Cellular Protein Aggregates: Formation, Biological Effects, and Ways of Elimination.

The accumulation of protein aggregates is the hallmark of many neurodegenerative diseases. The dysregulation of protein homeostasis (or proteostasis) caused by acute proteotoxic stresses or chronic expression of mutant proteins can lead to protein aggregation. Protein aggregates can interfere with a variety of cellular biological processes and consume factors essential for maintaining proteostasis, leading to a further imbalance of proteostasis and further accumulation of protein aggregates, creating a vicious cycle that ultimately leads to aging and the progression of age-related neurodegenerative diseases. Over the long course of evolution, eukaryotic cells have evolved a variety of mechanisms to rescue or eliminate aggregated proteins. Here, we will briefly review the composition and causes of protein aggregation in mammalian cells, systematically summarize the role of protein aggregates in the organisms, and further highlight some of the clearance mechanisms of protein aggregates. Finally, we will discuss potential therapeutic strategies that target protein aggregates in the treatment of aging and age-related neurodegenerative diseases.

Research progress of indole-fused derivatives as allosteric modulators: Opportunities for drug development.

Allosteric modulation is a direct and effective method for regulating the function of biological macromolecules, which play vital roles in various cellular activities. Unlike orthosteric modulators, allosteric modulators bind to sites distant from the protein's orthosteric/active site and can have specific effects on the protein's function or activity without competing with endogenous ligands. Compared to traditional orthosteric modulators, allosteric modulators offer several advantages, including reduced side effects, greater specificity, and lower toxicity, making them a promising strategy for developing novel drugs. Indole-fused architectures are widely distributed in natural products and bioactive drug leads, displaying diverse biological activities that attract the interest of both chemists and biologists in drug discovery. Currently, an increasing number of indole-fused compounds have exhibited potent activities in allosteric modulation. In this review, we provide a brief summary of examples of allosteric modulators based on the indole-fused complex architecture, highlighting the strategies for drug design/discovery and the structure-activity relationships of allosteric modulators from the perspective of medicinal chemistry.

Construction of cyclopenta[b]dihydronaphthofurans via TsOH-catalyzed consecutive biscyclization of dithioallylic alcohols and 1-styrylnaphthols.

An efficient TsOH-catalyzed consecutive biscyclization cascade reaction of dithioallylic alcohols with 1-styrylnaphthols is demonstrated for the concise construction of pharmaceutically important cyclopenta[b]dihydrobenzofuran scaffolds. This process involved an acid-catalyzed (3+2) cycloaddition followed by an intramolecular nucleophilic addition, providing cyclopenta[b]dihydronaphthofurans bearing a tetra- or fully substituted cyclopentane core in good yields with exclusive diastereoselectivities (>20 : 1 d.r.).

A straightforward access to trifluoromethylated natural products through late-stage functionalization.

Covering: 2011 to 2021Trifluoromethyl (CF3)-modified natural products have attracted increasing interest due to their magical effect in binding affinity and/or drug metabolism and pharmacokinetic properties. However, the chemo and regioselective construction of natural products (NPs) bearing a CF3 group still remains a long-standing challenge due to the complex chemical scaffolds and diverse reactive sites of NPs. In recent years, the development of late-stage functionalization strategies, including metal catalysis, organocatalysis, light-driven reactions, and electrochemical synthesis, has paved the way for direct trifluoromethylation process. In this review, we summarize the applications of these strategies in the late-stage trifluoromethylation of natural products in the past ten years with particular emphasis on the reaction model of each method. We also discuss the challenges, limitations, and future prospects of this approach.

Organo/Silver Dual Catalytic (3 + 2)/Conia-Ene Type Cyclization: Asymmetric Synthesis of Indane-Fused Spirocyclopenteneoxindoles.

Developing efficient strategies to synthesize spirocyclopenteneoxindoles is an attractive target due to their potential biological activity. This work described the thiourea/silver dual catalytic (3 + 2)/Conia-ene type reaction of 2-(2-oxoindolin-3-yl)malononitrile with ortho-ethynyl substituted nitrostyrene. The reaction features mild conditions and good atom- and step-economy. Three new C-C bonds were formed within one synthetic step, providing the indane-fused spirocyclopenteneoxindoles in good yields, with excellent chemo-, regio-, and stereoselectivity.

Impact of Lung Metastasis versus Metastasis of Bone, Brain, or Liver on Overall Survival and Thyroid Cancer-Specific Survival of Thyroid Cancer Patients: A Population-Based Study.

We investigate the impact of lung metastasis versus metastasis of bone, brain, or liver on overall survival (OS) and thyroid cancer-specific survival (TCSS) in patients with thyroid cancer (TC). Therefore, de-identified SEER 18 registry data of primary TC patients diagnosed between 2010 and 2016 were analyzed. The primary outcome was the prognosis of TC patients with lung metastasis compared with other sites. The secondary outcomes included the prognosis comparison between patients with and without surgery and between single and multiple metastasis sites. Isolated lung metastasis was associated with worse OS and TCSS than bone metastasis (both p < 0.05) and was associated with worse OS than liver metastasis (p = 0.0467). Surgery performed either for the primary or distant site was associated with better OS and TCSS in patients with metastasis of lung or bone (p < 0.05). Isolated lung metastasis was related to better OS and TCSS than lung−liver, lung−brain, and lung−other multiple metastases. The multivariable analysis revealed that age < 55 years, surgery to the primary site, and to the distant site(s) were associated with better outcomes, while T4 and Tx were associated with worse outcomes. Nevertheless, it revealed that the other race (i.e., any race other than white, black, or unknown) and male gender were associated with better TCSS only (p < 0.05). Isolated lung metastasis is associated with a worse prognosis in TC patients compared with bone or liver metastasis. Surgery performed either for the primary or distant site(s) is associated with better survival outcomes in TC patients with metastasis of lung or bone.

Design, Synthesis, and Biological Evaluation of Tetrahydro-α-carbolines as Akt1 Inhibitors That Inhibit Colorectal Cancer Cell Proliferation.

A series of densely functionalized THαCs were designed and synthesized as Akt1 inhibitors. Organocatalytic [3+3] annulation between indolin-2-imines 1 and nitroallylic acetates 2 provided rapid access to this pharmacologically interesting framework. In vitro kinase inhibitory abilities and cytotoxicity assays revealed that compound 3 af [(3S*,4S*)-4-(4-bromo-2-fluorophenyl)-9-methyl-3-nitro-1-tosyl-2,3,4,9-tetrahydro-1H-pyrido[2,3-b]indole] was the most potent Akt1 inhibitor, and mechanistic study indicated that compound 3 af suppressed the proliferation of colorectal cancer cells via inducing apoptosis and autophagy. Molecular docking suggested that the indole fragment of 3 af was inserted into the hydrophobic pocket of Akt1 protein, and the H-bond between 3 af and residue Lys179 also contributed to the stable binding. This article provides an efficient strategy to design and synthesize biologically important compounds as novel Akt1 inhibitors.

Diagnostic Value of Model-Based Iterative Algorithm in Tuberculous Pleural Effusion.

Although there are several diagnostic modalities for tuberculous pleurisy, there is still a lack of easy, cost-effective, and rapid methods for confirming the diagnosis. In order to facilitate clinicians to diagnose patients with tuberculous pleurisy at an early stage, help patients to obtain treatment early, and reduce lung damage, it is hoped that new techniques will be available in the future to help diagnose tuberculous pleurisy rapidly in the clinic. To this end, this paper investigates the problem of bidirectional consistency based on event-triggered iterative learning. Firstly, a dynamic linearized data model of TB pleurisy intelligent system is established using compact-form dynamic linearization method, and a parameter estimation algorithm of TB pleurisy data model is proposed; then, based on this data model, an output observer and a dead zone controller are designed, and an event-triggered distributed model-free iterative learning bidirectional consistency control strategy is constructed by combining with signal graph theory. In this paper, 112 patients with pleural effusion were collected, including 76 patients with confirmed or clinically diagnosed tuberculous pleural effusion and 36 patients with nontuberculous pleural effusion. Pleural effusion T-SPOT.TB, blood T-SPOT.TB, pleural effusion Xpert MTB/RIF, and pleural effusion adenosine deaminase (ADA) tests were performed before treatment in the included patients. The sensitivity of pleural effusion T-SPOT.TB was higher than that of peripheral blood T-SPOT.TB (76.32%, 58/76), pleural effusion Xpert MTB/RIF (65.79%, 50/76), and pleural effusion ADA (28.95%, 22/76); the differences were statistically significant (x 2 = 14.74, 25.22, and 76.45, P < 0.01). The specificity of the Xpert MTB/RIF test for pleural effusion (100%, 36/36) was higher than that for pleural effusion T-SPOT.TB (77.78%, 28/36), peripheral blood T-SPOT.TB, and pleural effusion T-SPOT.TB. The sensitivity of the combined Xpert MTB/RIF test (64.47%, 49/76) was lower than that of the pleural effusion T-SPOT.TB alone (97.37%, 74/76).

Thyrotropin suppression therapy using levothyroxine does not negatively affect breast cancer prognosis.

INTRODUCTION: Breast cancer (BC) and thyroid dysfunction are common in females, yet the relationship between thyroid hormone and BC is unclear. To search for the connection between thyrotropin and BC, we contradistinguished BC patients with or without synchronous second primary thyroid cancer (TC) with surgery using data from the Surveillance, Epidemiology, and End Results (SEER) database. Theoretically, according to the ATA (American Thyroid Association) guidelines, all TC patients were treated with thyrotropin suppressive therapy only from 2010 to 2015. MATERIALS AND METHODS: Data from BC patients with a synchronous second TC with surgery (BC2TC) and only BC patients (1BC) during 2010-2015 were extracted from the SEER database. Differences in the clinicopathological characteristics between BC2TC and 1BC patients were analyzed by chi-square tests. Comparisons of the disease-specific survival (DSS) and overall survival (OS) curves between these two groups were performed with the log-rank (Mantel-Cox) test. RESULTS: Within this dataset, we identified 134 BC2TC patients during the period from 2010 to 2015. Significant differences between the BC2TC and 1BC groups were found only for different ages and TNM (tumor-node-metastasis status) stages. There were no significant differences in DSS between the two cohorts (P = 0.060). The same tendencies in OS or DSS were observed for the different age groups and different TNM groups, even the stage I, N0 (without metastases to lymph nodes), and ER (+) (estrogen receptor (ER)-positive) groups. CONCLUSIONS: There were no remarkable differences in survival between the BC2TC and 1BC groups, and thyrotropin suppression therapy using levothyroxine did not negatively affect BC prognosis.

Asymmetric organocatalysis: an enabling technology for medicinal chemistry.

The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.

Design and Efficient Synthesis of RalA Inhibitors Containing the Dihydro-α-carboline Scaffold.

Ras-related protein RalA is a member of the Ras small GTPases superfamily. Its activation plays an important role in regulating tumor initiation, invasion, migration, and metastasis. In this study, we designed a new type of RalA inhibitor containing a dihydro-α-carboline scaffold. The structurally new dihydro-α-carboline derivatives could be efficiently synthesized in good yields through a newly developed three-component [3+2+1] cyclization reaction. Evaluation of the biological activity showed that some of the dihydro-α-carboline derivatives can inhibit RalA/B and proliferative activities of NSCLC cell lines. The 4-(pyridin-3-yl)-dihydro-α-carboline compound (3 o) was found to be the most potent derivative, with IC50 values of 0.43±0.03, 0.64±0.07, 0.93±0.10, and 1.54±0.15 µM against A549, H1299, H460, and H1975 cells, respectively. Mechanism investigation suggested that 3 o inhibits the RalA/B activation of A549, down-regulates Bcl-2, stimulates cytochrome c and PARP cleavage, and induces cell apoptosis. A molecular docking study revealed that 3 o can form stable hydrogen bonds with residues of RalA. Moreover, amide-π and alkyl-π interactions also contributed to the affinity between 3 o and RalA.

Survival of Patients with First and Metachronous Second Primary Breast Cancer or Lung Cancer Malignancy: Comparisons Using the SEER Database.

INTRODUCTION: Breast cancer (BC) and lung cancer (LuC) are common malignancies. The survival of patients with metachronous second primary malignancy (MSPM) of BC and LuC after a first primary of BC and LuC remains unclear. METHODS: Data of patients with BC and LuC, with or without MSPM of BC and LuC, who were diagnosed from 2000 to 2014, were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The baseline characteristics of the different groups were compared using chi-square tests. The survival curves were compared using the log-rank test. Survival analysis was also performed in other malignancies with data extracted from the SEER database using the same method. RESULTS: Significant differences in most of the demographics and clinicopathological factors were found between the groups. Patients with LuC with an MSPM of BC (LuC2BC) exhibited better survival than those with LuC (P < 0.001), while patients with BC with an MSPM of LuC (BC2LuC) exhibited worse survival than those with BC (P < 0.001). A similar trend was found in other malignancies. Prostate cancer (PC) followed by thyroid cancer (TC) (PC2TC) and TC followed by PC (TC2PC) did not show an obvious survival trend against their index malignancy (IM). CONCLUSIONS: MSPM benefits the IM prognosis if the survival rate of MSPM is better than that of the IM and vice versa. However, the situation is somewhat confusing when the survival differences between MSPM and IM are minimal.

Novel HSP90-PI3K Dual Inhibitor Suppresses Melanoma Cell Proliferation by Interfering with HSP90-EGFR Interaction and Downstream Signaling Pathways.

Melanoma is the deadliest form of skin cancer, and its incidence has continuously increased over the past 20 years. Therefore, the discovery of a novel targeted therapeutic strategy for melanoma is urgently needed. In our study, MTT-based cell proliferation assay, cell cycle, and apoptosis assays through flow cytometry, protein immunoblotting, protein immunoprecipitation, designing of melanoma xenograft models, and immunohistochemical/immunofluorescent assays were carried out to determine the detailed molecular mechanisms of a novel HSP90-PI3K dual inhibitor. Our compound, named DHP1808, was found to suppress A375 cell proliferation through apoptosis induction by activating the Fas/FasL signaling pathway; it also induced cell-cycle arrest and inhibited the cell migration and invasion of A375 cells by interfering with Hsp90-EGFR interactions and downstream signaling pathways. Our results indicate that DHP1808 could be a promising lead compound for the Hsp90/PI3K dual inhibitor.

pH-sensitive magnetic drug delivery system via layer-by-layer self-assembly of CS/PEG and its controlled release of DOX.

Cancer is one of the biggest killers threat to human life and health and is still difficult to treat mainly due to the lack of targeted drug delivery stages and limitations associated with delivering drugs to targeted cancer tissues. The goal of this work was to develop a magnetic, pH-sensitive formulation for targeted delivery of chemotherapeutic agents to cancer cells. Then the functional drug delivery system (Fe3O4@CS/PEG-DOX) was synthesized by the layer-by-layer (LbL) self-assembly technique. And the drug loading content is calculated to be 19.1%. In addition, the Fe3O4@CS/PEG-DOX exhibited excellent pH-sensitivity, 73.1% DOX was released within 48 h at pH 4.0. Furthermore, all the release behaviors fit the Higuchi model very well and the dissolution of CS/PEG layers played a key role on DOX release from Fe3O4@CS/PEG-DOX. The results of toxicity analysis in human liver hepatocellular carcinoma cells (HepG2) revealed that Fe3O4@CS/PEG-DOX exhibited high anti-tumor activity, while the Fe3O4@CS/PEG nanocomposites were practically non-toxic. Therefore, all the results demonstrated that the Fe3O4@CS/PEG-DOX could have an important impact on the development of targeted intracellular delivery nanodevices for cancer therapy.

Recent Advances in Characterizing Natural Products that Regulate Autophagy.

Autophagy, an intricate response to nutrient deprivation, pathogen infection, Endoplasmic Reticulum (ER)-stress and drugs, is crucial for the homeostatic maintenance in living cells. This highly regulated, multistep process has been involved in several diseases including cardiovascular and neurodegenerative diseases, especially in cancer. It can function as either a promoter or a suppressor in cancer, which underlines the potential utility as a therapeutic target. In recent years, increasing evidence has suggested that many natural products could modulate autophagy through diverse signaling pathways, either inducing or inhibiting. In this review, we briefly introduce autophagy and systematically describe several classes of natural products that implicated autophagy modulation. These compounds are of great interest for their potential activity against many types of cancer, such as ovarian, breast, cervical, pancreatic, and so on, hoping to provide valuable information for the development of cancer treatments based on autophagy.

Enantio- and diastereoselective synthesis of spiropyrazolones via an organocatalytic [1 + 2 + 3] multicomponent reaction.

An asymmetric catalytic multicomponent reaction of malononitrile, benzaldehyde, and α-arylidene pyrazolinones to produce spiropyrazolones has been reported. The [1 + 2 + 3] multicomponent reaction was catalyzed by chiral cinchona alkaloids to provide spiropyrazolones in high yields, with excellent enantioselectivities and good diastereoselectivities. We also performed control experiments and proposed a plausible catalytic cycle based on the observed experimental results to explain the reaction process and stereoselectivity of the asymmetric multicomponent reaction.

Organocatalytic diastereoselective [3+2] cyclization of MBH carbonates with dinucleophiles: synthesis of bicyclic imidazoline derivatives that inhibit MDM2-p53 interaction.

An efficient organocatalytic cyclization strategy was developed to synthesize pharmacologically interesting bicyclic imidazoline derivatives. Morita-Baylis-Hillman carbonates were applied as C3 electrophiles to react with N,C-dinucleophiles for the first time, yielding the desired products in good to excellent yields with outstanding diastereoselectivities. The optically pure bicyclic imidazolines were expeditiously prepared by utilizing the readily available chiral ketene aminals as building blocks. The products were found to inhibit MDM2-p53 binding and cell proliferation. The most potent compound 5c induced the accumulation of MDM2, p53 and p21 proteins in HCT116 cells and blocked interaction between MDM2 and p53.

Asymmetric Construction of 4 H-Pyrano[3,2- b]indoles via Cinchonine-Catalyzed 1,4-Addition of 2-Ylideneoxindole with Malononitrile.

A highly enantioselective [4 + 2] annulation of 2-ylideneoxindole with malononitrile has been accomplished by cinchonine catalysis under mild conditions. The corresponding enantiomerically enriched 4 H-pyrano[3,2- b]indoles were generated in moderate to high yields (up to 94%) with excellent enantioselectivities (up to 98% ee). To explain the stereoselectivity of the organocatalytic Michael-ammonization cascade, we also carried out the control experiments and proposed plausible transition-state models for the catalytic cycle based on the observed stereochemistry of the products. In addition, some of the products showed moderate antibacterial activity against S. aureus and S. epidermidis in vitro, which might be considered as a potential clue for the discovery of new antimicrobial agents.

Recent advances in the synthesis of C2-spiropseudoindoxyls.

Compared with the numerous reviews on the construction of C3 spirooxindoles, few reviews have examined the synthesis of structurally analogous C2-spiropseudoindoxyl derivatives. This scaffold has attracted substantial attention from synthetic chemists because of its relevance to medicinal chemistry. This review summarizes the recent progress in the synthesis of many heterocycle and carbocycle fused spiropseudoindoxyl compounds. The article is divided into sections according to the type of catalysis, including metal catalysis, high-iodine reagent mediation, and organic catalysis. We also discuss challenges and future directions based on the progress in the field. We believe that this review will update researchers focused on the synthesis of C2-spiropseudoindoxyl compounds and will encourage further growth in this field.

Primary small cell neuroendocrine carcinoma combined with squamous carcinoma of the ureter after renal transplantation: a rare case report.

A 47-year-old female presented with a 1-month history of painless gross hematuria after undergoing kidney transplant 4 years. Computed tomography revealed mass-like soft tissue density in the middle-lower portion of the right autologous ureter, which was up to the upper margin of the fourth lumbar vertebra, down to the distal ureter near the entrance of the bladder. The patient underwent right autologous nephroureterectomy resection. Gross examination showed a white, partly yellow mass in the middle-lower portion of ureter. Light microscopy showed a small cell neuroendocrine carcinoma (SCNEC) admixed with squamous carcinoma, invading the ureter wall to periureteric fat tissue, and there was invasion of the lymphatic and renal portal vein. The SCNEC was diffusely positive for CD56 and syn, and squamous carcinoma was positive for P40, P63 and CK5/6. Ureteral SCNEC is a rare malignant tumor with high invasiveness and poor prognosis. Diagnosis mainly depends on pathologic morphology and immunohistochemical markers. Positive neuroendocrine markers are one of the important references for this tumor. Surgical treatment and postoperative radiotherapy and chemotherapy are the main treatments according to cases reported.