Targeting of SUMOylation leads to cBAF complex stabilization and disruption of the SS18::SSX transcriptome in Synovial Sarcoma.

Synovial Sarcoma (SS) is driven by the SS18::SSX fusion oncoprotein. and is ultimately refractory to therapeutic approaches. SS18::SSX alters ATP-dependent chromatin remodeling BAF (mammalian SWI/SNF) complexes, leading to the degradation of canonical (cBAF) complex and amplified presence of an SS18::SSX-containing non-canonical BAF (ncBAF or GBAF) that drives an SS-specific transcription program and tumorigenesis. We demonstrate that SS18::SSX activates the SUMOylation program and SSs are sensitive to the small molecule SAE1/2 inhibitor, TAK-981. Mechanistically, TAK-981 de-SUMOylates the cBAF subunit SMARCE1, stabilizing and restoring cBAF on chromatin, shifting away from SS18::SSX-ncBAF-driven transcription, associated with DNA damage and cell death and resulting in tumor inhibition across both human and mouse SS tumor models. TAK-981 synergized with cytotoxic chemotherapy through increased DNA damage, leading to tumor regression. Targeting the SUMOylation pathway in SS restores cBAF complexes and blocks the SS18::SSX-ncBAF transcriptome, identifying a therapeutic vulnerability in SS, positioning the in-clinic TAK-981 to treat SS.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Genome-Wide Identification and Expression Profiling of Heavy Metal ATPase (HMA) Genes in Peanut: Potential Roles in Heavy Metal Transport.

The heavy metal ATPase (HMA) family belongs to the P-type ATPase superfamily and plays an essential role in the regulation of metal homeostasis in plants. However, the gene family has not been fully investigated in peanut. Here, a genome-wide identification and bioinformatics analysis was performed on AhHMA genes in peanut, and the expression of 12 AhHMA genes in response to Cu, Zn, and Cd was evaluated in two peanut cultivars (Silihong and Fenghua 1) differing in Cd accumulation. A total of 21 AhHMA genes were identified in the peanut genome, including ten paralogous gene pairs derived from whole-genome duplication, and an additional gene resulting from tandem duplication. AhHMA proteins could be divided into six groups (I-VI), belonging to two clades (Zn/Co/Cd/Pb-ATPases and Cu/Ag-ATPases). Most AhHMA proteins within the same clade or group generally have a similar structure. However, significant divergence exists in the exon/intron organization even between duplicated gene pairs. RNA-seq data showed that most AhHMA genes are preferentially expressed in roots, shoots, and reproductive tissues. qRT-PCR results revealed that AhHMA1.1/1.2, AhHMA3.1/3.2, AhHMA7.1/7.4, and AhHMA8.1 might be involved in Zn transport in peanut plants, while AhHMA3.2 and AhHMA7.5 might be involved in Cd transport. Our findings provide clues to further characterize the functions of AhHMA genes in metal uptake and translocation in peanut plants.

Postpolypectomy syndrome without abdominal pain led to sepsis/septic shock and gastrointestinal bleeding: A case report.

BACKGROUND: Postpolypectomy syndrome (PPS) is a rare postoperative complication of colonic polypectomy. It presents with abdominal pain and fever accompanied by coagulopathy and elevated inflammatory markers. Its prognosis is usually good, and it only requires outpatient treatment or observation in a general ward. However, it can be life-threatening. CASE SUMMARY: The patient was a 58-year-old man who underwent two colonic polypectomies, each resulting in life-threatening sepsis, septic shock, and coagulopathy. Each of the notable manifestations was a rapid drop in blood pressure, an increase in heart rate, loss of consciousness, and heavy sweating, accompanied by shortness of breath and decreased oxygen in the finger pulse. Based on the criteria of organ dysfunction due to infection, we diagnosed him with sepsis. The patient also experienced severe gastrointestinal bleeding after the second operation. Curiously, he did not complain of any abdominal pain throughout the course of the illness. He had significantly elevated concentrations of inflammatory markers and coagulopathy. Except for the absence of abdominal pain, his fever, significant coagulopathy, and elevated inflammatory marker concentrations were all consistent with PPS. Abdominal computed tomography and superior mesenteric artery computed tomography angiography showed no free air or vascular damage. Thus, the diagnosis of colon perforation was not considered. The final blood culture results indicated Moraxella osloensis. The patient was transferred to the intensive care unit and quickly improved after fluid resuscitation, antibiotic treatment, oxygen therapy, and blood transfusion. CONCLUSION: PPS may induce dysregulation of the systemic inflammatory response, which can lead to sepsis or septic shock, even in the absence of abdominal pain.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

[Effect and mechanism of Bovis Calculus on ulcerative colitis by inhibiting IL-17/IL-17RA/Act1 signaling pathway].

This study aimed to elucidate the effect and underlying mechanism of Bovis Calculus in the treatment of ulcerative colitis(UC) through network pharmacological prediction and animal experimental verification. Databases such as BATMAN-TCM were used to mine the potential targets of Bovis Calculus against UC, and the pathway enrichment analysis was conducted. Seventy healthy C57BL/6J mice were randomly divided into a blank group, a model group, a solvent model(2% polysorbate 80) group, a salazosulfapyridine(SASP, 0.40 g·kg~(-1)) group, and high-, medium-, and low-dose Bovis Calculus Sativus(BCS, 0.20, 0.10, and 0.05 g·kg~(-1)) groups according to the body weight. The UC model was established in mice by drinking 3% dextran sulfate sodium(DSS) solution for 7 days. The mice in the groups with drug intervention received corresponding drugs for 3 days before modeling by gavage, and continued to take drugs for 7 days while modeling(continuous administration for 10 days). During the experiment, the body weight of mice was observed, and the disease activity index(DAI) score was recorded. After 7 days of modeling, the colon length was mea-sured, and the pathological changes in colon tissues were observed by hematoxylin-eosin(HE) staining. The levels of tumor necrosis factor-α(TNF-α), interleukin-1ß(IL-1ß), interleukin-6(IL-6), and interleukin-17(IL-17) in colon tissues of mice were detected by enzyme-linked immunosorbent assay(ELISA). The mRNA expression of IL-17, IL-17RA, Act1, TRAF2, TRAF5, TNF-α, IL-6, IL-1ß, CXCL1, CXCL2, and CXCL10 was evaluated by real-time polymerase chain reaction(RT-PCR). The protein expression of IL-17, IL-17RA, Act1, p-p38 MAPK, and p-ERK1/2 was investigated by Western blot. The results of network pharmacological prediction showed that Bovis Calculus might play a therapeutic role through the IL-17 signaling pathway and the TNF signaling pathway. As revealed by the results of animal experiments, on the 10th day of drug administration, compared with the solvent model group, all the BCS groups showed significantly increased body weight, decreased DAI score, increased colon length, improved pathological damage of colon mucosa, and significantly inhibited expression of TNF-α,IL-6,IL-1ß, and IL-17 in colon tissues. The high-dose BCS(0.20 g·kg~(-1)) could significantly reduce the mRNA expression levels of IL-17, Act1, TRAF2, TRAF5, TNF-α, IL-6, IL-1ß, CXCL1, and CXCL2 in colon tissues of UC model mice, tend to down-regulate mRNA expression levels of IL-17RA and CXCL10, significantly inhibit the protein expression of IL-17RA,Act1,and p-ERK1/2, and tend to decrease the protein expression of IL-17 and p-p38 MAPK. This study, for the first time from the whole-organ-tissue-molecular level, reveals that BCS may reduce the expression of pro-inflammatory cytokines and chemokines by inhibiting the IL-17/IL-17RA/Act1 signaling pathway, thereby improving the inflammatory injury of colon tissues in DSS-induced UC mice and exerting the effect of clearing heat and removing toxins.

Ginkgo biloba extract attenuates cisplatin-induced renal interstitial fibrosis by inhibiting the activation of renal fibroblasts through down-regulating the HIF-1α/STAT3/IL-6 pathway in renal tubular epithelial cells.

BACKGROUND: Activation of renal fibroblasts into myofibroblasts plays an important role in promoting renal interstitial fibrosis (RIF). Ginkgo biloba extract (EGb) can alleviate RIF induced by cisplatin (CDDP). PURPOSE: To elucidate the effect of EGb treatment on cisplatin-induced RIF and reveal its potential mechanism. METHODS: The two main active components in EGb were determined by high-performance liquid chromatography (HPLC) analysis. Rats were induced by CDDP and then treated with EGb, 2ME2 (HIF-1α inhibitor) or amifostine. After HK-2 cells and HIF-1α siRNA HK-2 cells were treated with CDDP, EGb or amifostine, the conditioned medium from each group was cultured with NRK-49F cells. The renal function of rats was detected. The renal damage and fibrosis were evaluated by H&E and Masson trichrome staining. The IL-6 content in the cell medium was detected by ELISA. The expression levels of indicators related to renal fibrosis and signaling pathway were examined by western blotting and qRT-PCR. RESULTS: HPLC analysis showed that the contents of quercetin and kaempferol in EGb were 36.0 µg/ml and 45.7 µg/ml, respectively. In vivo, EGb and 2ME2 alleviated renal damage and fibrosis, as well as significantly decreased the levels of α-SMA, HIF-1α, STAT3 and IL-6 in rat tissues induced by CDDP. In vitro, the levels of HIF-1α, STAT3 and IL-6 were significantly increased in HK-2 cells and HIF-1α siRNA HK-2 cells induced by CDDP. Notably, HIF-1α siRNA significantly decreased the levels of HIF-1α, STAT3 and IL-6 in HK-2 cells, as well as the IL-6 level in medium from HK-2 cells. Additionally, the α-SMA level in NRK-49F cells was significantly increased after being cultured with conditioned medium from HK-2 cells or HIF-1α siRNA HK-2 cells exposed to CDDP. Furthermore, exogenous IL-6 increased the α-SMA level in NRK-49F cells. Importantly, the expression levels of the above-mentioned indicators were significantly decreased after the HK-2 cells and HIF-1α siRNA HK-2 cells were treated with EGb. CONCLUSION: This study revealed that EGb improves CDDP-induced RIF, and the mechanism may be related to its inhibition of the renal fibroblast activation by down-regulating the HIF-1α/STAT3/IL-6 pathway in renal tubular epithelial cells.

Inhibition of a signaling modality within the gp130 receptor enhances tissue regeneration and mitigates osteoarthritis.

Adult mammals are incapable of multitissue regeneration, and augmentation of this potential may shift current therapeutic paradigms. We found that a common co-receptor of interleukin 6 (IL-6) cytokines, glycoprotein 130 (gp130), serves as a major nexus integrating various context-specific signaling inputs to either promote regenerative outcomes or aggravate disease progression. Via genetic and pharmacological experiments in vitro and in vivo, we demonstrated that a signaling tyrosine 814 (Y814) within gp130 serves as a major cellular stress sensor. Mice with constitutively inactivated Y814 (F814) were resistant to surgically induced osteoarthritis as reflected by reduced loss of proteoglycans, reduced synovitis, and synovial fibrosis. The F814 mice also exhibited enhanced regenerative, not reparative, responses after wounding in the skin. In addition, pharmacological modulation of gp130 Y814 upstream of the SRC and MAPK circuit by a small molecule, R805, elicited a protective effect on tissues after injury. Topical administration of R805 on mouse skin wounds resulted in enhanced hair follicle neogenesis and dermal regeneration. Intra-articular administration of R805 to rats after medial meniscal tear and to canines after arthroscopic meniscal release markedly mitigated the appearance of osteoarthritis. Single-cell sequencing data demonstrated that genetic and pharmacological modulation of Y814 resulted in attenuation of inflammatory gene signature as visualized by the anti-inflammatory macrophage and nonpathological fibroblast subpopulations in the skin and joint tissue after injury. Together, our study characterized a molecular mechanism that, if manipulated, enhances the intrinsic regenerative capacity of tissues through suppression of a proinflammatory milieu and prevents pathological outcomes in injury and disease.

Synthesis of Novel Kidney-Type Glutaminase Allosteric Inhibitors Targeting the Critical Lys-320 Residue.

Reversible allosteric inhibitors of kidney-type glutaminase (GLS1, KGA) showed incomplete inhibition of cancer cell proliferation and poor in vivo efficacy. Here, we investigate some irreversible inhibitors targeting the critical K320 residue responsible for GLS1 biological activity. The (trifluoromethoxy)phenylacetic acid motif was replaced by α,ß-unsaturated carboxylic acids, and the resulting terminally substituted CB839 derivatives (e.g., GJ2 and GJ5) showed good stability in solid form at room temperature, and better liver microsome stability and in vivo pharmacokinetics than coumarin. Both compounds showed binding to the wild-type KGA, whose K D is 106-fold stronger than that of CB839, but only weak binding to the KGA K320A mutant and no inhibition of GDH proteins. Interestingly, GJ2 treatment significantly decreased the trypsin digestion of KGA, tumor cell clonal formation, and cancer cell growth rate. Taking these results together, targeting the critical K320 residue of GLS1 might be a new strategy to make a potent GLS1 allosteric inhibitor.

Genome-Wide Identification and Expression Analysis Reveals Roles of the NRAMP Gene Family in Iron/Cadmium Interactions in Peanut.

The natural resistance-associated macrophage protein (NRAMP) family plays crucial roles in metal uptake and transport in plants. However, little is known about their functions in peanut. To understand the roles of AhNRAMP genes in iron/cadmium interactions in peanut, genome-wide identification and bioinformatics analysis was performed. A total of 15 AhNRAMP genes were identified from the peanut genome, including seven gene pairs derived from whole-genome duplication and a segmental duplicated gene. AhNRAMP proteins were divided into two distinct subfamilies. Subfamily I contains eight acid proteins with a specific conserved motif 7, which were predicted to localize in the vacuole membrane, while subfamily II includes seven basic proteins sharing specific conserved motif 10, which were localized to the plasma membrane. Subfamily I genes contained four exons, while subfamily II had 13 exons. AhNRAMP proteins are perfectly modeled on the 5m94.1.A template, suggesting a role in metal transport. Most AhNRAMP genes are preferentially expressed in roots, stamens, or developing seeds. In roots, the expression of most AhNRAMPs is induced by iron deficiency and positively correlated with cadmium accumulation, indicating crucial roles in iron/cadmium interactions. The findings provide essential information to understand the functions of AhNRAMPs in the iron/cadmium interactions in peanuts.

l-Borneol and d-Borneol promote transdifferentiation of astrocytes into neurons in rats by regulating Wnt/Notch pathway to exert neuroprotective effect during recovery from cerebral ischaemia.

BACKGROUND: The Chinese medicines Borneolum and l-Borneolum have neuroprotective effects on acute cerebral ischaemia-reperfusion (IR) in rats. Research on their effects during recovery from cerebral IR is lacking. Cerebral ischaemia can activate astrocytes for conversion into neurons. Neurogenesis cannot be achieved without nutritional support from an improved brain microenvironment through the blood circulation. PURPOSE: The purpose of this study was to determine whether Borneolum and l-Borneolum can promote transdifferentiation of astrocytes into neurons by regulating the Wnt/Notch pathway to exert neuroprotective effects during recovery from cerebral ischaemia. STUDY DESIGN AND METHODS: A suture crossing the external carotid artery to occlude the middle cerebral artery was used to prepare a model of cerebral IR (Longa et al., 1989). The Longa neurological function score, modified neurological severity score, tape removal test and grid misstep experiment were used to evaluate motor nerve function. Triphenyltetrazolium chloride was used to determine the extent of cerebral infarction. Left/right hemisphere contrast was used to measure brain atrophy. Astrocytes labelled with adeno-associated virus were used to track their fate after transdifferentiation. Laser speckle contrast imaging was used to observe the effects of l-Borneolum and Borneolum on cerebral blood flow. Immunofluorescence and western blotting were used to investigate their mechanisms. RESULTS: l-Borneolum and Borneolum significantly improved neurological function and limb movement in rats with cerebral ischaemia during recovery and increased cerebral blood flow. l-Borneolum improved forelimb motor coordination more effectively than Borneolum and promoted transdifferentiation of astrocytes to GABAergic neurons in the striatal region. The expression of Wnt3a and Notch-1 was downregulated. The expression of vascular endothelial growth factor was not significantly changed. Borneolum improved forelimb sensitivity and alleviated cerebral infarction and brain atrophy more effectively than l-Borneolum, which promoted transdifferentiation of astrocytes into neurons and nestin expression and neurogenesis in the striatal zone. The expression of glycogen synthase kinase-3ß and ß-catenin was upregulated. l-Borneolum and Borneolum had no significant neuroprotective effect on the cortex and hippocampus. CONCLUSIONS: l-Borneolum and Borneolum exerted neuroprotective effects on cerebral ischaemia during recovery by promoting neurogenesis and blood circulation in the striatal and subventricular zones. Their mechanisms may be related to the Wnt3a and Notch-1 pathways.

Application of oXiris-continuous hemofiltration adsorption in patients with sepsis and septic shock: A single-centre experience in China.

oXiris is a new, high-adsorption membrane filter in continuous hemofiltration adsorption to reduce the inflammatory response in sepsis. The investigators retrospectively reviewed patients with sepsis/septic shock who underwent at least one oXiris-treatment from November 2020 to March 2022. The demographic data, baseline levels before treatment, clinical datas, prognosis, and the occurrence of adverse events during treatment were recorded. 90 patients were enrolled in this study. The hemodynamic indices, sequential organ failure assessment score, lactate, inflammatory biomarkers levels were significantly improved at 12 h and 24 h after treatment. Procalcitonin and interleukin-6 reduction post-treatment of oXiris were most pronounced in infection from skin and soft tissue, urinary and abdominal cavity. Logistic regression analysis showed that pre-treatment sequential organ failure assessment score (p = 0.034), percentage decrease in sequential organ failure assessment score (p = 0.004), and age (p = 0.011) were independent risk factors for intensive care unit mortality. In conclusion, oXiris-continuous hemofiltration adsorption may improve hemodynamic indicators, reduce the use of vasoactive drugs, reduce lactate level and infection indicators. Of note, oXiris improve organ function in sepsis, which may result to higher survival rate.

d-Borneol enhances cisplatin sensitivity via autophagy dependent EMT signaling and NCOA4-mediated ferritinophagy.

BACKGROUND: d-Borneol has been widely used as a drug absorption enhancer, but there are few studies on the anti-resistance ability of d-borneol combined with cisplatin in cisplatin-resistant non-small cell lung cancer cells. Ferroptosis, autophagy and epithelial-mesenchymal transition (EMT) have been reported to be associated with drug resistance. PURPOSE: To investigate the molecular mechanisms and sensitizing effects of d-borneol combined with cisplatin to against drug cisplatin resistance from the perspective of ferroptosis, autophagy and EMT resistance. METHODS: H460/CDDP xenograft tumor model was established to verify the antitumor activity and safety in vivo. RNA sequencing was used to predict target molecules and signaling pathways. Reactive oxygen species (ROS) were used as marker of ferroptosis, and its level was determined by a dichlorodihydrofluorescein diacetate fluorescent probe and flow cytometry. Levels of glutathione (GSH), malondialdehyde (MDA), and antioxidants such as superoxide dismutase (SOD) and thioredoxin (Trx) involved in the balance of oxidative stress were measured by an assay kit or enzyme-linked immunosorbent assay. Western blotting and real-time polymerase chain reaction were used to assess the regulatory mechanism of EMT markers, autophagy, and ferroptosis signaling pathways. RESULTS: d-Borneol in combination with cisplatin reduced tumor volume and weight, enhanced tumor-inhibiting effects, and alleviated cisplatin-induced damage to the liver and kidney in vivo. RNA-sequencing showed that differentially expressed genes were enriched in ferroptosis. d-Borneol in combination with cisplatin promoted ROS accumulation, increased the content of MDA levels, and decreased GSH, SOD, Trx, and heme oxygenase-1 expression to induce oxidative damage. d-Borneol combination with cisplatin induced ferroptosis by promoting nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy and regulating intracellular iron ion transport via upregulating PRNP and downregulating PCBP2. In addition, d-borneol combined with cisplatin promoted autophagy by upregulating expression of LC3II/ATG5/Beclin-1 and inhibited the EMT by increasing the expression of epithelial marker E-cadherin and decreasing mesenchymal markers (N-cadherin and vimentin) and transcription factors (Snail and ZEB1). CONCLUSION: For the first time, our study implies that d-borneol enhanced cisplatin sensitivity by inducing ferroptosis, promoting autophagy and inhibiting EMT progression, thereby enhancing antitumor activity. It suggests that d-borneol could be developed as a novel chemosensitizers.

d-Borneol enhances cisplatin sensitivity via p21/p27-mediated S-phase arrest and cell apoptosis in non-small cell lung cancer cells and a murine xenograft model.

BACKGROUND: Cisplatin (CDDP) is commonly used to treat non-small cell lung cancer (NSCLC), but the appearance of drug resistance greatly hinders its efficacy. Borneol may promote drug absorption; however, synergism between borneol and CDDP in suppressing NSCLC is not clearly understood. Hence, we investigated borneol as a novel chemosensitizer to support chemotherapeutic efficacy and reduce side effects. METHODS: We compared viability after exposure to d-borneol, l-borneol, and synthetic borneol in two NSCLC cell lines, A549 and H460, and selected the most sensitive cells. We then assessed synergy between borneol forms and CDDP in cisplatin-resistant NSCLC cells, H460/CDDP. Next, we identified effective concentrations and exposure times. Subsequently, we evaluated cell migration via wound healing and cell proliferation via clone formation assay. Then, we focused on P-glycoprotein (P-gp) function, cell cycle, apoptosis, and RNA sequencing to elucidate underlying molecular mechanisms for synergy. Finally, we used an H460/CDDP xenograft tumor model to verify antitumor activity and safety in vivo. Data were examined using one-way analysis of variance (ANOVA) for multiple datasets or t-test for comparisons between two variables. RESULTS: d-Borneol was more effective in H460 than A549 cells. d-Borneol combined with CDDP showed greater inhibition of cell proliferation, migration, and clone formation in H460/CDDP cells than CDDP alone. RNA sequencing (RNA-seq) analysis identified differentially expressed genes enriched in cell cycle pathways. The impact of d-borneol on CDDP chemosensitivity involved arrest of the cell cycle at S phase via p27/p21-mediated cyclinA2/D3-CDK2/6 signaling and activation of intrinsic apoptosis via p21-mediated Bax/Bcl-2/caspase3 signaling. Further, d-borneol ameliorated drug resistance by suppressing levels and activity of P-gp. Cotreatment with d-borneol and CDDP inhibited tumor growth in vivo and reduced CDDP-caused liver and kidney toxicity. CONCLUSIONS: d-Borneol increased the efficacy of cisplatin and reduced its toxicity. This compound has the potential to become a useful chemosensitizer for drug-resistance NSCLC.

Genome-Wide Identification and Transcript Analysis Reveal Potential Roles of Oligopeptide Transporter Genes in Iron Deficiency Induced Cadmium Accumulation in Peanut.

The oligopeptide transporter (OPT) family is a group of proton-coupled symporters that play diverse roles, including metal homeostasis. However, little is known about this family of peanuts. To reveal the potential roles of AhOPT genes in Fe/Cd interactions, peanut AhOPT genes were genome-widely identified, and the relationships between gene expression and Cd accumulation were detected in two contrasting peanut cultivars (Fenghua 1 and Silihong) under Fe-sufficient or Fe-deficient conditions. A total of 40 AhOPT genes were identified in peanuts, which were divided into two subfamilies (PT and YS). Most AhOPT genes underwent gene duplication events predominated by whole-genome duplication. Clustered members generally have similar protein structures. However, gene structural divergences occurred in most of the duplicated genes. Transcription analysis revealed that AhOPT3.2/3.4 and AhYSL3.1/3.2 might be responsible for Fe deficiency tolerance, while AhOPT3.1/3.4, AhOPT7.1/7.2, and AhYSL1.1 be involved in Fe/Cd interactions. These genes might be regulated by transcription factors, including ATHB-12, ATHB-6, DIVARICATA, MYB30, NAC02, DOF3.4, IDD7, and LUX. Reduced expressions of AhYSL3.1/3.2 and higher expressions of AhOPT3.4 might contribute to higher Fe-deficiency tolerance in Silihong. Higher expression of AhOPT7.3 and AhOPT6.1 might be responsible for low Cd accumulation in Fenghua 1. Our results confirmed that AhOPT3/6/7 and AhYSL1/3 might be involved in the transport of Fe and/or Cd in peanuts and provided new clues to understanding potential mechanisms of Fe/Cd interactions.

Rolling back human pluripotent stem cells to an eight-cell embryo-like stage.

After fertilization, the quiescent zygote experiences a burst of genome activation that initiates a short-lived totipotent state. Understanding the process of totipotency in human cells would have broad applications. However, in contrast to in mice1,2, demonstration of the time of zygotic genome activation or the eight-cell (8C) stage in in vitro cultured human cells has not yet been reported, and the study of embryos is limited by ethical and practical considerations. Here we describe a transgene-free, rapid and controllable method for producing 8C-like cells (8CLCs) from human pluripotent stem cells. Single-cell analysis identified key molecular events and gene networks associated with this conversion. Loss-of-function experiments identified fundamental roles for DPPA3, a master regulator of DNA methylation in oocytes3, and TPRX1, a eutherian totipotent cell homeobox (ETCHbox) family transcription factor that is absent in mice4. DPPA3 induces DNA demethylation throughout the 8CLC conversion process, whereas TPRX1 is a key executor of 8CLC gene networks. We further demonstrate that 8CLCs can produce embryonic and extraembryonic lineages in vitro or in vivo in the form of blastoids5 and complex teratomas. Our approach provides a resource to uncover the molecular process of early human embryogenesis.

The Role of Cytochrome P450 Enzymes in COVID-19 Pathogenesis and Therapy.

Coronavirus disease 2019 (COVID-19) has become a new public health crisis threatening the world. Dysregulated immune responses are the most striking pathophysiological features of patients with severe COVID-19, which can result in multiple-organ failure and death. The cytochrome P450 (CYP) system is the most important drug metabolizing enzyme family, which plays a significant role in the metabolism of endogenous or exogenous substances. Endogenous CYPs participate in the biosynthesis or catabolism of endogenous substances, including steroids, vitamins, eicosanoids, and fatty acids, whilst xenobiotic CYPs are associated with the metabolism of environmental toxins, drugs, and carcinogens. CYP expression and activity are greatly affected by immune response. However, changes in CYP expression and/or function in COVID-19 and their impact on COVID-19 pathophysiology and the metabolism of therapeutic agents in COVID-19, remain unclear. In this analysis, we review current evidence predominantly in the following areas: firstly, the possible changes in CYP expression and/or function in COVID-19; secondly, the effects of CYPs on the metabolism of arachidonic acid, vitamins, and steroid hormones in COVID-19; and thirdly, the effects of CYPs on the metabolism of therapeutic COVID-19 drugs.

Self-Assembled Micellar Glutaminase Allosteric Inhibitor for Effective Therapeutic Intervention.

INTRODUCTION: Kidney-type glutaminase (KGA) has been an important anti-tumor drug target, and KGA allosteric inhibitors attracted much interest for their superior enzymatic specificity with good drug safety profiles. For glutaminase allosteric inhibitors such as BPTES, CB-839 and Selen derivatives, the low solubility remains as the main factor that limits in vivo efficacy. The 1,3,4-Selenadiazole compound CPD 23 showed improved in vivo efficacy but worse solubility; however, the graft polymer polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCap-PVA-PEG), Soluplus® (SOL) stood out as an excellent delivery carrier for CPD 23. METHODS: The CPD 23@SOL micelles were prepared, optimized and evaluated through on the basis of solubility improvement and loading capacity. Characterizations of particle size and Zeta potential by dynamic light scattering, morphology by transmission electron microscopy and solid state by X-ray powder diffraction were closely conducted. The biological studies included the tumor cell growth inhibition, blood and liver microsomal stability, in vivo pharmacokinetics and tissue biodistribution. RESULTS: At 1:20 ratio of CPD 23:SOL, CPD 23@SOL micelles were well-dispersed, spherical and stable, with size less than 200 nm with encapsulation efficiency of more than 90%. This SOL micellar system significantly increased the aqueous solubility of CPD 23 by 15,000 folds. Particularly, CPD 23@SOL micelles demonstrated higher stability in blood and liver microsomes, showing approximately 86% remaining at 2 h incubation and about 66% at 4 h, respectively. In addition, with or without micellar formulation, CPD 23 maintained essentially the same inhibitory activity in tumor cells. Interestingly, CPD 23@SOL micelles significantly improved the pharmacokinetic exposure, prolonged the in vivo circulation and dramatically changed tissue biodistributions of CPD 23. CONCLUSION: The current work provided an encouraging and practical delivery system for novel Selenadiazoles and glutaminase allosteric inhibitors whose poor water-soluble characteristic has been a bottleneck for the field.