refractory benign esophagus strictures worth further investigation. The fully-covered stent has longer degradation period, which may be more suitable for clinical use.
Animals ; Esophagus ; surgery ; Models, Animal ; Stents ; adverse effects ; standards ; Swine ; Treatment Outcome

Chaetominine is a quinazoline alkaloid originating from the endophytic fungus Aspergillus fumigatus CY018. In this study, we showed evidence that chaetominine has cytotoxic and apoptotic effects on human leukemia K562 cells and investigated the pathway involved in chaetominine-induced apoptosis in detail. Chaetominine inhibited K562 cell growth, with an IC50 value of 35 nM, but showed little inhibitory effect on the growth of human peripheral blood mononuclear cells. The high apoptosis rates, morphological apoptotic features, and DNA fragmentation caused by chaetominine indicated that the cytotoxicity was partially caused by its pro-apoptotic effect. Under chaetominine treatment, the Bax/Bcl-2 ratio was upregulated (from 0.3 to 8), which was followed by a decrease in mitochondrial membrane potential, release of cytochrome c from mitochondria into the cytosol, and stimulation of Apaf-1. Furthermore, activation of caspase-9 and caspase-3, which are the main executers of the apoptotic process, was observed. These results demonstrated that chaetominine induced cell apoptosis via the mitochondrial pathway. Chaetominine inhibited K562 cell growth and induced apoptotic cell death through the intrinsic pathway, which suggests that chaetominine might be a promising therapeutic for leukemia.
Apoptosis ; Aspergillus fumigatus ; Caspase 3 ; Caspase 9 ; Cell Death ; Cell Line* ; Cytochromes c ; Cytosol ; DNA Fragmentation ; Fungi ; Humans* ; Inhibitory Concentration 50 ; K562 Cells ; Leukemia* ; Membrane Potential, Mitochondrial ; Mitochondria

Anticoagulants ; adverse effects ; Humans ; Platelet Count ; Thrombocytopenia ; chemically induced