The chemically stable analogue of resolvin D1 ameliorates experimental autoimmune encephalomyelitis by mediating the resolution of inflammation.

While Resolvin D1 (RvD1) shows promise in resolving inflammation in experimental autoimmune encephalomyelitis (EAE), its pro-resolving roles on dendritic cells (DCs) remain unknown, and the chemical instability of RvD1 poses significant challenges to its drug development. This study aims to investigate whether 4-(2'-methoxyphenyl)-1-[2'-[N-(2″-pyridinyl)-p-fluorobenzamido]ethyl]piperazine (p-MPPF), a novel chemically stable analogue of RvD1, can play a pro-resolving role in EAE, particularly on DCs, and if p-MPPF could serve as a potential substitute for RvD1. We showed that both RvD1 and p-MPPF mediated the resolution of inflammation in EAE, as evidenced by ameliorated EAE progression, attenuated pathological changes in the spinal cord, altered cytokine expression profile in serum, and reduced proportion of pro-inflammatory immune cells in the spleen. Utilizing DCs derived from both the spleen and bone marrow of EAE, our investigation showed that RvD1 and p-MPPF prevented DC maturation, decreased pro-inflammatory cytokine secretion, shifted DCs away from a pro-inflammatory phenotype, increased the phagocytosis capacity of DCs, and suppressed their ability to induce differentiation of CD4+ T cells into Th1 and Th17 subsets. For underlying intracellular mechanisms, we found that RvD1 and p-MPPF down-regulated the lactate dehydrogenase A signaling pathways. Comparisons between RvD1 and p-MPPF showed that they exerted overlapped pro-resolving effects to a large extent. This study demonstrates that both RvD1 and p-MPPF exert therapeutic effects on EAE by mediating inflammation resolution, which is closely associated with modulating DC immune function towards a tolerogenic phenotype. SPM mimetics may serve as a more promising therapeutic drug.

Molecular structure and characterization of the Thermochromatium tepidum light-harvesting 1 photocomplex produced in a foreign host.

Purple phototrophic bacteria possess light-harvesting 1 and reaction center (LH1-RC) core complexes that play a key role in converting solar energy to chemical energy. High-resolution structures of LH1-RC and RC complexes have been intensively studied and have yielded critical insight into the architecture and interactions of their proteins, pigments, and cofactors. Nevertheless, a detailed picture of the structure and assembly of LH1-only complexes is lacking due to the intimate association between LH1 and the RC. To study the intrinsic properties and structure of an LH1-only complex, a genetic system was constructed to express the Thermochromatium (Tch.) tepidum LH1 complex heterologously in a modified Rhodospirillum rubrum mutant strain. The heterologously expressed Tch. tepidum LH1 complex was isolated in a pure form free of the RC and exhibited the characteristic absorption properties of Tch. tepidum. Cryo-EM structures of the LH1-only complexes revealed a closed circular ring consisting of either 14 or 15 αß-subunits, making it the smallest completely closed LH1 complex discovered thus far. Surprisingly, the Tch. tepidum LH1-only complex displayed even higher thermostability than that of the native LH1-RC complex. These results reveal previously unsuspected plasticity of the LH1 complex, provide new insights into the structure and assembly of the LH1-RC complex, and show how molecular genetics can be exploited to study membrane proteins from phototrophic organisms whose genetic manipulation is not yet possible.

Energy Transfer and Exciton Relaxation in B880-B800-RC Complex through Two-Dimensional Electronic Spectroscopy.

The light-harvesting (LH) and reaction center (RC) core complex of purple bacterium Roseiflexus castenholzii, B880-B800-RC, are different from those of the typical photosynthetic unit, (B850-B800)x-B880-RC. To investigate the excitation flowing dynamics in this unique complex, two-dimensional electronic spectroscopy is employed. The obtained time constants for the exciton relaxation in B880, exciton relaxation in B800, B800 → B880 energy transfer (EET), and B880 → closed RC EET are 43 fs, 177 fs, 1.9 ps, and 205 ps, respectively. These time constants result in an overall EET efficiency similar to that of the typical photosynthetic unit. Analysis of the oscillatory signals reveals that while several vibronic coherences are involved in the exciton relaxation process, only one prominent vibronic coherence, with a frequency of 27 cm-1 and coupled to the B880 electronic transition, may contribute to the B800 → B880 EET process.

Structural insights into the unusual core photocomplex from a triply extremophilic purple bacterium, Halorhodospira halochloris.

Halorhodospira (Hlr.) halochloris is a triply extremophilic phototrophic purple sulfur bacterium, as it is thermophilic, alkaliphilic, and extremely halophilic. The light-harvesting-reaction center (LH1-RC) core complex of this bacterium displays an LH1-Qy transition at 1,016 nm, which is the lowest-energy wavelength absorption among all known phototrophs. Here we report the cryo-EM structure of the LH1-RC at 2.42 Å resolution. The LH1 complex forms a tricyclic ring structure composed of 16 αßγ-polypeptides and one αß-heterodimer around the RC. From the cryo-EM density map, two previously unrecognized integral membrane proteins, referred to as protein G and protein Q, were identified. Both of these proteins are single transmembrane-spanning helices located between the LH1 ring and the RC L-subunit and are absent from the LH1-RC complexes of all other purple bacteria of which the structures have been determined so far. Besides bacteriochlorophyll b molecules (B1020) located on the periplasmic side of the Hlr. halochloris membrane, there are also two arrays of bacteriochlorophyll b molecules (B800 and B820) located on the cytoplasmic side. Only a single copy of a carotenoid (lycopene) was resolved in the Hlr. halochloris LH1-α3ß3 and this was positioned within the complex. The potential quinone channel should be the space between the LH1-α3ß3 that accommodates the single lycopene but does not contain a γ-polypeptide, B800 and B820. Our results provide a structural explanation for the unusual Qy red shift and carotenoid absorption in the Hlr. halochloris spectrum and reveal new insights into photosynthetic mechanisms employed by a species that thrives under the harshest conditions of any phototrophic microorganism known.

Efficacy and safety of direct oral anticoagulants for the treatment of cancer-associated venous thromboembolism: A systematic review and Bayesian network meta-analysis / Eficacia y seguridad de los anticoagulantes orales directos para el tratamiento de la tromboembolia venosa asociada al cáncer: una revisión sistemática y un metaanálisis en red bayesiana

Introduction: Direct oral anticoagulants (DOACs) could effectively prevent the occurrence of cancer-associated venous thromboembolism (CAVTE), which incidence rate was estimated to be 4–20%. But the efficacy and safety remain controversial between DOACs and low molecular weight heparin (LMWH).Materials and methodsPubMed, Cochrane Library, Embase, ClinicalTrials.gov databases for randomized controlled trials (RCTs) were systematically searched from inception to March 15, 2022. A random-effects model was used to report the odds ratio (OR) and 95% confidence interval (CI) for both direct and network meta-analyses.ResultsSeven studies were included totaling 3242 patients. A lower rate of recurrence VTE was noted in the DOACs compared with LMWH (OR 0.62, 95% CI 0.47–0.82, I2=0.0%). The aspect of major bleeding (MB) was similar (OR 1.30, 95% CI 0.77–2.18, I2=34.9%). When assessing clinically relevant nonmajor bleeding (CRNMB) (OR 1.61, 95% CI 1.17–2.22, I2=20.7%) and clinically relevant bleeding (CRB) (OR 1.39, 95% CI 1.11–1.74, I2=0.0%), a higher risk of events was observed in DOACs. In subgroup analyses, the MB of gastrointestinal and genitourinary malignancies had a higher rate in the DOACs. For ranking, apixaban ranked the first in prevention of VTE and reducing MB events. Edoxaban had the highest risk drug in MB. In terms of CRNMB and CRB, LMWH showed the lowest risk.ConclusionsCompared with LMWH, DOACs seemed to have a decreased risk of recurrence VTE while increasing CRNMB and CRB. DOACs and LMWH were equivalent to the aspect of MB, but DOACs had a higher MB risk in patients with gastrointestinal and genitourinary malignancies. Apixaban may be the lowest risk compared to the other DOACs in precaution of VTE and reducing bleeding events. (AU)

Introducción: Los anticoagulantes orales directos (ACOD) son eficaces en la prevención de la tromboembolia venosa (TEV) relacionada con el cáncer, cuya tasa de incidencia se estima en 4-20%. Sin embargo, la eficacia y seguridad de ACOD y heparina de bajo peso molecular (HBPM) siguen siendo controvertidas.Materiales y métodosDesde el inicio hasta el 15 de marzo de 2022 se realizaron búsquedas sistemáticas en las bases de datos de ensayos controlados aleatorios (ECA) en PubMed, The Cochrane Library, Embase, ClinicalTrials.gov. Se utilizó el modelo de efectos aleatorios para informar la razón de probabilidades (RP) y los intervalos de confianza (IC) de 95% para los metaanálisis directos y de red.ResultadosSe incluyeron siete estudios con un total de 3.242 pacientes. En comparación con HBPM, los ACOD tienen una tasa más baja de recurrencia de TEV (OR 0,62, IC 95%: 0,47 a 0,82, I2 = 0,0%). La frecuencia de hemorragias mayores fue similar (OR 1,30, IC 95% 0,77 a 2,18, I2 = 34,9%). Se observó un mayor riesgo de eventos en los ACOD. Cuando se evaluaron las hemorragias no mayores clínicamente relevantes (CRNMB) (OR 1,61, IC 95%: 1,17 a 2,22, I2 = 20,7%) y las hemorragias clínicamente relevantes (OR 1,39, IC 95%: 1,11 a 1,74, I2 = 0,0%), En los análisis de subgrupos, las hemorragias mayores en las neoplasias malignas gastrointestinales y genitourinarias fueron más frecuentes con los ACOD. Apixabán ocupó el primer lugar en la prevención de TEV y la reducción de eventos hemorrágicos mayores. Edoxabán tuvo el mayor riesgo de hemorragias mayores. Las HBPM demostraron tener menor riesgo de hemorragias mayores clínicamente relevantes y hemorragias clínicamente relevantes. (AU)

A suppository-base-matrix tablet for time-dependent colon-specific delivery system

Our research has focused on the main design features and release performances of time-dependent colon-specific (TDCS) delivery tablets, which relies on the relative constancy that is observed in the small intestinal transit time of dosage forms. But inflammatory bowel disease（IBD）can affect the transit time, and usually results in watery stool. Compared to the TDCS and wax-matrix TDCS tablet, a promising time-dependent colon-specific delivery system was investigated. In our study, a suppository-base-matrix coated tablet was evaluated. Water soluble suppository-base helps the expansion of tablet, facilitates uniform film dissolution and achives high osmotic pressure. Combining the expansion of carboxymethyl starch sodium (CMS-Na) and the moisture absorption of NaCl, the coated TDCS tablet obtained a burst and targeted drug delivery system. A very good correlation between in vitro drug release and in vivo outcome was observed. This TDCS coated tablet provides a promising strategy to control drug release to the desired lower gastrointestinal region.

Nossa pesquisa focou-se nas principais características de planejamento e de desempenho de liberação cólon-específica tempo-dependente (TDCS) de comprimidos, que leva em conta a constância relativa observada no tempo de trânsito intestinal das formas de dosagem. A doença inflamatória do intestino (IBD) pode afetar o tempo de trânsito e, geralmente, resulta em fezes aquosas. Comparando ao TDCS e a comprimidos TDCS com matriz-cerosa, investigou-se sistema promissor de liberação cólon-específica tempo-dependente. Em nosso estudo, avaliou-se comprimido revestido com matriz base de supositório. A base de supositório solúvel em água auxilia a expansão do comprimido, facilita a dissolução uniforme do filme e atinge alta pressão osmótica. Associando a expansão do carboximetil amido sódico (CMS-Na) à absorção de umidade do NaCl, o comprimido revestido TDCS originou sistema de liberação direcionado e de erupção. Observou-se correlação muito boa entre a liberação in vitro e a in vivo do fármaco. Este comprimido revestido TDCS representa estratégia promissora para o controle da liberação do fármaco na região gastrintestinal mais baixa.