Chromomycins from soil-derived Streptomyces sp. inhibit the growth of human non-small cell lung cancer cells by targeting c-FLIP.

Three chromomycin derivatives, chromomycins A3 (1, CA3), A5 (2, CA5), and monodeacetylchromomycin A3 (3, MDA-CA3), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA5 is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA3 based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1-3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC50 values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.

Analysis of status and influencing factors of mental health in patients with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder with varied clinical courses and prognoses, not only did the patients suffer from physical impairment, but also various physical and psychiatric comorbidities. Growing evidence have suggested that mental disorders in SLE patients, can lead to various adverse consequences. AIM: To explored the features and influencing factors of mental health in patients with SLE and clarifying the correlations between mental health and personality characteristics and perceived social support. The results would provide a basis for psychological intervention in patients with SLE. METHODS: The clinical data of 168 patients with SLE admitted at the First Affiliated Hospital of Hainan Medical University between June 2020 and June 2022 were collected. Psychological assessment and correlation analysis were conducted using the Symptom Checklist-90 (SCL-90) and Perceived Social Support Scale, and the collected data were compared with the national norms in China. The relevant factors influencing mental health were identified by statistical analysis. A general information questionnaire, the Revised Life Orientation Test, and Short-Form 36-Item Health Survey were employed to assess optimism level and quality of life (QoL), respectively. RESULTS: Patients with SLE obtained higher scores for the somatization, depression, anxiety, and phobic anxiety subscales than national norms (P < 0.05). A correlation was identified between total social support and total SCL-90 score or each subscale (P < 0.05). The factors significantly affecting patients' mental health were hormone dosage and disease activity index (DAI) (P < 0.05). The average optimism score of patients with SLE was 14.36 ± 4.42, and 30 cases were in the middle and lower levels. A positive correlation was found between optimism level and QoL scores. CONCLUSION: Patients with SLE develop psychological disorders at varying degrees, which are significantly influenced by hormone dosage and DAI. Patients' mental health should be closely monitored during clinical diagnosis and treatment and provided adequate support in establishing positive, healthy thinking and behavior patterns and improving their optimism level and QoL.

Laparoscopy is non-inferior to open surgery for rectal cancer: A systematic review and meta-analysis.

BACKGROUND: Laparoscopic surgery has been endorsed by clinical guidelines for colon cancer, but not for rectal cancer on account of unapproved oncologic equivalence with open surgery. AIMS: We started this largest-to-date meta-analysis to comprehensively evaluate the safety and efficacy of laparoscopy in the treatment of rectal cancer compared with open surgery. MATERIALS & METHODS: Both randomized and nonrandomized controlled trials comparing laparoscopic proctectomy and open surgery between January 1990 and March 2020 were searched in PubMed, Cochrane Library and Embase Databases (PROSPERO registration number CRD42020211718). The data of intraoperative, pathological, postoperative and survival outcomes were compared between two groups. RESULTS: Twenty RCTs and 93 NRCTs including 216,615 patients fulfilled the inclusion criteria, with 48,888 patients received laparoscopic surgery and 167,727 patients underwent open surgery. Compared with open surgery, laparoscopic surgery group showed faster recovery, less complications and decreased mortality within 30 days. The positive rate of circumferential margin (RR = 0.79, 95% CI: 0.72 to 0.85, p < 0.0001) and distal margin (RR = 0.75, 95% CI: 0.66 to 0.85 p < 0.0001) was significantly reduced in the laparoscopic surgery group, but the completeness of total mesorectal excision showed no significant difference. The 3-year and 5-year local recurrence, disease-free survival and overall survival were all improved in the laparoscopic surgery group, while the distal recurrence did not differ significantly between the two approaches. CONCLUSION: Laparoscopy is non-inferior to open surgery for rectal cancer with respect to oncological outcomes and long-term survival. Moreover, laparoscopic surgery provides short-term advantages, including faster recovery and less complications.

The Uptake, Transfer, and Detoxification of Cadmium in Plants and Its Exogenous Effects.

Cadmium (Cd) exerts a toxic influence on numerous crucial growth and development processes in plants, notably affecting seed germination rate, transpiration rate, chlorophyll content, and biomass. While considerable advances in Cd uptake and detoxification of plants have been made, the mechanisms by which plants adapt to and tolerate Cd toxicity remain elusive. This review focuses on the relationship between Cd and plants and the prospects for phytoremediation of Cd pollution. We highlight the following issues: (1) the present state of Cd pollution and its associated hazards, encompassing the sources and distribution of Cd and the risks posed to human health; (2) the mechanisms underlying the uptake and transport of Cd, including the physiological processes associated with the uptake, translocation, and detoxification of Cd, as well as the pertinent gene families implicated in these processes; (3) the detrimental effects of Cd on plants and the mechanisms of detoxification, such as the activation of resistance genes, root chelation, vacuolar compartmentalization, the activation of antioxidant systems and the generation of non-enzymatic antioxidants; (4) the practical application of phytoremediation and the impact of incorporating exogenous substances on the Cd tolerance of plants.

Asperuloside inhibits the activation of pancreatic cancer-associated fibroblasts via activating transcription factor 6.

BACKGROUND: Pancreatic cancer-associated fibroblasts (CAFs) play a crucial role in tumor progression and immune evasion. Asperuloside (ASP) is an iridoid glycoside with potential anti-tumor properties. This study aimed to explore the molecular mechanisms of ASP on CAFs, particularly focusing on its effects on activating transcription factor 6 (ATF6), a key regulator of endoplasmic reticulum stress. METHOD: CAFs were treated with different concentrations of ASP (0, 1, 3, and 5 mM), and the role of ATF6 was investigated by over-expressing it in CAFs. Subsequently, western blot was used to detect ATF6, α-smooth muscle actin (α-SMA), fibroblast activating protein (FAP), and vimentin protein levels in CAFs. The collagen gel contraction assay and Transwell assay were applied to evaluate the contraction and migration ability of CAFs. In addition, the interleukin (IL)-6, C-C motif chemokine ligand (CCL)-2, and C-X-C motif chemokine ligand (CXCL)-10 levels were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: CAFs had significantly higher expression levels of α-SMA, FAP, and vimentin compared to normal fibroblasts (NFs). ASP significantly inhibited the activation, contraction, and migration of CAFs in a concentration-dependent manner. ASP treatment also reduced the expression of cytokines (IL-6, CCL2, and CXCL10) and down-regulated ATF6 levels. Over-expression of ATF6 mitigated the inhibitory effects of ASP. CONCLUSION: ASP exerts its anti-tumor effects by down-regulating ATF6, thereby inhibiting the activation and function of pancreatic CAFs. These findings suggest that ASP could be a promising therapeutic agent for pancreatic cancer by modulating the tumor microenvironment.

HER2-targeting antibody drug conjugate FS-1502 in HER2-expressing metastatic breast cancer: a phase 1a/1b trial.

Currently approved HER2-targeting antibody-drug conjugates (ADCs) for HER2-positive breast cancer (BC) are associated with safety concerns. In this multicenter, single-arm, dose-escalation (phase 1a) and dose-expansion (phase 1b) phase 1 trial (NCT03944499), patients with HER2-expressing advanced solid tumors received FS-1502 (an anti-HER2 ADC) with a 3 + 3 design in phase 1a; patients with metastatic HER2-positive BC received FS-1502 at the recommended phase 2 dose (RP2D) in phase 1b. The primary end points were dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and RP2D for phase 1a and objective response rate (ORR) for phase 1b. A total of 150 patients with HER2-expressing solid tumors (n = 5) and BC (n = 145) were enrolled (female, n = 146, 97.3%). One DLT each was reported at 3.0 and 3.5 mg/kg; the MTD was not reached. The RP2D was 2.3 mg/kg once every 3 weeks. Five (3.3%) patients experienced pneumonitis; four (2.7%) had grade 3 reversible ocular events. Of 67 HER2-positive BC patients receiving the RP2D, the best ORR was 53.7% (95% CI, 41.1-66.0%), including PRs confirmed (confirmed ORR, 37.5%) and pending for confirmation. FS-1502 was well tolerated with limited ocular and pulmonary findings and demonstrated promising antitumor activity in HER2-positive BC patients.

Research advances in predicting the expansion of hypertensive intracerebral hemorrhage based on CT images: an overview.

Hematoma expansion (HE) is an important risk factor for death or poor prognosis in patients with hypertensive intracerebral hemorrhage (HICH). Accurately predicting the risk of HE in patients with HICH is of great clinical significance for timely intervention and improving patient prognosis. Many imaging signs reported in literatures showed the important clinical value for predicting HE. In recent years, the development of radiomics and artificial intelligence has provided new methods for HE prediction with high accuracy. Therefore, this article reviews the latest research progress in CT imaging, radiomics, and artificial intelligence of HE, in order to help identify high-risk patients for HE in clinical practice.

Is it a normal phenomenon for pediatric patients to have brain leptomeningeal contrast enhancement on 3-tesla magnetic resonance imaging?

Determining whether sevoflurane sedation in children leads to "pseudo" prominent leptomeningeal contrast enhancement (pLMCE) on 3 Tesla magnetic resonance imaging will help reduce overdiagnosis by radiologists and clarify the pathophysiological changes of pLMCE.

Design, synthesis and herbicidal activity of novel cyclohexanedione derivations containing pyrazole and pyridine groups as potential HPPD inhibitors.

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27; HPPD) is one of the important target enzymes in the development of herbicides. To discover novel HPPD inhibitors with unique molecular, 39 cyclohexanedione derivations containing pyrazole and pyridine groups were designed and synthesized. The preliminary herbicidal activity test results showed that some compounds had obvious inhibitory effects on monocotyledon and dicotyledonous weeds. The herbicidal spectrums of the highly active compounds were further determined, and the compound G31 exhibited the best inhibitory rate over 90% against Plantago depressa Willd and Capsella bursa-pastoris at the dosages of 75.0 and 37.5 g ai/ha, which is comparable to the control herbicide mesotrione. Moreover, compound G31 showed excellent crop safety, with less than or equal to 10% injury rates to corn, sorghum, soybean and cotton at a dosage of 225 g ai/ha. Molecular docking and molecular dynamics simulation analysis revealed that the compound G31 could stably bind to Arabidopsis thaliana HPPD (AtHPPD). This study indicated that the compound G31 could be used as a lead molecular structure for the development of novel HPPD inhibitors, which provided an idea for the design of new herbicides with unique molecular scaffold.

Effect of mutation at c.493T>C locus of transcription factor HNF1α gene on its protein level.

Hepatocyte nuclear factor 1α (HNF1α) is a transcription factor that is crucial for the regulation to maintain the function of pancreatic ß-cell, hepatic lipid metabolism, and other processes. Mature-onset diabetes of the young type 3 is a monogenic form of diabetes caused by HNF1α mutations. Although several mutation sites have been reported, the specific mechanisms remain unclear, such hot-spot mutation as the P291fsinsC mutation and the P112L mutation and so on. In preliminary studies, we discovered one MODY3 patient carrying a mutation at the c.493T>C locus of the HNF1α gene. In this study, we analyzed the pathogenic of the mutation sites by using the Mutation Surveyor software and constructed the eukaryotic expression plasmids of the wild-type and mutant type of HNF1α to detect variations in the expression levels and stability of HNF1α protein by using Western blot. The analyses of the Mutation Surveyor software showed that the c.493T>C site mutation may be pathogenic gene and the results of Western blot showed that both the amount and stability of HNF1α protein expressed by the mutation type plasmid were reduced significantly compared to those by the wild type plasmid (P<0.05). This study suggests that the c.493T>C (p.Trp165Arg) mutation dramatically impacts HNF1α expression, which might be responsible for the development of the disease and offers fresh perspectives for the following in-depth exploration of MODY3's molecular pathogenic process.

Methylation enables the use of fluorine-free ether electrolytes in high-voltage lithium metal batteries.

Lithium metal batteries represent a promising technology for next-generation energy storage, but they still suffer from poor cycle life due to lithium dendrite formation and cathode cracking. Fluorinated solvents can improve battery longevity by improving LiF content in the solid-electrolyte interphase; however, the high cost and environmental concerns of fluorinated solvents limit battery viability. Here we designed a series of fluorine-free solvents through the methylation of 1,2-dimethoxyethane, which promotes inorganic LiF-rich interphase formation through anion reduction and achieves high oxidation stability. The anion-derived LiF interphases suppress lithium dendrite growth on the lithium anode and minimize cathode cracking under high-voltage operation. The Li+-solvent structure is investigated through in situ techniques and simulations to draw correlations between the interphase compositions and electrochemical performances. The methylation strategy provides an alternative pathway for electrolyte engineering towards high-voltage electrolytes while reducing dependence on expensive fluorinated solvents.

[Detection, Generation, and Control of Disinfection By-products of Reclaimed Water].

At the time when water resources are in short supply,wastewater recycling is both an important environmental protection strategy and also a resource strategy. Disinfection is essential to ensure the biological safety of reclaimed wastewater by killing pathogens and preventing the spread of waterborne diseases. However,the disinfection process could inevitably produce toxic disinfection byproducts(DBPs)due to the reaction between the disinfectants and wastewater organic matters. Regarding wastewater DBPs,this study reviewed their identification methods,formation conditions(including precursors,the effect of water quality,disinfectants,and operational parameters on DBPs),and control methods(including source control,process control,and end control). In addition,future research trends of wastewater DBPs were discussed.

In-depth theoretical analysis of the influence of an external electric field on charge transport parameters.

It is important to develop materials with environmental stability and long device shelf life for use in organic field-effect transistors (OFETs). The microscopic, molecular-level nature of the organic layer in OFETs is not yet well understood. The stability of geometric and electronic structures and the regulation of the external electric field (EEF) on the charge transport properties of four typical homogeneous organic semiconductors (OSCs) were investigated by density functional theory (DFT). The results showed that under the EEF, the structural changes in single-bond linked oligomers were more sensitive and complex than those of condensed molecules, and there were non-monotonic changes in their reorganization energy (λ) during charge transport under an EEF consisting of decreases and then increases (Series D). The change in λ under an EEF can be preliminarily and qualitatively determined by the change in the frontier molecular orbitals (FMOs) - the number of C-atoms with nonbonding characteristics. For single-bonded molecules, the transfer integral is basically unchanged under a low EEF, but it will greatly change at a high EEF. Because the structure and properties of the molecule will greatly change under different EEFs, the effect of an EEF should be fully considered when determining the intrinsic mobility of OSCs, which could cause a deviation 0.3-20 times in mobility. According to detailed calculations, one heterogeneous oligomer, TH-BTz, was designed. Its λ can be greatly reduced under an EEF, and the change in the energy level of FMOs can be adjusted to different degrees. This study provides a reasonable idea for verification of the experimental mobility value and also provides guidance for the directional design of stable high-mobility OSCs.

Pharmacokinetics, Safety, and Tolerability of Tenapanor in Healthy Chinese and Caucasian Volunteers: A Randomized, Open-Label, Single-Center, Placebo-Controlled Phase 1 Study.

Background: Tenapanor is a locally acting selective sodium-hydrogen exchanger 3 inhibitor with the potential to treat sodium/phosphorus and fluid overload in various cardiac-renal diseases, which has been approved for constipation-predominant irritable bowel syndrome in the US. The pharmacokinetics (PK) of tenapanor and its metabolite tenapanor-M1 (AZ13792925), as well as the safety and tolerability of tenapanor, were investigated in healthy Chinese and Caucasian subjects. Methods: This randomized, open-label, single-center, placebo-controlled phase 1 study (https://www.chinadrugtrials.org.cn; CTR20201783) enrolled Chinese and Caucasian healthy volunteers into 4 parallel cohorts (3 cohorts for Chinese subjects, 1 cohort for Caucasian subjects). In each cohort, 15 subjects were expected to be included and received oral tenapanor (10 or 30 mg as single dose, or 50 mg as a single dose followed by a twice-daily repeated dose from Day 5 to 11, with a single dose in the morning on Day 11) or placebo in a 4 : 1 ratio. Results: 59 healthy volunteers received tenapanor 10 mg (n = 12 Chinese), 30 mg (n = 12 Chinese), or 50 mg (n = 12 (Chinese), n = 11 (Caucasian)) or placebo (n = 12, 3 per cohort). After single and twice-daily repeated doses, tenapanor plasma concentrations were all below the limit of quantitation; tenapanor-M1 appeared slowly in plasma. In single-ascending dose evaluation (10 to 50 mg) of Chinese subjects, the mean Cmax, AUC0-t, and AUC0-∞ of tenapanor-M1 increased with increasing dose level, and AUC0-t increased approximately dose proportionally. The Cmax accumulation ratio was 1.55 to 6.92 after 50 mg repeated dose in Chinese and Caucasian subjects. Exposure to tenapanor-M1 was generally similar between the Chinese and Caucasian subjects. Tenapanor was generally well-tolerated and the safety profile was similar between the Chinese and Caucasian participants receiving tenapanor 50 mg, as measured by vital signs, physical and laboratory examination, 12-lead ECG, and adverse events. No serious adverse event or adverse event leading to withdrawal occurred. Conclusion: Tenapanor was well-tolerated, with similar PK and safety profiles between Chinese and Caucasian subjects. This trial is registered with CTR20201783.

High voltage electrolytes for lithium-ion batteries with micro-sized silicon anodes.

Micro-sized silicon anodes can significantly increase the energy density of lithium-ion batteries with low cost. However, the large silicon volume changes during cycling cause cracks for both organic-inorganic interphases and silicon particles. The liquid electrolytes further penetrate the cracked silicon particles and reform the interphases, resulting in huge electrode swelling and quick capacity decay. Here we resolve these challenges by designing a high-voltage electrolyte that forms silicon-phobic interphases with weak bonding to lithium-silicon alloys. The designed electrolyte enables micro-sized silicon anodes (5 µm, 4.1 mAh cm-2) to achieve a Coulombic efficiency of 99.8% and capacity of 2175 mAh g-1 for >250 cycles and enable 100 mAh LiNi0.8Co0.15Al0.05O2 pouch full cells to deliver a high capacity of 172 mAh g-1 for 120 cycles with Coulombic efficiency of >99.9%. The high-voltage electrolytes that are capable of forming silicon-phobic interphases pave new ways for the commercialization of lithium-ion batteries using micro-sized silicon anodes.

Efficacy of acellular fish skin graft in the management of chronic ulcer: a systematic review and meta-analysis.

BACKGROUND: The wounds failing to heal through a timely and orderly standard of care (SOC) treatment are considered as chronic wounds, which add significant burden to healthcare systems around the world. SOC treatment has been commonly applied for management of chronic wounds, but SOC alone may not be adequate to heal all ulcers effectively. Fish skin graft (FSG) is a xenogenic skin substitute which could be used for accelerating skin healing. The current study was performed with the view of evaluating the effectiveness of FSG as an adjuvant treatment of SOC for chronic ulcer treatment. METHODS: Two authors independently searched the following electronic databases: PubMed, Embase, and CENTRAL, using keywords including "diabetic foot ulcer," "fish skin graft," and "wound healing." Clinical studies that evaluated the clinical outcomes of FSG in treatment of chronic ulcers were included in this meta-analysis. Random- or fixed-effect modeled meta-analyses were performed according to the heterogeneity test result (i.e., I2), to analyze the clinical outcome of FSG. RESULTS: A total of 8 studies were included in qualitative synthesis and meta-analysis, with 145 patients treated by SOC and 245 patients treated by SOC plus FSG. There was no significant difference between two groups for time to healing (MD = 1.99, 95% CI: -3.70~7.67, p = 0.493). The complete healing rate was significantly higher in FSG group compared with SOC alone (OR = 3.44, 95% CI: 2.03~5.82, p < 0.001***). Mean percentage area reduction (PAR) was reported in six studies, with a range of 71.6~97.3%. However, many of these studies did not report the value of standard deviation (SD), so we could not pool the data. No significantly different ulcer recurrence rate (RR = 0.60, 95% CI: 0.07~5.27, p = 0.645) and severe adverse events (SAEs) risk (RR = 1.67, 95% CI: 0.42~6.61, p = 0.467) were found between two groups. CONCLUSIONS: The application of FSG treatment for patients with chronic ulcers that do not respond well to SOC management could significantly increase the complete healing rate compared with SOC alone, without increased recurrence rate and SAEs risk.

Impact of propofol and sevoflurane anesthesia on cognition and emotion in gastric cancer patients undergoing radical resection.

BACKGROUND: Propofol and sevoflurane are commonly used anesthetic agents for maintenance anesthesia during radical resection of gastric cancer. However, there is a debate concerning their differential effects on cognitive function, anxiety, and depression in patients undergoing this procedure. AIM: To compare the effects of propofol and sevoflurane anesthesia on postoperative cognitive function, anxiety, depression, and organ function in patients undergoing radical resection of gastric cancer. METHODS: A total of 80 patients were involved in this research. The subjects were divided into two groups: Propofol group and sevoflurane group. The evaluation scale for cognitive function was the Loewenstein occupational therapy cognitive assessment (LOTCA), and anxiety and depression were assessed with the aid of the self-rating anxiety scale (SAS) and self-rating depression scale (SDS). Hemodynamic indicators, oxidative stress levels, and pulmonary function were also measured. RESULTS: The LOTCA score at 1 d after surgery was significantly lower in the propofol group than in the sevoflurane group. Additionally, the SAS and SDS scores of the sevoflurane group were significantly lower than those of the propofol group. The sevoflurane group showed greater stability in heart rate as well as the mean arterial pressure compared to the propofol group. Moreover, the sevoflurane group displayed better pulmonary function and less lung injury than the propofol group. CONCLUSION: Both propofol and sevoflurane could be utilized as maintenance anesthesia during radical resection of gastric cancer. Propofol anesthesia has a minimal effect on patients' pulmonary function, consequently enhancing their postoperative recovery. Sevoflurane anesthesia causes less impairment on patients' cognitive function and mitigates negative emotions, leading to an improved postoperative mental state. Therefore, the selection of anesthetic agents should be based on the individual patient's specific circumstances.

Downregulation of peripheral luteinizing hormone rescues ovariectomy-associated cognitive deficits in APP/PS1 mice.

Alzheimer's disease (AD) is more prevalent in women than men, supposing due to the decline of estrogens in menopause, accompanied by increased gonadotropins such as luteinizing hormone (LH). We and others found that the transcription factor early growth response-1 (EGR1) regulates cholinergic function including the expression of acetylcholinesterase (AChE) and plays a significant role in cognitive decline of AD. Here we investigated in APP/PS1 mice by ovariectomy (OVX) and estradiol (E2) supplementation or inhibition of LH the effect on hippocampus-related cognition and related molecular changes. We found that OVX-associated cognitive impairment was accompanied by increased dorsal hippocampal EGR1 expression, which was rescued by downregulating peripheral LH rather than by supplementing E2. We also found in postmortem AD brains a higher expression of pituitary LH-mRNA and higher EGR1 expression in the posterior hippocampus. Both, in human and mice, there was a significant positive correlation between respectively posterior/dorsal hippocampal EGR1 and peripheral LH expression. We conclude that peripheral increased LH and increased posterior hippocampal EGR1 plays a significant role in AD pathology.