Network modeling-based identification of the switching targets between pyroptosis and secondary pyroptosis.

The newly identified cell death type, pyroptosis plays crucial roles in various diseases. Most recently, mounting evidence accumulates that pyroptotic signaling is highly correlated with coronavirus disease 2019 (COVID-19). Thus, understanding the induction of the pyroptotic signaling and dissecting the detail molecular control mechanisms are urgently needed. Based on recent experimental studies, a core regulatory model of the pyroptotic signaling is constructed to investigate the intricate crosstalk dynamics between the two cell death types, i.e., pyroptosis and secondary pyroptosis. The model well reproduces the experimental observations under different conditions. Sensitivity analysis determines that only the expression level of caspase-1 or GSDMD has the potential to individually change death modes. The decrease of caspase-1 or GSDMD level switches cell death from pyroptosis to secondary pyroptosis. Besides, eight biochemical reactions are identified that can efficiently switch death modes. While from the viewpoint of bifurcation analysis, the expression level of caspase-3 is further identified and twelve biochemical reactions are obtained. The coexistence of pyroptosis and secondary pyroptosis is predicted to be observed not only within the bistable range, but also within proper monostable range, presenting two potential different control mechanisms. Combined with the landscape theory, we further explore the stochastic dynamic and global stability of the pyroptotic system, accurately quantifying how each component mediates the individual occurrence probability of pyroptosis and secondary pyroptosis. Overall, this study sheds new light on the intricate crosstalk of the pyroptotic signaling and uncovers the regulatory mechanisms of various stable state transitions, providing potential clues to guide the development for prevention and treatment of pyroptosis-related diseases.

Cell death modes are specified by the crosstalk dynamics within pyroptotic and apoptotic signaling.

The crosstalk between pyroptosis and apoptosis pathways plays crucial roles in homeostasis, cancer, and other pathologies. However, its molecular regulatory mechanisms for cell death decision-making remain to be elucidated. Based on the recent experimental studies, we developed a core regulatory network model of the crosstalk between pyroptosis and apoptosis pathways. Sensitivity analysis and bifurcation analysis were performed to assess the death mode switching of the network. Both the approaches determined that only the level of caspase-1 or gasdermin D (GSDMD) has the potential to individually change death modes. The decrease of caspase-1 or GSDMD switches cell death from pyroptosis to apoptosis. Seven biochemical reactions among the 21 reactions in total that are essential for determining cell death modes are identified by using sensitivity analysis. While with bifurcation analysis of state transitions, nine reactions are suggested to be able to efficiently switch death modes. Monostability, bistability, and tristability are observed under different conditions. We found that only the reaction that caspase-1 activation induced by stimuli can trigger tristability. Six and two of the nine reactions are identified to be able to induce bistability and monostability, respectively. Moreover, the concurrence of pyroptosis and apoptosis is observed not only within proper bistable ranges, but also within tristable ranges, implying two potentially distinct regulatory mechanisms. Taken together, this work sheds new light on the crosstalk between pyroptosis and apoptosis and uncovers the regulatory mechanisms of various stable state transitions, which play important roles for the development of potential control strategies for disease prevention and treatment.

Quantifying Landscape-Flux via Single-Cell Transcriptomics Uncovers the Underlying Mechanism of Cell Cycle.

Recent developments in single-cell sequencing technology enable the acquisition of entire transcriptome data. Understanding the underlying mechanism and identifying the driving force of transcriptional regulation governing cell function directly from these data remains challenging. This study reconstructs a continuous vector field of the cell cycle based on discrete single-cell RNA velocity to quantify the single-cell global nonequilibrium dynamic landscape-flux. It reveals that large fluctuations disrupt the global landscape and genetic perturbations alter landscape-flux, thus identifying key genes in maintaining cell cycle dynamics and predicting associated functional effects. Additionally, it quantifies the fundamental energy cost of the cell cycle initiation and unveils that sustaining the cell cycle requires curl flux and dissipation to maintain the oscillatory phase coherence. This study enables the inference of the cell cycle gene regulatory networks directly from the single-cell transcriptomic data, including the feedback mechanisms and interaction intensity. This provides a golden opportunity to experimentally verify the landscape-flux theory and also obtain its associated quantifications. It also offers a unique framework for combining the landscape-flux theory and single-cell high-through sequencing experiments for understanding the underlying mechanisms of the cell cycle and can be extended to other nonequilibrium biological processes, such as differentiation development and disease pathogenesis.

Plasmonic Ag Nanoparticle-Loaded n-p Bi2O2CO3/α-Bi2O3 Heterojunction Microtubes with Enhanced Visible-Light-Driven Photocatalytic Activity.

In this study, n-p Bi2O2CO3/α-Bi2O3 heterojunction microtubes were prepared via a one-step solvothermal route in an H2O-ethylenediamine mixed solvent for the first time. Then, Ag nanoparticles were loaded onto the microtubes using a photo-deposition process. It was found that a Bi2O2CO3/α-Bi2O3 heterostructure was formed as a result of the in situ carbonatization of α-Bi2O3microtubes on the surface. The photocatalytic activities of α-Bi2O3 microtubes, Bi2O2CO3/α-Bi2O3 microtubes, and Ag nanoparticle-loaded Bi2O2CO3/α-Bi2O3 microtubes were evaluated based on their degradation of methyl orange under visible-light irradiation (λ > 420 nm). The results indicated that Bi2O2CO3/α-Bi2O3 with a Bi2O2CO3 mass fraction of 6.1% exhibited higher photocatalytic activity than α-Bi2O3. Loading the microtubes with Ag nanoparticles significantly improved the photocatalytic activity of Bi2O2CO3/α-Bi2O3. This should be ascribed to the internal static electric field built at the heterojunction interface of Bi2O2CO3 and α-Bi2O3 resulting in superior electron conductivity due to the Ag nanoparticles; additionally, the heterojunction at the interfaces between two semiconductors and Ag nanoparticles and the local electromagnetic field induced by the surface plasmon resonance effect of Ag nanoparticles effectively facilitate the photoinduced charge carrier transfer and separation of α-Bi2O3. Furthermore, loading of Ag nanoparticles leads to the formation of new reactive sites, and a new reactive species ·O2− for photocatalysis, compared with Bi2O2CO3/α-Bi2O3.

Novel glycosylation zinc(II)-cryptolepine complexes perturb mitophagy pathways and trigger cancer cell apoptosis and autophagy in SK-OV-3/DDP cells.

With the aim of shedding some light on the mechanism of action of zinc(II) complexes in antiproliferative processes and molecular signaling pathways, three novel glycosylated zinc(II)-cryptolepine complexes, i.e., [Zn(QA1)Cl2] (Zn(QA1)), [Zn(QA2)Cl2] (Zn(QA2)), and [Zn(QA3)Cl2] (Zn(QA3)), were prepared by conjugating a glucose moiety with cryptolepine, followed by complexation of the resulting glycosylated cryptolepine compounds N-((1-(2-morpholinoethyl)-1H-1,2,3-triazol-4-yl)methyl)-benzofuro[3,2-b]quinolin-11-amine (QA1), 2-(4-((benzofuro[3,2-b]quinolin-11-ylamino)methyl)-1H-1,2,3-triazol-1-yl)ethan-1-ol (QA2), and (2S,3S,4R,5R,6S)-2-(4-((benzofuro[3,2-b]quinolin-11-ylamino)-methyl)-1H-1,2,3-triazol-1-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (QA3) with zinc(II), and their anticancer activity was evaluated. In MTT assays, Zn(QA1)-Zn(QA3) were more active against cisplatin-resistant ovarian SK-OV-3/DDP cancer cells (SK-OV-3cis) than ZnCl2 and the QA1-QA3 ligands, with IC50 values of 1.81 ± 0.50, 2.92 ± 0.32, and 1.01 ± 0.11 µM, respectively. Complexation of glycosylated cryptolepine QA3 with zinc(II) increased the antiproliferative activity of the ligand, suggesting that Zn(QA3) could act as a chaperone to deliver the active ligand intracellularly, in contrast with other cryptolepine metal complexes previously reported. In vivo and in vitro investigations suggested that Zn(QA3) exhibited enhanced anticancer activity with treatment effects comparable to those of the clinical drug cisplatin. Furthermore, Zn(QA1)-Zn(QA3) triggered SK-OV-3cis cell apoptosis through mitophagy pathways in the order Zn(QA1) > Zn(QA1) > Zn(QA2). These results demonstrate the potential of glycosylated zinc(II)-cryptolepine complexes for the development of chemotherapy drugs against cisplatin-resistant SK-OV-3cis cells.

Management of Schwannoma in the hepatoduodenal ligament: A case report and review of the literature.

RATIONALE: Schwannomas are neoplasms that originate from Schwann cells of the peripheral nerve sheath with a low malignant potential. Considering that Schwannomas often occur in the upper extremities, trunk, head, and neck, but in the hepatoduodenal ligament has seldom been reported. PATIENT CONCERNS: A 70-year-old man was referred to our hospital for further evaluation of distension in upper abdomen. Abdominal ultrasonography reported that an anechoic mass was found between the pancreatic head and portal vein, which was measured to be about 5.5 × 4 × 4 cm. No blood flow signal was found within the mass by color doppler ultrasound. Subsequently, abdominal contrast enhanced computed tomography revealed that a well-defined round soft-tissue was above the pancreatic head and adjacent to the common heapatic artery, and it had no obvious enhancement in the arterial phase and portal phase. DIAGNOSES: Schwannomas in the hepatoduodenal ligament. INTERVENTIONS: After the work-up of a multidisciplinary team, a right complete excision was carried out and schwannoma was diagnosed by pathology. OUTCOMES: The patient's postoperative course was uneventful, and he left the hospital 10 days after the operation. Additionally, at the time of writing, recurrence was not observed with a follow-up of 17 months. LESSONS: schwannomas in the hepatoduodenal ligament are extremely rare with benign behavior. Surgical resection is the gateway to cure it; however, accurate preoperative diagnosis of the schwannomas in the hepatoduodenal ligament is a huge challenge because neither the clinical symptoms nor the imaging manifestations are specific.

[Effect of acupoint catgut embedding, fire needle, auricular acupuncture on female post-adolescent acne and serum sex hormone].

OBJECTIVE: To compare the difference of serum sex hormone between female patients with post-adolescent acne and healthy women, and to explore the efficacy and action mechanism of acupoint catgut embedding, fire needle, auricular acupuncture on skin lesion in female patients of post-adolescent acne. METHODS: A total of 107 female patients of post-adolescent acne were divided into an integrated acupuncture group (54 cases, 4 cases were excluded) and a medication group (53 cases, 5 cases were excluded). The patients in the integrated acupuncture group were treated with comprehensive treatment of acupoint catgut embedding, fire needle, auricular acupuncture; the acupoint catgut embedding was applied at Dazhui (GV 14), Yintang (GV 29), Yangbai (GB 14) through Yuyao (EX-HN 4) and other acupoints based on syndrome differentiation; the fire needle was applied at skin lesion; the auricular acupuncture was applied at erjian (HX6，7i), e (AT1), kou (CO1), etc. The patients in the medication group were treated with oral administration of tanshinone capsules (4 capsules each time, 3 times a day) and external use of adapalene gel (one treatment per day at night). Patients in the two groups were treated for 8 weeks. The skin lesion of acne was evaluated before treatment as well as 4 weeks and 8 weeks after treatment in the two groups; the serum levels of testosterone (T) and estradiol (E2) were tested 24 hours before menstruation in the integrated acupuncture group (50 cases) and healthy control group (46 cases), and the change of serum sex hormone after treatment was observed in 21 patients with sex hormone disorder in the integrated acupuncture group. RESULTS: Before treatment, the level of E2 in the integrated acupuncture group was significantly lower than that in the healthy control group (P<0.01), but T/E2 in the integrated acupuncture group was significantly higher than that in the healthy control group (P<0.01). After treatment, the level of E2 was significantly increased (P<0.01) and T/E2 was reduced (P<0.01) in the 21 patients with sex hormone disorder in the integrated acupuncture group. The skin lesion scale of acne was significantly reduced in the two groups after 4-week and 8-week treatment (all P<0.01); the difference between the two groups was not significant after 4-week treatment (P>0.05); the skin lesion scale of acne in the integrated acupuncture group was significantly lower than that in the medication group after 8-week treatment (P<0.01). The efficacy between the two groups was not significant after 4-week the treatment (P>0.05); after 8-week treatment, the cured and effective rate was 66.0% (33/50) in the integrated acupuncture group, which was superior to 45.8% (22/48) in the medication group (P<0.05). CONCLUSION: Compared with healthy women, the level of serum sex hormone of E2 is reduced in the female patients of post-adolescent acne, resulting in relative increased level of T; the acupoint catgut embedding, fire needle, auricular acupuncture have better efficacy than medication for post-adolescent acne, which have regulation effects on sex hormone disorder.

Luminescence and energy transfer of Tb3+-doped BaO-Gd2O3-Al2O3-B2O3-SiO2 glasses.

Transparent Tb3+-doped BaO-Gd2O3-Al2O3-B2O3-SiO2 glasses with the greater than 4g/cm3 were prepared by high temperature melting method and its luminescent properties have been investigated by measured UV-vis transmission, excitation, emission and luminescence decay spectra. The transmission spectrum shows there are three weak absorption bands locate at about 312, 378 and 484nm in the glasses and it has good transmittance in the visible spectrum region. Intense green emission can be observed under UV excitation. The effective energy transfer from Gd3+ ion to Tb3+ ion could occur and sensitize the luminescence of Tb3+ ion. The green emission intensity of Tb3+ ion could change with the increasing SiO2/B2O3 ratio in the borosilicate glass matrix. With the increasing concentration of Tb3+ ion, 5D4→7FJ transitions could be enhanced through the cross relaxation between the two nearby Tb3+ ions. Luminescence decay time of 2.12ms from 546nm emission is obtained. The results indicate that Tb3+-doped BaO-Gd2O3-Al2O3-B2O3-SiO2 glasses would be potential scintillating material for applications in X-ray imaging.

Luminescence properties of Tb(3+)-doped borosilicate scintillating glass under UV excitation.

Transparent Li2O-BaO-La2O3-Al2O3-B2O3-SiO2 glasses doped with Tb(3+) ion were prepared by high temperature melting method. Luminescence properties of Tb(3+)-doped borosilicate glasses have been investigated by transmission, excitation, emission and luminescence decay measurements. The transmission spectrum shows the glass has good transmittance in the visible region. Under the 236 nm UV excitation the intense green emission from (5)D4 level is observed in Tb(3+)-doped borosilicate glass, comparable in intensity to the violet-blue emission starting from the (5)D3 level. The green emission intensity of Tb(3+) ion firstly increases and then decreases with the decreasing B2O3/SiO2 ratio in glass matrix. (5)D4→(7)FJ (J=6, 5, 4 and 3) transitions of Tb(3+) ion in borosilicate glass are greatly enhanced with increasing concentration of Tb(3+) through the cross relaxation [Tb(3+) ((5)D3)+Tb(3+) ((7)F6)→Tb(3+) ((5)D4)+Tb(3+) ((7)F0)] between two Tb(3+) ions. Luminescence decay time of 2.13 ms is obtained for the emission transitions starting from (5)D4 level in 2.5Li2O-20BaO-20La2O3-2.5Al2O3-20B2O3-35SiO2-0.5Tb4O7 glass. The results show that Tb(3+)-doped borosilicate glasses would be potential candidates for scintillating material for static X-ray imaging.

Luminescent properties of Tb3+ and Gd3+ ions doped aluminosilicate oxyfluoride glasses.

Tb(3+) and Gd(3+) ions doped lithium-barium-aluminosilicate oxyfluoride glasses have been prepared. The transmission, emission and excitation spectra were measured. It has been found that those Tb(3+)-doped lithium-barium-aluminosilicate oxyfluoride glasses exhibit good UV-excited luminescence. The luminescence intensity of Tb(3+) ion increases for those (Tb(3+), Gd(3+))-codoped glasses. Energy transfer process from Gd(3+) ion to Tb(3+) ion is indicated.