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Medically underserved places: are usually major care teams efficient with appealing to and keeping common experts?
Colorectal cancer (CRC) is a common digestive tract malignant tumor and is the third cancer-related death worldwide. Valosine containing protein (VCP/p97) is a member of the AAA ATPase family, plays an important role in the ubiquitin-mediated degradation of misfolded proteins. Studies have shown that p97 is overexpressed in colorectal cancer and is a potential therapeutic target. Herein, a series of novel p97 inhibitors were designed, synthesized and biologically assayed. Based on the enzymatic results, structure-activity relationships (SAR) were discussed in detail. Some potent compounds were further evaluated to inhibit the proliferation of CRC cell lines HCT-116. The results showed that some compounds were active against CRC cell lines with IC50 values of less than 1 μM. Among the screened compounds, compound 10 exhibited good microsomal stabilities, pharmacokinetic properties and displayed strong antiproliferative activity against the HCT-116 cell line (0.4 μM). Furthermore, compound 10 exhibited strong in vivo anticancer efficacy in the human CRC (HCT-116) mouse xenograft model.Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative molecules were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB.In most male mammals, testis undergoes increased proliferation activity and the onset of spermatogenesis during pubertal development. However, their gene expression patterns and roles in sheep remain unclear. Therefore, we used Illumina Hiseq 2000 sequencing to identify differentially expressed genes (DEGs) from 0, 30, 60, 90, 120, 150 and 180 postnatal days and characterize the transcriptional level of sheep testicular development. Among them, the DEGs changed the most in 90-150 stages. a total of 2546 (1454 up and 1092 down) and 6867 (4683 up and 2184 down) DEGs were identified in D120 vs. D90 and D150 vs. D120, respectively. Functional enrichment analysis revealed that in earlier pubertal development, testis showed higher gene expression in organ morphogenesis, vasculogenesis, neurogenesis and hormone secretion, while in later pubertal development, genes with higher expression mainly concentrated in regulating spermatogenesis process. Tubastatin A mouse These results indicated that testis development undergoes the transition from organ growth to spermatogenesis and the genes related to hormone secretion were expressed highly earlier than spermatogenesis during pubertal process. In addition, we found several genes such as ZFP36, TNF, HSD3B1, HSD11B2 played key roles in androgen secretion and SPAG family, SYCP family, SPATA family, SPO11, CABYR, TNP1, TNP2 and CFAP43 performed functions during spermatogenesis process. Taken together, multi-genes cooperation prompt testis development in pubertal process. Our transcriptional atlas of sheep testis provides a comprehensive insight about testicular development and pubertal process.In a protocol for the resynchronization of ovulation starting 14 days (D14) after timed artificial insemination, the effects of short-action injectable progesterone (P4i) administration and the length of treatment with an intravaginal progesterone (P4) device on follicular dynamics, the conception rate (P/AI) and the percentage of false positives were evaluated in 1065 Nelore heifers previously timed-inseminated. On D14, P4 devices were inserted, and heifers allocated, based on a 2 × 2 factorial design, to receive (P4i) or not 50 mg of P4i (NoP4i), and to remove the P4 device after 6 (6Day) or 8 days (8Day). At the time of P4 device removal (D20 and D22), non-pregnancy diagnosis was performed using vascularization of the corpus luteum (VCL) evaluated. At this time, non-pregnant heifers received 150 μg of D-cloprostenol, 0.6 mg of estradiol cypionate and 300IU of eCG. TAI was performed 48 h after P4 device removal. For these heifers, ultrasound examinations were performed at P4 device removal and at TAI to eva= 0.001). In conclusion, for resynchronization 14 days after TAI, it is not necessary to inject P4i at the beginning of the protocol. In addition, P4 device removal after 6 instead of 8 days increases the percentage of false positives because of the earlier diagnosis (20 days after TAI), but does not interfere in P/AI of resynchronization protocol. Furthermore, the percentage of false positives is higher in heifers that did not ovulate to 1st TAI protocol.Autoimmune diseases afflict nearly 10% of the world's population and have a serious impact on survival and quality of life. Unfortunately, the specific pathogenesis of almost all autoimmune diseases is still unclear, with more research findings identifying some key pathogenic genes at the genetic level and several pathogenic inflammatory factor phenotypes. ERAP1 has been suggested as a potential therapeutic target for several autoimmune diseases, especially MHC-Ⅰ related. How the structure and antigenic peptide processing function of ERAP1 affect the pathogenesis of these autoimmune diseases needs to be elucidated more clearly. Genetic studies on single nucleotide polymorphism of ERAP1 provide a good bridge to better understand the relationship and pattern between ERAP1 structure, function, and disease. However, existing reviews have focused on the genetic association of ERAP1 SNPs with autoimmune diseases, and no one has specifically addressed how ERAP1 gene polymorphisms embodied at the protein level specifically mediate antigenic peptide editing and the development of multiple autoimmune diseases. In this paper, we present a comprehensive review of these ERAP1 SNPs associated with multiple autoimmune diseases, in particular the polymorphisms affecting their protein structure and enzyme function, and attempt to unravel the underlying structural and biochemical mechanisms by which ERAP1 affects the pathogenesis of multiple autoimmune diseases through the SNP-protein structure-function-disease relationship. This study will provide theoretical help and ideas for understanding the relationship between ERAP1 and autoimmune diseases and for drug design targeting wild-type and mutant proteins with different polymorphisms.Photodynamic therapy (PDT) induces apoptosis of cancer cells by generating cytotoxic reactive oxygen species, the therapeutic effect of which, however, is impeded by intrinsic/inducible apoptosis-resistant mechanisms in cancer cells and hypoxia of tumor microenvironment (TME); also, PDT-induced anti-tumor immunity activation is insufficient. To deal with these obstacles, a novel biomimetic nanoplatform is fabricated for the precise delivery of photosensitizer chlorin e6 (Ce6), hemin and PEP20 (CD47 inhibitory peptide), integrating oxygen-boosted PDT, ferroptosis activation and CD47-SIRPα blockade. Hemin's catalase-mimetic activity alleviates TME hypoxia and enhances PDT. The nanoplatform activates ferroptosis via both classical (down-regulating glutathione peroxidase 4 pathway) and non-classical (inducing Fe2+ overload) modes. Besides the role of hemin in consuming glutathione and up-regulating heme oxygenase-1 expression, interestingly, we observe that Ce6 enhance ferroptosis activation via both classical and non-classical modes. The anti-cancer immunity is reinforced by combining PEP20-mediated CD47-SIRPα blockade and PDT-mediated T cell activation, efficiently suppressing primary tumor growth and metastasis. PEP20 has been revealed for the first time to sensitize ferroptosis by down-regulating system Xc-. This work sheds new light on the mechanisms of PDT-ferroptosis activation interplay and bridges immunotherapy and ferroptosis activation, laying the theoretical foundation for novel combinational modes of cancer treatment.The development of chemoresistance is a major hurdle for the treatment of colorectal cancer (CRC), which contributes remarkably to the poor clinical prognosis. Nanodrug delivery systems show great potential in overcoming chemoresistance, but limited by the lack of identification of chemoresistance targets from cancer patients. In the present study, we enrolled chemotherapy-resistant or sensitive CRC patients and used the next-generation RNA sequencing to reveal that Asporin (ASPN) is highly expressed in tumor tissues from oxaliplatin (OXA)-resistant patients and closely correlated with a poor prognosis of CRC. Downregulation of ASPN reversed OXA resistance and promoted cell apoptosis both in vitro and in vivo. To overcome ASPN-mediated OXA resistance, we constructed a nanoparticle-based co-delivery system (denoted as PPO-siASPN) for simultaneous delivery of OXA and siRNA targeting ASPN (siASPN). PPO-siASPN not only facilitated the intracellular delivery of OXA through the enhanced cellular uptake, but effectively suppressed ASPN expression for synergistic antitumor activity in vitro and in vivo. In the more clinically relevant patient-derived xenograft (PDX) mouse model, systemic administration of PPO-siASPN achieved a remarkable therapeutic effect. This study uncovered the critical role of ASPN in causing OXA resistance in CRC patients and suggests a promising nanoformulation that may be more effective than current standard-of-care medications.The poor translation of nanomedicines from bench to bedside can be attributed to (i) lack of a delivery system with precise drug compositions with no batch-to-batch variations, (ii) off-target or undesirable release of payload, and (iii) lack of a method to monitor the fate of the specific drug of interest, which often has to be modified with a fluorescent tag or replaced with a model drug which can be tracked. To overcome these translation hurdles, we developed dual responsive organelle targeted nanoreactors (DRONEs) with precise drug composition, site specific payload release and which enable accurate in-vivo monitoring. DRONEs consist of a polyprodrug inner core composed of a dual responsive backbone containing a photosensitizer (Protoporphyrin IX) grafted with functionalized polyethylene glycol (PEG) outer shell to prolong blood circulation and a tumour homing pro-apoptotic peptide (CGKRKD[KLAKLAK]2) (THP). DRONEs can significantly reduce the tumour burden in an orthotopic glioblastoma model due to its BBB penetrating and tumour homing capabilities.
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