A shock flash breaking out of a dusty red supergiant.

Shock-breakout emission is light that arises when a shockwave, generated by the core-collapse explosion of a massive star, passes through its outer envelope. Hitherto, the earliest detection of such a signal was at several hours after the explosion1, although a few others had been reported2-7. The temporal evolution of early light curves should provide insights into the shock propagation, including explosion asymmetry and environment in the vicinity, but this has been hampered by the lack of multiwavelength observations. Here we report the instant multiband observations of a type II supernova (SN 2023ixf) in the galaxy M101 (at a distance of 6.85 ± 0.15 Mpc; ref. 8), beginning at about 1.4 h after the explosion. The exploding star was a red supergiant with a radius of about 440 solar radii. The light curves evolved rapidly, on timescales of 1-2 h, and appeared unusually fainter and redder than predicted by the models9-11 within the first few hours, which we attribute to an optically thick dust shell before it was disrupted by the shockwave. We infer that the breakout and perhaps the distribution of the surrounding dust were not spherically symmetric.

Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL.

The mechanism by which cells decide to skip mitosis to become polyploid is largely undefined. Here we used a high-content image-based screen to identify small-molecule probes that induce polyploidization of megakaryocytic leukemia cells and serve as perturbagens to help understand this process. Our study implicates five networks of kinases that regulate the switch to polyploidy. Moreover, we find that dimethylfasudil (diMF, H-1152P) selectively increased polyploidization, mature cell-surface marker expression, and apoptosis of malignant megakaryocytes. An integrated target identification approach employing proteomic and shRNA screening revealed that a major target of diMF is Aurora kinase A (AURKA). We further find that MLN8237 (Alisertib), a selective inhibitor of AURKA, induced polyploidization and expression of mature megakaryocyte markers in acute megakaryocytic leukemia (AMKL) blasts and displayed potent anti-AMKL activity in vivo. Our findings provide a rationale to support clinical trials of MLN8237 and other inducers of polyploidization and differentiation in AMKL.

Non-coding RNA-based regulation of inflammation.

Inflammation is a multifactorial process and various biological mechanisms and pathways participate in its development. The presence of inflammation is involved in pathogenesis of different diseases such as diabetes mellitus, cardiovascular diseases and even, cancer. Non-coding RNAs (ncRNAs) comprise large part of transcribed genome and their critical function in physiological and pathological conditions has been confirmed. The present review focuses on miRNAs, lncRNAs and circRNAs as ncRNAs and their potential functions in inflammation regulation and resolution. Pro-inflammatory and anti-inflammatory factors are regulated by miRNAs via binding to 3'-UTR or indirectly via affecting other pathways such as SIRT1 and NF-κB. LncRNAs display a similar function and they can also affect miRNAs via sponging in regulating levels of cytokines. CircRNAs mainly affect miRNAs and reduce their expression in regulating cytokine levels. Notably, exosomal ncRNAs have shown capacity in inflammation resolution. In addition to pre-clinical studies, clinical trials have examined role of ncRNAs in inflammation-mediated disease pathogenesis and cytokine regulation. The therapeutic targeting of ncRNAs using drugs and nucleic acids have been analyzed to reduce inflammation in disease therapy. Therefore, ncRNAs can serve as diagnostic, prognostic and therapeutic targets in inflammation-related diseases in pre-clinical and clinical backgrounds.

Correction: Recent progress in SERS monitoring of photocatalytic reactions.

Correction for 'Recent progress in SERS monitoring of photocatalytic reactions' by Xinlu Zheng et al., Chem. Soc. Rev., 2024, 53, 656-683, https://doi.org/10.1039/D3CS00462G.

Recent progress in SERS monitoring of photocatalytic reactions.

Surface-enhanced Raman spectroscopy (SERS) is a powerful analytical technique renowned for its ultra-high sensitivity. Extensive research in SERS has led to the development of a wide range of SERS substrates, including plasmonic metals, semiconductors, metal organic frameworks, and their assemblies. Some of these materials are also excellent photocatalysts, and by taking advantage of their bifunctional characteristics, the photocatalytic processes that occur on their surface can be monitored in situ via SERS. This provides us with unique opportunities to gain valuable insights into the intricate details of the photocatalytic processes that are challenging to access using other techniques. In this review, we highlight key development in in situ and/or real-time SERS-tracking of photocatalytic reactions. We begin by providing a brief account of recent developments in SERS substrates, followed by discussions on how SERS can be used to elucidate crucial aspects of photocatalytic processes, including: (1) the influence of the surrounding media on charge carrier extraction; (2) the direction of charge carrier transfer; (3) the pathway of photocatalytic activation; and (4) differentiation between the effects of photo-thermal and energetic electrons. Additionally, we discuss the benefits of tip-enhanced Raman spectroscopy (TERS) due to the ability to achieve high-spatial-resolution measurements. Finally, we address major challenges and propose potential directions for the future of SERS monitoring of photocatalytic reactions. By leveraging the capabilities of SERS, we can uncover new insights into photocatalytic processes, paving the way for advancements in sustainable energy and environmental remediation.

Photocatalytic Conversion of Methane to Ethanol at a Three-Phase Interface with Concentration-Matched Hydroxyl and Methyl Radicals.

The direct oxidation of CH4 to C2H5OH is attractive but challenging owing to the intricate processes involving carbon-chain growth and hydroxylation simultaneously. The inherent difficulty arises from the strong tendency of CH4 to overoxidize in the commonly used pressurized powder suspension systems rich in reactive oxygen radicals (ROR), which are specifically designed for CH4 concentration and activation. Meanwhile, the strong tendency of nucleophilic attack of potent ROR on the C-C bond of the resulting product C2H5OH ultimately leads to a higher selectivity for C1 oxygenates. This study addresses this multifaceted issue by designing a three-phase interface based on a hydrophilic floating Fe(III)-cross-linked macroporous alginate hydrogel film encapsulated with C3N4 [Fe(III)@ACN] to simultaneously enhance the accessibility of H2O and CH4 molecules to the active sites and species within the macroporous channel. The hydrophilic properties of Fe(III)@ACN allow the in situ production of H2O2 from C3N4 through the water oxidation reaction under irradiation. The concurrent photoinduced Fe(II) triggers Fenton reaction with H2O2 to produce •OH. The enhanced mass transfer of CH4 at the three-phase interface ensures the efficient formation of •CH3 by reacting with •OH, ultimately facilitating carbon-chain growth in the conversion pathway from CH4 to CH3OH and finally to C2H5OH with •CH3 and •OH present in comparable concentrations. Thus, the Fe(III)@ACN catalyst exhibits a remarkable 96% selectivity for alcohol, achieving a 90% selectivity for C2H5OH in the alcohol products. The C2H5OH production rate reaches 171.7 µmol g-1 h-1 without the need for precious-metal additive.

Three biomarkers (HER2, PD-L1, and microsatellite status) in a large cohort of metastatic gastroesophageal adenocarcinomas: The MD Anderson Cancer Center experience.

Human epidermal growth factor receptor-2 (HER2), programmed death-ligand 1 (PD-L1), and microsatellite (MS) status are well-established biomarkers in gastroesophageal adenocarcinomas (GEAs). However, it is unclear how the combination of these biomarkers is associated with clinicopathological factors and prognosis. This retrospective study included baseline metastatic GEA patients who were tested for all three biomarkers (HER2, PD-L1, and MS status) at the MD Anderson Cancer Center between 2012 and 2022. Stratification was performed according to the combination of biomarker profiles: triple negative (TN), single positive (SP), and multiple positive (MP). Comparative analyses of clinicopathological factors and survival using combinations of biomarkers were performed. Among the 698 GEA patients analyzed, 251 (36.0%) were classified as TN, 334 (47.9%) as SP, and 113 (16.1%) as MP. The MP group showed a significant association with tumors located in the esophagus (p < .001), well to moderate differentiation (p < .001), and the absence of signet ring cells (p < .001). In the survival analysis, MP group had a significantly longer overall survival (OS) compared to the other groups (MP vs. TN, p < .001 and MP vs. SP, p < .001). Multivariate Cox regression analysis revealed that MP serves as an independent positive prognostic indicator for OS (hazard ratio = 0.63, p < .01). Our findings indicate that MP biomarkers are associated with a favorable prognosis in metastatic GEA. These results are reflective of clinical practice and offer valuable insights into how therapeutics and future biomarkers could influence therapy/prognosis.

Hypoxia signaling in hepatocellular carcinoma: Challenges and therapeutic opportunities.

Hepatocellular carcinoma (HCC) is one of the most common cancers with a relatively high cancer-related mortality. The uncontrolled proliferation of HCC consumes a significant amount of oxygen, causing the development of a hypoxic tumor microenvironment (TME). Hypoxia-inducible factors (HIFs), crucial regulators in the TME, activate several cancer hallmarks leading to the hepatocarcinogenesis of HCC and resistance to current therapeutics. As such, HIFs and their signaling pathways have been explored as potential therapeutic targets for the future management of HCC. This review discusses the current understanding of the structure and function of HIFs and their complex relationship with the various cancer hallmarks. To address tumor hypoxia, this review provides an insight into the various potential novel therapeutic agents for managing HCC, such as hypoxia-activated prodrugs, HIF inhibitors, nanomaterials, antisense oligonucleotides, and natural compounds, that target HIFs/hypoxic signaling pathways in HCC. Because of HCC's relatively high incidence and mortality rates in the past decades, greater efforts should be put in place to explore novel therapeutic approaches to improve the outcome for HCC patients.

GSTM3 enhances radiosensitivity of nasopharyngeal carcinoma by promoting radiation-induced ferroptosis through USP14/FASN axis and GPX4.

BACKGROUND: Radiotherapy is a critical treatment modality for nasopharyngeal carcinoma (NPC). However, the mechanisms underlying radiation resistance and tumour recurrence in NPC remain incompletely understood. METHODS: Oxidised lipids were assessed through targeted metabolomics. Ferroptosis levels were evaluated using cell viability, clonogenic survival, lipid peroxidation, and transmission electron microscopy. We investigated the biological functions of glutathione S-transferase mu 3 (GSTM3) in cell lines and xenograft tumours. Co-immunoprecipitation, mass spectrometry, and immunofluorescence were conducted to explore the molecular mechanisms involving GSTM3. Immunohistochemistry was performed to investigate the clinical characteristics of GSTM3. RESULTS: Ionising radiation (IR) promoted lipid peroxidation and induced ferroptosis in NPC cells. GSTM3 was upregulated following IR exposure and correlated with IR-induced ferroptosis, enhancing NPC radiosensitivity in vitro and in vivo. Mechanistically, GSTM3 stabilised ubiquitin-specific peptidase 14 (USP14), thereby inhibiting the ubiquitination and subsequent degradation of fatty acid synthase (FASN). Additionally, GSTM3 interacted with glutathione peroxidase 4 (GPX4) and suppressed GPX4 expression. Combining IR treatment with ferroptosis inducers synergistically improved NPC radiosensitivity and suppressed tumour growth. Notably, a decrease in GSTM3 abundance predicted tumour relapse and poor prognosis. CONCLUSIONS: Our findings elucidate the pivotal role of GSTM3 in IR-induced ferroptosis, offering strategies for the treatment of radiation-resistant or recurrent NPC.

Platelet TLR7 is essential for the formation of platelet-neutrophil complexes and low-density neutrophils in lupus nephritis.

OBJECTIVES: Platelets and low-density neutrophils (LDNs) are major players in the immunopathogenesis of SLE. Despite evidence showing the importance of platelet-neutrophil complexes (PNCs) in inflammation, little is known about the relationship between LDNs and platelets in SLE. We sought to characterize the role of LDNs and Toll-like receptor 7 (TLR7) in clinical disease. METHODS: Flow cytometry was used to immunophenotype LDNs from SLE patients and controls. The association of LDNs with organ damage was investigated in a cohort of 290 SLE patients. TLR7 mRNA expression was assessed in LDNs and high-density neutrophils (HDNs) using publicly available mRNA sequencing datasets and our own cohort using RT-PCR. The role of TLR7 in platelet binding was evaluated in platelet-HDN mixing studies using TLR7-deficient mice and Klinefelter syndrome patients. RESULTS: SLE patients with active disease have more LDNs, which are heterogeneous and more immature in patients with evidence of kidney dysfunction. LDNs are platelet bound, in contrast to HDNs. LDNs settle in the peripheral blood mononuclear cell (PBMC) layer due to the increased buoyancy and neutrophil degranulation from platelet binding. Mixing studies demonstrated that this PNC formation was dependent on platelet-TLR7 and that the association results in increased NETosis. The neutrophil:platelet ratio is a useful clinical correlate for LDNs, and a higher NPR is associated with past and current flares of LN. CONCLUSIONS: LDNs sediment in the upper PBMC fraction due to PNC formation, which is dependent on the expression of TLR7 in platelets. Collectively, our results reveal a novel TLR7-dependent crosstalk between platelets and neutrophils that may be an important therapeutic opportunity for LN.

Extracellular vesicles in the HCC microenvironment: Implications for therapy and biomarkers.

Hepatocellular carcinoma (HCC) stands as the sixth most prevalent cancer and the third leading cause of cancer mortality globally. Despite surgical resection being the preferred approach for early-stage HCC, most patients are diagnosed at intermediate to advanced stages, limiting treatment options to chemotherapy and immunotherapy, which often yield poor outcomes. Extracellular vesicles (EVs), minute lipid-bilayered particles released by diverse cells under various physiological and pathological conditions, are crucial for mediating communication between cells. Mounting evidence indicates that EVs sourced from different cells can profoundly influence the HCC tumor microenvironment (TME), thereby affecting the progression of HCC. Given their immunogenicity and liver-targeting properties, these EVs not only hold promise for HCC treatment but also provide avenues for advancing early diagnostic methods and assessing prognosis. This review not only describes the function of EVs within the HCC tumor microenvironment but also analyzes their therapeutic advantages and explores their significance in various therapeutic approaches for HCC, including chemotherapy, immunotherapy, combination therapy, and their role as innovative drug delivery carriers. Furthermore, it highlights the potential of EVs as biomarkers for the diagnosis and prognosis of HCC.

Aldehyde dehydrogenase 1 family: A potential molecule target for diseases.

Aldehyde dehydrogenase 1 (ALDH1), a crucial aldehyde metabolizing enzyme, has six family members. The ALDH1 family is expressed in various tissues, with a significant presence in the liver. It plays a momentous role in several pathophysiological processes, including aldehyde detoxification, oxidative stress, and lipid peroxidation. Acetaldehyde detoxification is the fundamental function of the ALDH1 family in participating in vital pathological mechanisms. The ALDH1 family can catalyze retinal to retinoic acid (RA) that is a hormone-signaling molecule and plays a vital role in the development and adult tissues. Furthermore, there is a need for further and broader research on the role of the ALDH1 family as a signaling molecule. The ALDH1 family is widely recognized as a cancer stem cell (CSC) marker and plays a significant role in the proliferation, invasion, metastasis, prognosis, and drug resistance of cancer. The ALDH1 family also participates in other human diseases, such as neurodegenerative diseases, osteoarthritis, diabetes, and atherosclerosis. It can inhibit disease progression by inhibiting/promoting the expression/activity of the ALDH1 family. In this review, we comprehensively analyze the tissue distribution, and functions of the ALDH1 family. Additionally, we review the involvement of the ALDH1 family in diseases, focusing on the underlying pathological mechanisms and briefly talk about the current status and development of ALDH1 family inhibitors. The ALDH1 family presents new possibilities for treating diseases, with both its upstream and downstream pathways serving as promising targets for therapeutic intervention. This offers fresh perspectives for drug development in the field of disease research.

Dried tangerine peel polysaccharide (DTPP) alleviates hepatic steatosis by suppressing TLR4/MD-2-mediated inflammation and endoplasmic reticulum stress.

Non-alcoholic fatty liver disease (NAFLD) is a complex pathogenic metabolic syndrome characterized by increased inflammation and endoplasmic reticulum stress. In recent years, natural polysaccharides derived from traditional Chinese medicine have shown significant anti-inflammatory effects, making them an attractive therapeutic option. However, little research has been conducted on the therapeutic potential of dried tangerine peel polysaccharide (DTPP) - one of the most important medicinal resources in China. The results of the present study showed that DTPP substantially reduced macrophage infiltration in vivo and suppressed the expression of pro-inflammatory factors and endoplasmic reticulum stress-related genes. Additionally, surface plasmon resonance analysis revealed that DTPP had a specific affinity to myeloid differentiation factor 2, which consequently suppressed lipopolysaccharide-induced inflammation via interaction with the toll-like receptor 4 signaling pathway. This study provides a potential molecular mechanism underlying the anti-inflammatory effects of DTPP on NAFLD and suggests DTPP as a promising therapeutic strategy for NAFLD treatment.

The analgesic effect of ultrasound-guided cervical erector spinae block in arthroscopic shoulder surgery: a randomized controlled clinical trial.

BACKGROUND: Erector spinae plane block (ESPB) is a novel fascial plane block technique that can provide effective perioperative analgesia for thoracic, abdominal and lumbar surgeries. However, the effect of cervical ESPB on postoperative analgesia after arthroscopic shoulder surgery is unknown. The aim of this study is to investigate the analgesic effect and safety of ultrasound-guided cervical ESPB in arthroscopic shoulder surgery. METHODS: Seventy patients undergoing arthroscopy shoulder surgery were randomly assigned to one of two groups: ESPB group (n = 35) or control group (n = 35). Patients in the ESPB group received an ultrasound-guided ESPB at the C7 level with 30 mL of 0.25% ropivacaine 30 min before induction of general anesthesia, whereas patients in the control group received no block. The primary outcome measures were the static visual analogue scale (VAS) pain scores at 4, 12, and 24 h after surgery. Secondary outcomes included heart rate (HR) and mean arterial pressure (MAP) before anesthesia (t1), 5 min after anesthesia (t2), 10 min after skin incision (t3), and 10 min after extubation (t4); intraoperative remifentanil consumption; the Bruggrmann comfort scale (BCS) score, quality of recovery-15 (QoR-15) scale score and the number of patients who required rescue analgesia 24 h after surgery; and adverse events. RESULTS: The static VAS scores at 4, 12 and 24 h after surgery were significantly lower in the ESPB group than those in the control group (2.17 ± 0.71 vs. 3.14 ± 1.19, 1.77 ± 0.77 vs. 2.63 ± 0.84, 0.74 ± 0.66 vs. 1.14 ± 0.88, all P < 0.05). There were no significant differences in HR or MAP at any time point during the perioperative period between the two groups (all P > 0.05). The intraoperative consumption of remifentanil was significantly less in the ESPB group compared to the control group (P < 0.05). The scores of BCS and QoR-15 scale were higher in the ESPB group 24 h after surgery than those in the control group (P < 0.05). Compared to the control group, fewer patients in the ESPB group required rescue analgesia 24 h after surgery (P < 0.05). No serious complications occurred in either group. CONCLUSIONS: Ultrasound-guided cervical ESPB can provide effective postoperative analgesia following arthroscopic shoulder surgery, resulting in a better postoperative recovery with fewer complications. TRIAL REGISTRATION: Chictr.org.cn identifier ChiCTR2300070731 (Date of registry: 21/04/2023, prospectively registered).

Effect of Ultrasound-Guided External Oblique Intercostal Block on Postoperative Recovery After Subxiphoid Video-Assisted Thoracoscopic Thymectomy: A Randomized Controlled Trial.

OBJECTIVE: Severe postoperative pain can occur after subxiphoid video-assisted thoracoscopic thymectomy (SVATT), affecting the quality of postoperative recovery. This study aimed to evaluate the effect of ultrasound-guided external oblique intercostal (EOI) block on recovery after SVATT. METHODS: A total of 60 patients undergoing SVATT were randomly divided into the EOI group (group E, n = 30) and the control group (group C, n = 30). Group E underwent ultrasound-guided bilateral EOI block at the 6th rib level and was injected 20 mL of 0.375% ropivacaine on each side. Group C was injected with 20 mL of 0.9% saline at the same site. After the operation, both groups received a patient-controlled intravenous analgesic (PCIA) pump. The 15-item Quality of Recovery (QoR-15) scores were recorded at 24 hours before surgery (T0), 24 hours after surgery (T3), and 48 hours after surgery (T4). The sufentanil usage in the first 24 hours postoperatively, the remifentanil dosage during surgery, the time of first pressing PCIA, and the cases of rescue analgesia were recorded. The visual analog scale (VAS) scores of patients at 6 (T1), 12 (T2), 24 (T3), and 48 hours (T4) after an operation during rest and coughing were recorded. The dermatomes of the sensory plane, block complications in group E, and the incidence of other postoperative adverse reactions in both groups were also recorded. RESULTS: Compared with group C, the QoR-15 scores of patients were significantly higher at T3 and T4 in the group E. The VAS scores were significantly lower at T1, T2, and T3 during rest and coughing in the group E. The sufentanil usage in the first 24 hours postoperatively, the remifentanil dosage during surgery, and the cases of rescue analgesia were significantly lower in group E, and the time of first pressing PCIA was significantly increased in group E (all P < .05). CONCLUSION: Ultrasound-guided EOI block can be safely used in patients undergoing SVATT, which can improve the quality of postoperative recovery and reduce postoperative pain.

Comparative Evaluation of the Efficacy and Safety Profiles of Various Ropivacaine Proportions in Cesarean Section.

Background: Ropivacaine (Ropi) is a widely utilized anesthetic in cesarean sections (CS), however its optimal dosage remains controversial. Objective: To assess the efficacy and safety of varying doses (10mg, 5mg, 4mg, and 3mg) of Ropi in subarachnoid block (SA) for CS. Methods: A prospective cohort study was conducted, and a total of 74 pregnant women undergoing CS at Nantong Maternal and Child Health Care Hospital between January and June 2023 were selected as the study population. Participants were stratified into groups based on Ropivacaine dosage: Group A (10 mg, n=18), Group B (5 mg, n=26), Group C (4 mg, n=15), and Group D (3 mg, n=15). The total Ropivacaine dosage administered via SA was consistently 10 mg across all groups. We measured anesthetic efficacy, safety profiles, abdominal wall muscle relaxation, pre- and post-anesthesia stress and inflammatory responses before and after anesthesia and compared among the four groups. Results: Group A exhibited the shortest onset time for block initiation and longest recovery duration (P < .05). Group D displayed the highest incidence of patients requiring additional anesthetics and experiencing adverse reactions, whereas the utilization rate of vasopressors was most pronounced in Group A (P < .05). Notably, Group D reported the lowest satisfaction rate regarding abdominal wall muscle relaxation (P < .05). Stress responses were significantly lower in Groups A, B, and C compared to Group D, while the levels of inflammatory factors in Groups B and C were higher than those in Group A but lower than those in Group D (P < .05). Conclusions: Administration of 4 mg hyperbaric Ropi in SA can achieve an optimal anesthesia effect in CS with a high level of safety, along with inducing mild abdominal wall muscle relaxation and attenuating stress and inflammatory responses pre- and post-anesthesia. Thus, it is recommended for clinical application.

Proton-Enriched Alginate-Graphene Hydrogel Microreactor for Enhanced Hydrogen Peroxide Photosynthesis.

Efficient synthesis of H2O2 via photocatalytic oxygen reduction without sacrificial agents is challenging due to inadequate proton supply from water and difficulty in maintaining O-O bond during O2 activation. Herein, we developed a straightforward strategy involving a proton-rich hydrogel cross-linked by metal ions [M(n)], which is designed to facilitate the selective production of H2O2 through proton relay and metal ion-assisted detachment of crucial intermediates. The hydrogel comprises CdS/graphene and alginate cross-linked by metal ions via O=C-O-M(n) bonds. Efficient O2 reduction and hydrogenation occurred, benefitting from the collaboration between proton-rich alginate and the photocatalytically active CdS/graphene. Meanwhile, the O=C-O-M(n) bonds enhance the electron density of α-carbon sites on graphene, crucial for O2 activation and *OOH intermediate detachment, preventing deeper O-O bond cleavage. The role of metal ions in promoting *OOH desorption was demonstrated through Lewis acidity-dependent activity, with Y(III) having the highest activity, followed by Lu(III), La(III), and Ca(II).

Targeting hypoxia-inducible factor-1, for cancer treatment: Recent advances in developing small-molecule inhibitors from natural compounds.

Rapid progress in molecular cancer biology coupled with the discovery of novel oncology drugs has opened new horizons for cancer target discovery. As one of the crucial signaling pathways related to tumorigenesis, hypoxia-inducible factor-1 (HIF-1) coordinates the activity of many transcription factors and their downstream molecules that impact tumor growth and metastasis. Accumulating evidence suggests that the transcriptional responses to acute hypoxia are mainly attributable to HIF-1α. Moreover, the overexpression of HIF-1α in several solid cancers has been found to be strongly associated with poor prognosis. Thus, pharmacological targeting of the HIF-1 signaling pathways has been considered as a new strategy for cancer therapy in the recent years. Although over the past decade, tremendous efforts have been made in preclinical studies to develop new HIF-1 inhibitors from natural products (reservoirs of novel therapeutic agents), to date, these efforts have not been successfully translated into clinically available treatments. In this review, we provide new insights into the bio-pharmacological considerations for selecting natural compounds as potential HIF-1 inhibitors to accelerate anti-cancer drug development. In addition, we highlighted the importance of assessing the dependency of cancer on HIF1A to shortlist cancer types as suitable disease models. This may subsequently lead to new paradigms for discovering more HIF-1 inhibitors derived from natural products and facilitate the development of potent therapeutic agents targeting specific cancer types.

Bacteria as a treasure house of secondary metabolites with anticancer potential.

Cancer stands in the frontline among leading killers worldwide and the annual mortality rate is expected to reach 16.4 million by 2040. Humans suffer from about 200 different types of cancers and many of them have a small number of approved therapeutic agents. Moreover, several types of major cancers are diagnosed at advanced stages as a result of which the existing therapies have limited efficacy against them and contribute to a dismal prognosis. Therefore, it is essential to develop novel potent anticancer agents to counteract cancer-driven lethality. Natural sources such as bacteria, plants, fungi, and marine microorganisms have been serving as an inexhaustible source of anticancer agents. Notably, over 13,000 natural compounds endowed with different pharmacological properties have been isolated from different bacterial sources. In the present article, we have discussed about the importance of natural products, with special emphasis on bacterial metabolites for cancer therapy. Subsequently, we have comprehensively discussed the various sources, mechanisms of action, toxicity issues, and off-target effects of clinically used anticancer drugs (such as actinomycin D, bleomycin, carfilzomib, doxorubicin, ixabepilone, mitomycin C, pentostatin, rapalogs, and romidepsin) that have been derived from different bacteria. Furthermore, we have also discussed some of the major secondary metabolites (antimycins, chartreusin, elsamicins, geldanamycin, monensin, plicamycin, prodigiosin, rebeccamycin, salinomycin, and salinosporamide) that are currently in the clinical trials or which have demonstrated potent anticancer activity in preclinical models. Besides, we have elaborated on the application of metagenomics in drug discovery and briefly described about anticancer agents (bryostatin 1 and ET-743) identified through the metagenomics approach.

Elabela-apelin-12, 17, 36/APJ system promotes platelet aggregation and thrombosis via activating the PANX1-P2X7 signaling pathway.

The elabela-apelin/angiotensin domain type 1 receptor-associated protein (APJ) system is an important regulator in certain thrombosis-related diseases such as atherosclerosis, myocardial infarction, and cerebral infarction. Our previous reports have revealed that apelin exacerbates atherosclerotic lesions. However, the relationship between the elabela-apelin/APJ system and platelet aggregation and atherothrombosis is unclear. The results of the present study demonstrate that elabela and other endogenous ligands such as apelin-12, -17, and -36 induce platelet aggregation and thrombosis by activating the pannexin1(PANX1)-P2X7 signaling pathway. Interestingly, the diuretic, spironolactone, a novel PANX1 inhibitor, alleviated elabela- and apelin isoforms-induced platelet aggregation and thrombosis. Significantly, two potential antithrombotic drugs were screened out by targeting APJ receptors, including the anti-HIV ancillary drug cobicistat and the traditional Chinese medicine monomer Schisandrin A. Both cobicistat and Schisandrin A abolished the effects of elabela and apelin isoforms on platelet aggregation, thrombosis, and cerebral infarction. In addition, cobicistat significantly attenuated thrombosis in a ponatinib-induced zebrafish trunk model. Overall, the elabela-apelin/APJ axis mediated platelet aggregation and thrombosis via the PANX1-P2X7 signaling pathway in vitro and in vivo. Blocking the APJ receptor with cobicistat/Schisandrin A or inhibiting PANX1 with spironolactone may provide novel therapeutic strategies against thrombosis.