Potential chemical transformation of phosphinic acid derivatives and their applications in the synthesis of drugs

The chemical transformation of phosphinic acid is a well-considered mature area of research on account of the historical significant reactions such as Kabachnik–Fields, Mannich, Arbuzov, Michaelis–Becker, etc. Considerable advances have been made over last years especially in metal-catalyzed, free-radical processes and asymmetric synthesis using catalytic enantioselective. As a result, the aim of this synopsis is to make the reader familiar with advances in the approaches of phosphinic acids toward the synthesis of highly functionalized and valuable buildings blocks. Another purpose of this survey is to provide the current status of the applications of phosphinic acids in the synthesis of drugs.     

Expansion and characteristics of human T regulatory type 1 cells in co-cultures simulating tumor microenvironment

Objective Chronic inflammation and cancer development are associated with dysregulated immune responses and the presence of regulatory T cells (T_reg). To study the role of T_reg in tumor cell escape from immune surveillance, an in vitro model simulating the tumor microenvironment and promoting the induction and expansion of IL-10⁺ T_reg type 1 (Tr1) was established. Methods An in vitro co-culture system (IVA) included an irradiated head and neck squamous cell carcinoma cell line, immature dendritic cells (iDC), CD4⁺CD25⁻ T cells and cytokines, IL-2 (10 IU/ml), IL-10 (20 IU/ml), IL-15 (20 IU/ml) ± 1 nM rapamycin. Autologous iDC and CD4⁺CD25⁻ T cells were obtained from the peripheral blood of 15 normal donors. Co-cultures were expanded for 10 days. Proliferating lymphocytes were phenotyped by multi-color flow cytometry. Their suppressor function was measured in CFSE inhibition assays ± neutralizing anti-IL-10 mAb and using transwell cultures. Culture supernatants were tested for IL-4, IL-10, TGF-β and IFN-γ in ELISA. Results In the IVA, low doses of IL-2, IL-10 and IL-15 promoted induction and expansion of CD3⁺CD4⁺CD25⁻IL2Rβ⁺IL2Rγ⁺FoxP3⁺CTLA-4⁺IL-10⁺ cells with suppressor activity (mean suppression ± SD = 58 ± 12%). These suppressor cells produced IL-10 (mean ± SD = 535 ± 12 pg/ml) and TGF-β (mean ± SD = 512 ± 38 pg/ml), but no IL-4 or IFN-γ. Suppressor function of co-cultures correlated with the percent of expanding IL-10⁺ Tr1 cells (r ² = 0.9; P < 0.001). The addition of rapamycin enriched Tr1 cells in all co-cultures. Neutralizing anti-IL-10 mAb abolished suppressive activity. Suppression was cell-contact independent. Conclusion The tumor microenvironment promotes generation of Tr1 cells which have the phenotype distinct from that of CD4⁺CD25^highFoxP3⁺ nTreg and mediate IL-10 dependent immune suppression in a cell-contact independent manner. Tr1 cells may play a critical role in cancer progression.     

Adenosine and Prostaglandin E2 Cooperate in the Suppression of Immune Responses Mediated by Adaptive Regulatory T Cells

Adaptive regulatory T cells (Tr1) are induced in the periphery upon encountering cognate antigens. In cancer, their frequency is increased; however, Tr1-mediated suppression mechanisms are not yet defined. Here, we evaluate the simultaneous involvement of ectonucleotidases (CD39/CD73) and cyclooxygenase 2 (COX-2) in Tr1-mediated suppression. Human Tr1 cells were generated from peripheral blood mononuclear cell-derived, sorted CD4⁺CD25⁻ T cells and incubated with autologous immature dendritic cells, irradiated COX-2⁺ or COX-2⁻ tumor cells, and IL-2, IL-10, and IL-15 (each at 10–15 IU/ml) for 10 days as described (Bergmann, C., Strauss, L., Zeidler, R., Lang, S., and Whiteside, T. L. (2007) Cancer Immunol. Immunother. 56, 1429–1442). Tr1 were phenotyped by multicolor flow cytometry, and suppression of proliferating responder cells was assessed in carboxyfluorescein diacetate succinimidyl ester-based assays. ATP hydrolysis was measured using a luciferase detection assay, and levels of adenosine or prostaglandin E₂ (PGE₂) in cell supernatants were analyzed by mass spectrometry or ELISA, respectively. Intracellular cAMP levels were measured by enzyme immunoassay. The COX-2⁺ tumor induced a greater number of Tr1 than COX-2⁻ tumor (p < 0.05). Tr1 induced by COX-2⁺ tumor were more suppressive, hydrolyzed more exogenous ATP (p < 0.05), and produced higher levels of adenosine and PGE₂ (p < 0.05) than Tr1 induced by COX-2⁻ tumor. Inhibitors of ectonucleotidase activity, A_2A and EP₂ receptor antagonists, or an inhibitor of the PKA type I decreased Tr1-mediated suppression (p < 0.05), whereas rolipram, a PDE₄ inhibitor, increased the intracellular cAMP level in responder cells and their susceptibility to Tr1-mediated suppression. Tr1 present in tumors or the peripheral blood of head and neck squamous cell carcinoma patients co-expressed COX-2, CD39, and CD73. A concomitant inhibition of PGE₂ and adenosine via the common intracellular cAMP pathway might be a novel approach for improving results of immune therapies for cancer.     

Modification of radiation-induced genetic damage in Drosophila melanogaster male germ cells with nucleic acid precursors. 3. Effects on the premeiotic cells

Using a 2-day brood pattern, the effect of 5-bromodeoxyuridine (BUdR) or 5-bromodeoxycytidine (BCdR) pre-treatment on the radiation-induced yield of sex-linked recessive lethals and translocations was studied in the spermatocytes and late gonial cells (p.i. DNA synthesis cells) of D. melanogaster. The p.i. DNA synthesis cells were irradiated (I.2 kR γ-radiation) in the pre-meiotic or post-meiotic stage. Irradiation of p.i. DNA synthesis cells in the pre-meiotic stage resulted in enhanced lethal frequency with BUdR (3.0%) and BCdR (2.9%) over the other pre-treatment conditions: saline (S), thymidine (TdR) and deoxycitydine (CdR) in the spermatocytes but not in the late gonial cells. The radiosensitizing property was evident with BCdR even when the p.i. DNA synthesis cells were irradiated in the post-meiotic stage; but not with BUdR pre-treatment. Probable reasons for the contradicting results reported in the literature were discussed.     

Modification of radiation-induced genetic damage in Drosophila melanogaster male germ cells with nucleic acid precursors II. Effects on post-meiotic cells

Following the observation that the nucleoside pre-treatment reduced the radiation-induced dominant lethality in the post-meiotic germ cells, similar experiments were conducted using the same treatment conditions to study the influence of the nucleoside(s) pre-treatment on the radiation-induced (1.2 kR) incidence of sex-linked recessive lethals and translocation events in the post-meiotic male germ cells of 1-day-old D. melanogaster. The nucleoside pre-treatment reduced the translocation frequency (not statistically significant) and the lethal mutation frequency (statistically significant) in the post-meiotic cells (pre-injection DNA synthesis cells) especially in the mature sperms sampled in brood a (br a). The radio-protective effect of the nucleosides on the mature sperms was confirmed using 7-day-old virgin males and different radiation doses (2.4 kR and 3.6 kR).The frequency of lethal mutation was lowest when irradiation was preceded by the injection of an equimolar solution of thymidine (TdR), deoxyadenosine (AdR), deoxycytidine (CdR) and deoxyguanosine (GdR). However, when the nucleosides were injected after irradiation (within 10–30 min) there was no change in the yield of radiation-induced lethals.The possible mechanisms for the radioprotective action of the nucleosides in the post-meiotic germ cells such as (a) “protection” by a radiochemical action of nucleosides competing for short-lived radicals that might otherwise cause damage to DNA and (b) biochemical-physiological mechanisms such as metabolic events increasing the radioresistance of the cells, providing excess energy for repair or favoring and partaking in the DNA repair synthesis were discussed. Further studies were felt necessary to elucidate this phenomenon.     

Effects of elevated CO2 concentrations on photosynthesis, growth and reproduction of branches of the tropical canopy tree species, Luehea seemannii Tr. & Planch.

Mature trees have already experienced substantial increases in CO₂ concentrations during their lifetimes, and will experience continuing increases in the future. Small open-top chambers were used to enclose branchlets that were at a height of between 20 and 25 m in the canopy of the tree species Luehea seemannii Tr. & Planch. in a tropical forest in Panamá. Elevated concentrations of CO₂ increased the rate of photosynthetic carbon fixation and decreased stomatal conductance of leaves, but did not influence the growth of leaf area per chamber, the production of flower buds and fruit nor the concentration of nonstructural carbohydrates within leaves. The production of flower buds was highly correlated with the leaf area produced in the second flush of leaves, indicating that the branchlets of mature trees of Luehea seemannii are autonomous to a considerable extent. Elevated levels of CO₂ did increase the concentration of nonstructural carbohydrates in woody stem tissue. Elevated CO₂ concentration also they increased the ratio of leaf area to total biomass of branchlets, and tended to reduce individual fruit weight. These data suggest that the biomass allocation patterns of mature trees may change under future elevated levels of CO₂. Although there were no effects on growth during the experiment, the possibility of increased growth in the season following CO₂ enrichment due to increased carbohydrate concentrations in woody tissue cannot be excluded.     

1型调节性T细胞的表型和功能

1型调节性T细胞(Tr1)在免疫耐受的诱导和维持过程中发挥重要作用。Tr1细胞通常在免疫耐受的环境中由外来抗原诱导产生,通过产生高水平的IL-10而发挥免疫抑制作用。而CD4 CD25 调节性T细胞(Tregs)可在胸腺中天然产生也可在外周被抗原诱导产生,通过细胞接触发挥抑制作用。现对Tr1细胞的表型、功能及其抑制作用机制等方面的研究进展进行综述。     

肠道菌群与过敏性紫癜性肾炎患儿肾功能及免疫功能的相关性研究

探讨肠道菌群与过敏性紫癜性肾炎患儿肾功能及免疫功能的相关性研究。

选取2021年9月—2023年9月于本院治疗的85例过敏性紫癜性肾炎患儿,标记为研究组。并纳入同期进行健康体检的68例同年龄段健康儿童作为对照组。采集患者空腹静脉血和粪便,采用qRT-PCR法定量分析肠道中大肠杆菌和双歧杆菌的数量,计算双歧杆菌/大肠杆菌（B/E）比值。使用全自动特定蛋白分析系统ARRAY360和流式细胞仪检测IgM、IgG、IgA、外周血CD4⁺ T淋巴细胞和CD8⁺ T淋巴细胞,计算CD4⁺/CD8⁺比值。过敏性紫癜性肾炎患儿肠道菌群与肾功能及免疫功能之间的相关性分析采用Pearson分析。

两组的性别、年龄、体质量指数差异均无统计学意义（P＜0.05）。与对照组相比,研究组大肠杆菌数量增加（P＜0.05）,血肌酐、尿素氮、血清尿酸、IgM、IgG、IgA、CD8⁺ T细胞水平升高（P＜0.05）,但双歧杆菌数量降低（P＜0.05）,B/E比值、CD4⁺ T细胞、CD4⁺/CD8⁺比值显著降低（P＜0.05）。过敏性紫癜性肾炎患儿肠道中的大肠杆菌数量分别与血肌酐、尿素氮、血清尿酸、IgM、IgG、IgA、CD8⁺ T细胞水平呈正相关（P＜0.001）,与CD4⁺ T细胞水平、CD4⁺/CD8⁺比值呈负相关（P＜0.001）;双歧杆菌、B/E比值分别与血肌酐、尿素氮、血清尿酸、IgM、IgG、IgA、CD8⁺ T细胞水平呈负相关（P＜0.001）,与CD4⁺ T细胞、CD4⁺/CD8⁺比值呈正相关（P＜0.001）。

过敏性紫癜性肾炎患儿肠道B/E比值显著降低,并与其肾功能及免疫功能指标存在相关性。

     

IgM memory and Waldenstr?m macroglobulinemia’s cell of origin

Waldenström macroglobulinemia (WM) is a neoplasm of mature IgM-expressing B-lymphocytes that is characterized by the occurrence of a monoclonal IgM (mIgM) paraprotein in blood serum and the infiltration of hematopoietic bone marrow with malignant lymphoplasmacytic cells. WM remains incurable despite the development of new therapeutic options. Owing in large measure to having a low incidence, indolent clinical course and good long-term control with proper clinical management, WM has not been investigated as extensively as other B-lineage neoplasms. Major knowledge gaps in our understanding of the natural history of WM include the cell of origin. With that shortcoming in mind, here we discuss the significance of a specific gain-of-function mutation in the adapter protein, myeloid differentiation primary response 88 (MYD88), that occurs with near-complete penetrance in WM and suggests that tumor development is under strong selective pressure for elevated MYD88 signaling. This provides an intriguing link to IgM memory B-cells, which comprise two types of B-lymphocytes ( natural effector IgM⁺IgD⁺ cells and IgM^-only IgM⁺IgD^- cells ) that depend, in part, on MYD88 signaling and constitute intriguing candidates for WM’s cell of origin. We review the features and developmental history of IgM memory in greater depth and propose that WM may be derived from primitive innate-like B-cells ( marginal zone B-cells and B1 B-cells ) that feed the IgM memory compartment. We conclude with a model of MYD88-dependent tumor development in the mature B-cell lineage that considers two different ( convergent or divergent) oncogenesis pathways with respect to the cells of origin.