Research Progress in the Regulation of the ABA Signaling Pathway by E3 Ubiquitin Ligases in Plants.

E3 ubiquitin ligases (UBLs), as enzymes capable of specifically recognizing target proteins in the process of protein ubiquitination, play crucial roles in regulating responses to abiotic stresses such as drought, salt, and temperature. Abscisic acid (ABA), a plant endogenous hormone, is essential to regulating plant growth, development, disease resistance, and defense against abiotic stresses, and acts through a complex ABA signaling pathway. Hormone signaling transduction relies on protein regulation, and E3 ubiquitin ligases play important parts in regulating the ABA pathway. Therefore, this paper reviews the ubiquitin-proteasome-mediated protein degradation pathway, ABA-related signaling pathways, and the regulation of ABA-signaling-pathway-related genes by E3 ubiquitin ligases, aiming to provide references for further exploration of the relevant research on how plant E3 ubiquitin ligases regulate the ABA pathway.

Apatinib beyond first progression is associated with prolonged overall survival in patients with advanced breast cancer: Results from an observational study.

In the present study, the efficacy and safety of a low dose of apatinib in the treatment of patients with advanced breast cancer (ABC) in a real-world setting were assessed, the impact of continuous anti-angiogenic therapy beyond progression was determined and the factors associated with efficacy were evaluated. A total of 63 patients with ABC who were treated with apatinib and for whom several lines of treatment had failed were retrospectively analyzed in Tangshan People's Hospital (Tangshan, China) between January 2016 and October 2022. Apatinib was administered orally combined with chemotherapy, endocrine therapy, targeted therapy or monotherapy at a dose of 250 mg per day. Apatinib administration was continued in certain patients beyond first progressive disease (PD), and these patients were defined as the continued anti-angiogenic treatment beyond first progression (CABF) group, while those who discontinued apatinib were defined as the non-CABF group. In the evaluation of the first efficacy, the objective response rate was 33.3%. A total of 26 patients continued to receive apatinib post-first PD and were allocated to the CABF group. The median overall survival (OS) time of the 63 patients was 16 months. Log-rank univariate analysis revealed that the OS time was significantly associated with molecular subtype (P=0.014), CABF (P=0.004), and the neutrophil-to-lymphocyte ratio (NLR) (P=0.011). Multivariate Cox regression analysis revealed that being in the non-CABF group and a high NLR were independent risk factors for lower OS time (P=0.017 and P=0.041, respectively). These results support the continued administration of low-dose apatinib beyond progression and the use of NLR as an easily accessible prognostic marker in patients with ABC treated with apatinib.

Synchronous double primary small cell lung cancer and invasive ductal breast carcinoma: a case report.

BACKGROUND: Although lung and breast cancers are common malignancies, the occurrence of primary synchronous neoplasms involving these organs has been rarely reported in literature. CASE PRESENTATION: A 75-year-old female patient presented at a local hospital with a ten-day history of dizziness and slurred speech. A CT contrast-enhanced scan revealed a 4.2 cm mass in the lower lobe of the right lung and a 3.8 cm space-occupying lesion in the right breast. Subsequent breast ultrasound identified a hypoechoic lesion measuring5.41 × 4.75 × 3.06 cm in the right breast, and an ultrasound-guided biopsy confirmed the presence of infiltrating ductal carcinoma of the right breast. The immunohistochemistry analysis of the breast mass revealed positive staining for ER, PR, HER-2, AR and Ki67 in the tumor cells, while negative staining was observed for P63, Calponin, CK5/6 and CK14. MR imaging of the head detected abnormal signals in the right frontal lobe (3.6 cm×2.9 cm in size), left cerebellar hemisphere, and punctate enhancement in the left temporal lobe, indicating potential metastasis. Pathological examination of a lung biopsy specimen confirmed the presence of small cell lung cancer (SCLC). Furthermore, immunohistochemistry analysis of the lung lesions demonstrated positive staining for TTF-1, CK-Pan, Syn, CgA, CD56, P53 (90%) and Ki67 (70%), and negative staining for NapsinA and P40 in the tumor cells. The patient's diagnosis of SCLC with stage cT2bN0M1c IVB and brain metastases (BM), as well as invasive ductal breast carcinoma (IDC), was confirmed based on the aforementioned results. Whereupon we proposed a treatment plan consisting of whole-brain radiation (40 Gy/20fractions), focal radiotherapy (60 Gy/20fractions), and adjuvant concurrent chemotherapy with oral etoposide (50 mg on days 1 to 20). CONCLUSIONS: To the best of our knowledge, the present case is the first of its kind to describe the synchronous double cancer, consisting of primary SCLC and IDC.

Ethylene glycol-linked amino acid diester prodrugs of oleanolic acid for PepT1-mediated transport: synthesis, intestinal permeability and pharmacokinetics.

The purposes of this study were to expand the structure of parent drugs selected for peptide transporter 1 (PepT1)-targeted ester prodrug design and to improve oral bioavailability of oleanolic acid (OA), a Biopharmaceutics Classification System (BCS) class IV drug. Through an ethoxy linker the carboxylic acid group of OA was conjugated with the carboxylic acid group of different amino acid promoieties to form six diester prodrugs. The effective permeability (P(eff)) of prodrugs was screened by in situ rat single-pass intestinal perfusion (SPIP) model in two buffers with different pH (6.0 and 7.4) as PepT1 employs a proton-gradient as the driving force. Compared to OA, 2.5-fold, 2.3-fold, 2.2-fold, 2.1-fold, and 1.9-fold enhancement of P(eff) in buffer with pH 6.0 was observed for L-Phe ester (5c), L-Val ester (5a), L-Lys ester (5e), D-Phe ester (5d), and D-Val ester (5b), respectively. Furthermore, P(eff) of 5a, 5c, 5d and 5e in pH 6.0 was significantly higher than that in pH 7.4 (p < 0.01), respectively. These results showed that the H(+) concentration of perfusion solution had great effect on the transport of the prodrugs across intestinal membrane. For the further evaluation of affinity to PepT1, inhibition studies were performed by coperfusing 0.1 mM prodrug with 50 mM glycyl-sarcosine (Gly-Sar, a typical substrate of PepT1). It turned out that the P(eff) of 5a, 5b, 5c and L-Tyr ester (6f) significantly reduced in the presence of Gly-Sar (1.7-fold, 2.2-fold, 1.9-fold, and 1.4-fold, respectively). We supposed that it may be attributed to PepT1 mediated transport of these prodrugs. 5a and 6f were selected as the optimal target prodrugs for oral absorption in vivo. Following intragastric administration of 300 mg/kg (calculated as OA) 5a, 6f and OA in three groups of rats, compared with group OA, Cmax for the group of 5a and 6f was enhanced by 1.56-fold and 1.54-fold, respectively. Fapp of group 5a and 6f was 2.21- and 2.04-fold increased, respectively, indicating that 5a and 6f had better oral absorption than OA. The combined results also suggest that diester prodrugs which conjugated two carboxylic acid groups of proper amino acid promoieties and parent drug through a linker can be used for PepT1-targeted prodrug design. With this strategy, oral bioavailability of OA in rats could be improved significantly.

[Short-term efficacy of intensity-modulated radiotherapy on esophageal carcinoma].

BACKGROUND AND OBJECTIVE: Intensity-modulated radiotherapy (IMRT) for esophageal carcinoma has seldom been reported; its clinical efficacy and toxicity are still uncertain. This study was to evaluate the short-term efficacy of IMRT on esophageal carcinoma, and to observe adverse events. METHODS: From June 2006 to March 2008, 37 patients with cervical and thoracic esophageal carcinoma were treated with IMRT. The treatment response, local control and survival were evaluated and the adverse events were observed. RESULTS: The minimal prescription dose of 100% of gross tumor volume (GTV D100) 95% of clinical target volume (CTV D95), and 95% of planning target volume (PTV D95) were (6 456+/-172)cGy, (6 293+/-145)cGy, and (5 988+/-53)cGy, respectively. The volumes of lung receiving irradiation of >or= 5 Gy, >or=10 Gy, >or=20 Gy and >or=30 Gy were (59.6+/-12.8)%, (39.5+/-8.7)%, (22.0+/-5.4)%, and (12.0+/-4.3)%, respectively. The mean lung dose (MLD) was (1 178+/-248)cGy. The overall response rate was 97.3% (36/37). The patients were followed-up for 8-29 months (median,13 months). The occurrence rates of grades 3-4 acute and late esophagitis, grades 2-4 acute and late pneumonitis were 16.2% and 7.2%, 10.8% and 8.1%. The 1-and 2-year local control rates were 72.9% and 72.9%. The 1-and 2-year overall survival rates were 80.9% and 67.4%. The 1-and 2-year disease-free survival rates were 73.5% and 51.4%. Local recurrence (69.2%) was the main reason of treatment failure. CONCLUSION: IMRT is an effective treatment for esophageal carcinoma with low occurrence of acute and late radiation-related pneumonitis, but local failure is still a main problem for treatment of patients with esophageal carcinoma.

Synthesis of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles as potential anticonvulsant agents.

A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles were synthesized. The anticonvulsant effect and neurotoxicity of the compounds (intraperitoneally) were evaluated with the maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests in mice. 2-Phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3g) was the most active and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 29.5 mg/kg, a median toxicity dose (TD(50)) of 285 mg/kg, and a protective index (PI) of 9.7, which is greater than the reference drug, carbamazepine, which has a PI of 6.4.

Design and synthesis of 5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline derivatives with anticonvulsant activity.

A series of 5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline derivatives were synthesized using 4-hydroxyquinolin-2(1H)-one as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and their neurotoxicities were measured by the rotarod test. The results of these tests demonstrated that 5-hexyloxy-[1,2,4]triazolo[4,3-a]quinoline (3f) was the most potent anticonvulsant, with median effective dose (ED(50)) of 19.0mg/kg and protective index (PI=TD(50)/ED(50)) values of 5.8 in the MES test. Compound 5-benzyloxy-[1,2,4]triazolo[4,3-a]quinoline (3j), exhibited a little weaker activity than compound 3f in controlling the seizure induced by MES test at the dose of 22.8 mg/kg, but it possessed lower neurotoxicity with PI value of 12.0, which was safer than marketed drug carbamazepine. To explain the possible mechanism of anticonvulsant activity, compound 3j was tested in pentylenetetrazole test, isoniazid test, thiosemicarbazide test, 3-mercaptopropionic acid and strychnine test.