Crohn's disease treatment and memory T-cell subset changes: insights from a case series.

Background: Crohn's disease (CD) is a chronic inflammatory bowel disease with significant morbidity, affecting millions worldwide. The intricacies of immune responses in CD, especially post-treatment, remain a vital area of exploration. While memory T (Tm)-cell subsets play a pivotal role in adaptive immunity, their specific function in patients with CD after treatment is not well-understood. This study aims to investigate the effect and function of Tm-cell subsets in these patients, addressing a crucial knowledge gap in the context of CD therapeutics. Methods: A total of eight patients diagnosed with CD were selected based on predefined inclusion criteria. All patients were treated with either anti-inflammatory agents, immunosuppressive drugs, or a combination of both. For comparison, healthy donors were enrolled based on exclusion of autoimmune or inflammatory diseases. Peripheral blood mononuclear cells (PBMCs) and lymphocytes were isolated from blood and lymph node tissue respectively. The phenotype and cytokine production of T lymphocytes from both CD patients and healthy donors were analyzed using flow cytometry. Statistical comparisons of the outcomes between CD patients and healthy donors were made using Mann-Whitney test (two-tailed) and Student t-test. Results: Post-treatment CD patients exhibited an altered T cell distribution with a notable increase in CD8+ T cells in PBMCs (P=0.0005), and altered frequencies of CD4+ and CD8+ T cells in mesenteric lymph nodes (MLNs). Tm cells showed decreased interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production, with significant alterations in the frequency of IFN-γ-producing CD8+ stem cell-like Tm (Tscm) cells in lesions of the MLNs from patients with CD (CD-M-Lys) compared to healthy MLNs from patients with CD (N-M-Lys) (P=0.0152). Differences in tissue-resident Tm (Trm)-cell subset frequencies were observed between the MLNs and small intestinal mucosa in CD patients. Conclusions: The treatments with anti-inflammatory agents and/or immunosuppressive drugs have a significant effect on the frequency and function of Tm-cell subsets. Clinically, these findings suggest a potential therapeutic avenue in modulating Tm-cell responses, which might be particularly beneficial for conditions where immune response modulation is crucial. Further clinical studies are warranted to explore the full therapeutic implications of these findings.

A prospective cohort study with serum anti-mullerian hormone levels change in patients undergoing uterine preservation after gestational trophoblastic neoplasia treatment with a methotrexate regimen.

Objectives: To monitor changes in serum anti-Mullerian hormone (AMH) levels of the patients with gestational trophoblastic neoplasia (GTN) who have undergone uterine preservation during treatment with a Methotrexate (MTX) regimen and associations with AMH variations. Methods: This observational prospective cohort study included 35 patients with low-risk GTN with uterine preservation during single-agent MTX chemotherapy at Hanoi Obstetrics and Gynecology Hospital from August 2021 to August 2022. Serum AMH levels were measured before initiation of chemotherapy and after the 1st, 2nd, and 3rd chemotherapy cycles. AMH evolution and its associations with some factors were analyzed. Results: The median basal AMH level before chemotherapy was 2.87 ng/mL (0.96 - 7.9 ng/mL) and negatively correlated with age. The serum AMH levels decreased significantly after each chemotherapy cycle (2.87 vs. 1.16, 0.91, 0.41 ng/mL). The median magnitude of the AMH levels decline after 1st, 2nd, and 3rd chemotherapy cycles were 51.2%, 69.4%, and 84.6% (p<0.001), respectively. AMH variation was associated with the basal AMH level, but not with age, ßhCG at diagnosis and menstrual status. Conclusion: Our study has shown that the serum AMH levels declined rapidly and steadily in all patients during chemotherapy for GTN. Although AMH cannot be used to monitor fertility potential lonely, these new studies improve our knowledge of ovarian toxicity and ovarian reserve during chemotherapy and strongly support the use of fertility preservation strategies.

Parotid metastasis of rare lung adenocarcinoma: A case report.

BACKGROUND: Lung cancer (LC) is the leading cause of malignancy-related deaths worldwide. The most common sites of metastasis include the nervous system, bone, liver, respiratory system, and adrenal glands. LC metastasis in the parotid gland is very rare, and its diagnosis presents a challenge. Here, we report a case of parotid metastasis in primary LC. CASE SUMMARY: The patient was a 74-year-old male who was discovered to have bilateral facial asymmetry inadvertently two years ago. The right earlobe was slightly swollen and without pain or numbness. Computed tomography (CT) examination showed bilateral lung space-occupying lesions. Pulmonary biopsy was performed and revealed adenocarcinoma (right-upper-lung nodule tissue). Positron emission tomography-CT examination showed: (1) Two hypermetabolic nodules in the right upper lobe of the lung, enlarged hypermetabolic lymph nodes in the right hilar and mediastinum, and malignant space-occupying lesion in the right upper lobe of the lung and possible metastasis to the right hilar and mediastinal lymph nodes; and (2) multiple hypermetabolic nodules in bilateral parotid glands. Parotid puncture biopsy was performed considering lung adenocarcinoma metastasis. Gene detection of lung biopsy specimens revealed an EGFR gene 21 exon L858R mutation. CONCLUSION: This case report highlights the challenging diagnosis of parotid metastasis in LC given its rare nature. Such lesions should be differentiated from primary tumors of the parotid gland. Simple radiological imaging is unreliable, and puncture biopsy is needed for final diagnosis of this condition.

Revealing the Marine Cycles of Volatile Sulfur Compounds and Their Biogeochemical Controls: A Case of the Western North Pacific.

Volatile sulfur compounds, such as dimethyl sulfide (DMS), carbonyl sulfide (OCS), and carbon disulfide (CS2), have significant implications for both atmospheric chemistry and climate change. Despite the crucial role of oceans in regulating their atmospheric budgets, our comprehension of their cycles in seawater remains insufficient. To address this gap, a field investigation was conducted in the western North Pacific to clarify the sources, sinks, and biogeochemical controls of these gases in two different marine environments, including relatively eutrophic Kuroshio-Oyashio extension (KOE) and oligotrophic North Pacific subtropical gyre. Our findings revealed higher concentrations of these gases in both seawater and the atmosphere in the KOE compared to the subtropical gyre. In the KOE, nutrient-rich upwelling stimulated rapid DMS biological production, while reduced seawater temperatures hindered the removal of OCS and CS2, leading to their accumulation. Furthermore, we have quantitatively evaluated the relative contribution of each pathway to the source and sink of DMS, OCS, and CS2 within the mixed layer and identified vertical exchange as a potential sink in most cases, transporting substantial amounts of these gases from the mixed layer to deeper waters. This research advances our understanding of sulfur gas source-sink dynamics in seawater, contributing to the assessment of their marine emissions and atmospheric budgets.

Assessment of residual cancer burden and survival in neoadjuvant chemotherapy of inoperable stage III breast cancer: A ten-year follow-up analysis in Vietnam.

BACKGROUND: Prognostic scores such as Residual Cancer Burden (RCB), Clinical Pathological Score (CPS), and Neo-Bioscore have been introduced to categorize breast cancer patients into different prognostic risk groups after neoadjuvant chemotherapy (NAC). PURPOSE: To evaluate the prognostic value of the residual cancer burden index in a large group of Vietnamese breast cancer patients treated with neoadjuvant chemotherapy in real-world settings. METHODS: 126 patients diagnosed with stage III breast cancer received neoadjuvant chemotherapy according to the AP regimes. After operation of BC, pathologic complete response (pCR) and Residual cancer burden (RCB) were evaluated. All breast cancer patients' survival were analyzed by using Kaplan-Meier and Log-Rank models. RESULTS: The average overall survival (OS) time was 75 months, with 90 (71.4%) recurrence and 82 (65%) mortality. The Kaplan Meier curve between OS and DFS with subgroups RCB indicate that the groups with higher RCB had a lower probability of survival, with statistical significance. Adjusted Cox regression model for age, menstruation, side of breast, clinical respose and overall stage illustrate that patients in RCB group 3 had a 2.7 times higher risk of mortality (95% CI: 1.28-5.67) compared to RCB group 0, p = 0.01. Patients with higher RCB levels had a higher risk of mortality. CONCLUSION: Stage IIIC, RCB score and RCB group are the independent prognostic factors for predicting survival time of breast cancer patients receiving neoadjuvant treatment.

The effect of metformin on senescence of T lymphocytes.

BACKGROUND: Immunosenescence occurs as people age, leading to an increased incidence of age-related diseases. The number of senescent T cells also rises with age. T cell senescence and immune response dysfunction can result in a decline in immune function, especially in anti-tumor immune responses. Metformin has been shown to have various beneficial effects on health, such as lowering blood sugar levels, reducing the risk of cancer development, and slowing down the aging process. However, the immunomodulatory effects of metformin on senescent T cells still need to be investigated. METHODS: PBMCs isolation from different age population (n = 88); Flow Cytometry is applied to determine the phenotypic characterization of senescent T lymphocytes; intracellular staining is applied to determine the function of senescent T cells; Enzyme-Linked Immunosorbent Assay (ELISA) is employed to test the telomerase concentration. The RNA-seq analysis of gene expression associated with T cell senescence. RESULTS: The middle-aged group had the highest proportion of senescent T cells. We found that metformin could decrease the number of CD8 + senescent T cells. Metformin affects the secretion of SASP, inhibiting the secretion of IFN-γ in CD8 + senescent T cells. Furthermore, metformin treatment restrained the production of the proinflammatory cytokine IL-6 in lymphocytes. Metformin had minimal effects on Granzyme B secretion in senescent T cells, but it promoted the production of TNF-α in senescent T cells. Additionally, metformin increased the concentration of telomerase and the frequency of undifferentiated T cells. The results of RNA-seq showed that metformin promoted the expression of genes related to stemness and telomerase activity, while inhibiting the expression of DNA damage-associated genes. CONCLUSION: Our findings reveal that metformin could inhibit T cell senescence in terms of cell number, effector function, telomerase content and gene expression in middle-aged individuals, which may serve as a promising approach for preventing age-related diseases in this population.

[Characteristics and Influencing Factors of Greenhouse Fluxes from Urban Lawn].

As an important component of urban green spaces, greenhouse gas uptake or emissions from urban lawns cannot be ignored. However, studies of greenhouse gas fluxes from subtropical urban lawns are relatively sparse. The static chamber-gas chromatography method was applied to monitor the ground-air exchange fluxes of various greenhouse gases(CO2, CH4, N2O, and CO) in typical urban lawns of Hangzhou City. Our results showed that the average fluxes had significant seasonal cycles but ambiguous diurnal variations. The grassland and the soil(naked soil without vegetation coverage) acted as sources of atmospheric N2O, with the average fluxes of (0.66±0.17) and (0.58±0.20) µg·(m2·min)-1 for N2O, respectively; however, they were also sinks of CH4 and CO, with the average fluxes of (-0.21±0.078) and (-0.26±0.10) µg·(m2·min)-1 for CH4 and (-6.36±1.28) and (-6.55±1.69) µg·(m2·min)-1 for CO, respectively. The average CO2emission fluxes of urban grassland and soil were(5.28±0.75) and (4.83±0.91) mg·(m2·min)-1, respectively. The correlation analysis indicated that the CO2 and N2O fluxes of grassland and soil were negatively correlated with precipitation, whereas the CH4 and CO fluxes were positively correlated with it. There was no significant correlation between grassland CH4 fluxes and soil temperature, and N2O fluxes had a significant negative correlation with soil temperature; the other greenhouse gas fluxes showed a significant positive correlation with soil temperature. In addition, the seasonal variation in CO2 (R2=0.371 and 0.314) and N2O(R2=0.371 and 0.284) fluxes from both grassland and soil was affected by precipitation, whereas CO fluxes (R2=0.290 and 0.234) were mainly driven by soil temperature compared with the other greenhouse gases.

A Fluorescent Chemosensor for Detection pH and Cu2+ Ion Base on 7-((2-Aminoethyl)amino)-5-Bromo-6-Hydroxy-1-Methylquinolin-1-ium-3-Sulfonate: Experimental and DFT Calculation.

A quinoline derivative 7-((2-aminoethyl)amino)-5-bromo-6-hydroxy-1-methylquinolin-1-ium-3-sulfonate (QEt) containing quinoline ring, -[Formula: see text] sulfonate, -OH phenol, and amine groups was synthesized and studied luminescence properties. The aqueous solutions QEt 10µM change luminescence color from green (λem = 490 nm) to yellow (λem = 563 nm) as increasing pH and the intensity at a peak of 563 nm is linearly proportional with pH value in the range of pH = 3,0-4,0. The QEt solution can be used as a chemosensor for Cu2+ with an LOD value at 0.66 [Formula: see text]. Along with the experiment, the structure, absorption and emission spectra of QEt have been investigated by TD-DFT calculation. The result shows that the absorption band centered at 420 nm is due to the electron transition from HOMO to LUMO (π → π*). The results also help to assign emission band centered at 490 nm is due to the S1 → S0 transition (LUMO → HOMO singlet transition), at 563 nm is due to the T1 → S0 transition (LUMO → HOMO triplet transition). The dependence of the relative intensity of each emission peak on pH, which is experimentally recorded, is explained based on the results of theoretical TD-DFT calculation.

Unusual reaction of (E)-2-[(benzo[d]thia-zol-2-yl-imino)-meth-yl]-5-(di-ethyl-amino)-phenol with tri-phenyl-borane: crystal structures and optical properties.

The mol-ecular and crystal structure of (E)-2-[(benzo[d]thia-zol-2-yl-imino)-meth-yl]-5-(di-ethyl-amino)-phenol (C18H19N3O2S, Et2N-Bz) and its unexpected reaction product with tri-phenyl-borane, 2,2-diphenyl-1,3-dioxa-2-borata-1,2-di-hydro-naphthalene [systematic name: N,N-diethyl-2,2-diphenyl-2H-1,3λ3,2λ4-ben-zodioxaborinin-7-amine, C23H24BNO2, (I)] are described. For Et2N-Bz, the hydroxyl group is involved in an intra-molecular hydrogen bond with the imino nitro-gen atom and the C=N bond displays an E configuration. The crystal packing is characterized by layers of inversion dimers parallel to the (10) plane and chains of mol-ecule in the a-axis direction formed through C-H⋯O inter-actions. Complex (I) crystallizes with two mol-ecules (A and B) in the asymmetric unit, which differ in the orientation of the ethyl groups. The 1,3-dioxa-2-borata-1,2,3,4-tetra-hydro-naphthalene ring displays a slight envelope conformation with the boron atom as the flap. In the crystal packing, chains of alternating A and B mol-ecules formed by C-H⋯O hydrogen bonds run in the b-axis direction. The UV-vis absorption and emission properties of the compounds are discussed and their aggregation-induced emission properties are further investigated.

Rotationplasty type BIIIb as an effective alternative to limb salvage procedure in adults: Two case reports.

BACKGROUND: Rotationplasty is often performed for malignant tumors, but type BIIIb rotationplasty is rarely reported, and there needs to be more evidence of the procedure and treatment. The purpose of this case study was to report a new direction in the use of type BIIIb rotationplasty in treating patients with limb salvage and long-term non-healing infections. CASE SUMMARY: Case 1: A 47-year-old man underwent radiotherapy for hemangioendothelioma in his left thigh, resulting in a femoral fracture. Despite the use of plates, intramedullary nailing, and external fixators, the femoral bone failed to unite due to infectious nonunion. Multiple operations were unable to control the infection, leaving the patient immobile. We performed a modified tibia-pelvic-constrained hip rotationplasty, utilizing a constrained prosthetic hip between the tibia and pelvis following a femur resection. Two years post-surgery, the patient was able to walk with the prosthetic device without any signs of recurring infection. The corresponding functional scores were 72 points for the Musculoskeletal Tumor Society (MSTS), 53 for the Functional Mobility Assessment (FMA), 93 for the Toronto Extremity Salvage Score (TESS), and 56 for the MOS 36-item short form health survey (SF-36). Case 2: A 59-year-old woman presented with liposarcoma in her left thigh. Magnetic resonance imaging revealed tumors in the medial, anterior, and posterior femur muscles, encircling the femoral vessels and nerves. Fortunately, there were no symptoms of sciatic dysfunction, and the tumor had not invaded the sciatic nucleus. After one year of follow-up, the patient expressed satisfaction with limb preservation post-type BIIIb rotationplasty. The corresponding functional scores were 63 points for the MSTS, 47 for the FMA, 88 for the TESS, and 52 for the SF-36. CONCLUSION: Our study suggests that type BIIIb rotationplasty may be an alternative to amputation in patients with incurable infections. For malignant tumors of the lower extremities without invasion of the sciatic nerve, type BIIIb rotationplasty remains an excellent alternative to amputation. This surgical method may prevent amputation, improve functional outcomes, and facilitate biological reconstruction.

[Response of vegetation to terrestrial water storage in Southwest China]. / 西南地区植被对陆地水储量的响应.

To explore the responses of vegetation growth to change in terrestrial water storage in Southwest China, we analyzed the change trend and relationship between vegetation and terrestrial water storage anomaly (TWSA) in Southwest China from January 2003 to December 2021 by using TWSA data of Gravity Recovery and Climate Experi-ment (GRACE) satellite and normalized differential vegetation index (NDVI) data. The results showed that NDVI in Southwest China during the study period showed an overall upward trend. Meanwhile, TWSA showed a significant downward trend in central and southern Tibet, and a significant upward trend in northwest Tibet and southeast region of Southwest China. Results of Pearson correlation analysis showed that there were significant spatial differences in responses of NDVI to TWSA changes in Southwest China. NDVI had a significant negative response to TWSA changes in most regions of Tibet, but a significant positive response to TWSA changes in most regions of southeast region of Southwest China. Such differences were driven by climate change and topography.

Risk factors of portal vein system thrombosis after splenectomy: a meta-analysis.

BACKGROUND: The primary aim of the present study was to explore risk factors for portal vein system thrombosis following splenectomy. METHODS: A systematic search of PubMed, Embase and Cochrane libraries was conducted to identify original studies that fulfilled the inclusion criteria. Raw data on potential risk factors for portal vein system thrombosis after splenectomy were extracted for meta-analysis. Subsequently, a sensitivity analysis was conducted to verify the stability of the results. RESULTS: Eighteen studies with 626 thrombosis events from 1807 splenectomy met the inclusion criteria. Larger spleen volume (SMD 0.44, P = 0.000), broader splenic vein diameter (WMD 2.30, P = 0.000), broader portal vein diameter (WMD 2.08, P = 0.000), a lower velocity of portal blood flow (WMD -0.91, P = 0.001), decreased platelet count (WMD -5.14, P = 0.007), decreased white blood cell (WMD -0.40, P = 0.027), decreased haemoglobin (WMD -9.14, P = 0.002), ascites (OR 1.81, P = 0.003) and bleeding history before surgery (OR 1.88, P = 0.002) were identified to be factors that exacerbated the risk of portal vein system thrombosis after splenectomy. Sex, age, preoperative prothrombin time, postoperative platelet count, postoperative D-dimer, operation time and intraoperative blood loss, did not increase the risk of thrombosis. CONCLUSION: Larger spleen volume, broader splenic vein diameter, broader portal vein diameter, a lower velocity of portal blood flow, ascites, bleeding history before surgery, decreased platelet count, white blood cell and haemoglobin may increase the risk of portal vein system thrombosis.

Clinical implications of micro lymph node metastasis for patients with gastric cancer.

BACKGROUND: Lymph node size is considered as a criterion for possible lymph node metastasis in imageology. Micro lymph nodes are easily overlooked by surgeons and pathologists. This study investigated the influencing factors and prognosis of micro lymph node metastasis in gastric cancer. METHODS: 191 eligible gastric cancer patients who underwent D2 lymphadenectomy from June 2016 to June 2017 in the Third Surgery Department at the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Specimens were resected en bloc and the postoperative retrieval of micro lymph nodes was carried out by the operating surgeon for each lymph node station. Micro lymph nodes were submitted for pathological examination separately. According to the results of pathological results, patients were divided into the "micro-LNM (micro lymph node metastasis)" group (N = 85) and the "non micro-LNM" group (N = 106). RESULTS: The total number of lymph nodes retrieved was 10,954, of which 2998 (27.37%) were micro lymph nodes. A total of 85 (44.50%) gastric cancer patients had been proven to have micro lymph node metastasis. The mean number of micro lymph nodes retrieved was 15.7. The rate of micro lymph node metastasis was 8.1% (242/2998). Undifferentiated carcinoma (90.6% vs. 56.6%, P = 0.034) and more advanced Pathological N category (P < 0.001) were significantly related to micro lymph node metastasis. The patients with micro lymph node metastasis had a poor prognosis (HR for OS of 2.199, 95% CI = 1.335-3.622, P = 0.002). For the stage III patients, micro lymph node metastasis was associated with shorter 5-year OS (15.6% vs. 43.6%, P = 0.0004). CONCLUSIONS: Micro lymph node metastasis is an independent risk factor for poor prognosis in gastric cancer patients. Micro lymph node metastasis appears to be a supplement to N category in order to obtain more accurate pathological staging.

Important Roles and Formation of Atmospheric Organosulfates in Marine Organic Aerosols: Influence of Phytoplankton Emissions and Anthropogenic Pollutants.

Organosulfates (OSs) could be potentially important compounds in marine organic aerosols, while their formation in marine atmospheres is far from clear due to a lack of cruise observations. In this work, shipboard atmospheric observations were conducted over the Yellow Sea and Bohai Sea to investigate the abundance and formation of biogenic isoprene/monoterpene-OSs in marine aerosols. The quantified OSs and NOSs accounted for 0.04-6.9% of marine organic aerosols and were 0.07-2.2% of the non-sea-salt (nss) sulfate in terms of sulfur content. Isoprene-related (nitrooxy-)OSs occupied 27-87% of the total quantified OSs, following the abundance order of summer > autumn > spring or winter. This order was driven by the marine phytoplankton biomass and sea surface temperature (SST), which controlled the seawater and atmospheric isoprene concentration levels. Under the severe impacts of anthropogenic pollutants from the East Asia continent in winter, monoterpene nitrooxy-OSs, generated with NOx involved in, increased to 34.4 ± 35.5 ng/m3 and contributed 68% of the quantified (nitrooxy-)OSs. Our results highlight the notable roles of biogenic OSs in marine organic aerosols over regions with high biological activity and high SST. The formation of biogenic OSs and their roles in altering marine aerosol properties calls for elaboration through cruise observations in different marine environments.

Contrasting effects of different light regimes on the photoreactivities of allochthonous and autochthonous chromophoric dissolved organic matter.

Chromophoric dissolved organic matter (CDOM) plays an important role in ultraviolet (UV) light absorption in the ocean. CDOM is known to originate from either an allochthonous or autochthonous source and has varying compositions and levels of reactivity; however, the effects of individual radiation treatments and the combined effects of UVA and UVB on allochthonous and autochthonous CDOM remain poorly understood. Thus, here, we measured changes in the common optical properties of CDOM collected from China's marginal seas and the Northwest Pacific, using full-spectrum, UVA (315-400 nm), and UVB (280-315 nm) irradiation to induce photodegradation over the same time period (60 h). Excitation-emission matrices (EEMs) combined with parallel factor analysis (PARAFAC) identified four components: marine humic-like C1, terrestrial humic-like C2, soil fulvic-like C3, and tryptophan-like C4. Although the behaviours of these components during full-spectrum irradiation exhibited similar decreasing tendencies, three components (C1, C3, and C4) underwent direct photodegradation under UVB exposure, whereas C2 was more susceptible to UVA degradation. The diverse photoreactivities of the source-dependent components to different light treatments led to differing photochemical behaviours of other optical indices [aCDOM(355), aCDOM(254), SR, HIX, and BIX]. The results indicate that irradiation preferentially reduced the high humification degree or humic substance content of allochthonous DOM, and promoted the transformation from the allochthonous humic DOM components to recently produced components. Although values for the samples from different sources overlapped frequently, principal component analysis (PCA) indicated that the overall optical signatures could be linked to the original CDOM source features. The degradation of CDOM humification, aromaticity, molecular weight, and autochthonous fractions under exposure can drive the CDOM biogeochemical cycle in marine environments. These findings can aid in a better understanding of the effects of different combinations of light treatments and CDOM characteristics on CDOM photochemical processes.

K2CO3/18-Crown-6-Catalyzed Selective H/D Exchange of Heteroarenes with Bromide as a Removable Directing Group.

The K2CO3/18-crown-6-catalyzed H/D exchange of heretoarenes in high atom % deuterium incorporation is disclosed. The use of a weak base as a catalyst leads to excellent site selectivity and broad functional group tolerance. Control experiments indicated that the use of bromide, which enhances the adjacent C-H bond reactivity, as a removable directing group is essential. Moreover, conversion of bromide to other functional groups is also performed to construct other useful deuterated compounds.

Mitochondrial stress induces hepatic stellate cell activation in response to the ATF4/TRIB3 pathway stimulation.

BACKGROUND: The activation of hepatic stellate cells (HSCs) is the key step in the pathogenesis of liver fibrosis, which directly leads to fibrotic pathological changes in the hepatic tissue. Mitochondrial stress exacerbates inflammatory diseases by inducing pathogenic shifts in normal cells. However, the role of mitochondrial stress in HSC activation remains to be elucidated.  METHODS: We analyzed the effect of mitochondrial stress on HSC activation. An in vivo hepatic fibrosis model was established by intraperitoneal injection of 40% carbon tetrachloride (CCl4) for 12 weeks. Additionally, using in vitro approach, HSC-T6 cells were treated with 10 ng/mL platelet-derived growth factor-BB (PDGF-BB) for 24 h. RESULTS: Transcriptional activator 4 (ATF4) is highly expressed in fibrotic liver tissue samples and activated HSCs. We found that AAV8-shRNA-Atf4 alleviated liver fibrosis in rats. ATF4 promoted the activation of HSCs, which was induced by mitochondrial stress. The mechanisms involved ATF4 binding to a specific region of the tribble homologue 3 (TRIB3) promoter. Further, TRIB3 promoted HSCs activation mediated by mitochondrial stress. CONCLUSIONS: ATF4 induces mitochondrial stress by upregulating TRIB3, leading to the activation of HSCs. Therefore, the inhibition of ATF4 during mitochondrial stress may be a promising therapeutic target for liver fibrosis.

Poly(I:C)-induced maternal immune activation causes elevated self-grooming in male rat offspring: Involvement of abnormal postpartum static nursing in dam.

Introduction: Maternal immune activation (MIA) is closely related to the onset of autism-like behaviors in offspring, but the mechanism remains unclear. Maternal behaviors can influence offspring's development and behaviors, as indicated in both human and animal studies. We hypothesized that abnormal maternal behaviors in MIA dams might be other factors leading to delayed development and abnormal behaviors in offspring. Methods: To verify our hypothesis, we analyzed poly(I:C)-induced MIA dam's postpartum maternal behavior and serum levels of several hormones related to maternal behavior. Pup's developmental milestones and early social communication were recorded and evaluated in infancy. Other behavioral tests, including three-chamber test, self-grooming test, open field test, novel object recognition test, rotarod test and maximum grip test, were performed in adolescence of pups. Results: Our results showed that MIA dams exhibit abnormal static nursing behavior but normal basic care and dynamic nursing behavior. The serum levels of testosterone and arginine vasopressin in MIA dams were significantly reduced compared with control dams. The developmental milestones, including pinna detachment, incisor eruption and eye opening, were significantly delayed in MIA offspring compared with control offspring, while the weight and early social communication showed no significant differences between the two groups. Behavioral tests performed in adolescence showed that only male MIA offspring display elevated self-grooming behaviors and reduced maximum grip. Discussion: In conclusion, MIA dams display abnormal postpartum static nursing behavior concomitantly with reduced serum levels of testosterone and arginine vasopressin, possibly involving in the pathogenesis of delayed development and elevated self-grooming in male offspring. These findings hint that improving dam's postpartum maternal behavior might be a potential regime to counteract delayed development and elevated self-grooming in male MIA offspring.

CM3-SII polysaccharide obtained from Cordyceps militaris ameliorates hyperlipidemia in heterozygous LDLR-deficient hamsters by modulating gut microbiota and NPC1L1 and PPARα levels.

Accumulating evidence has demonstrated that polysaccharides derived from edible fungi have lipid-lowering effects in mice. However, the lipid metabolism mechanisms in mice and humans are different. We have previously elucidated the structural characteristics of the alkali-extracted polysaccharide CM3-SII obtained from Cordyceps militaris. This study aimed to investigate whether CM3-SII could ameliorate hyperlipidemia in a heterozygous low-density lipoprotein receptor (LDLR)-deficient hamster model of hyperlipidemia. Our data demonstrated that CM3-SII significantly decreased total plasma cholesterol, non-high-density lipoprotein cholesterol, and triglyceride levels in heterozygous LDLR-deficient hamsters. Unlike ezetimibe, CM3-SII could enhance the concentration of plasma apolipoprotein A1 and the expression of liver X receptor α/ATP-binding cassette transporter G8 mRNA pathway and suppress the expression of Niemann-Pick C1-like 1, which help to reduce cholesterol levels further. Moreover, the results of molecular docking analysis demonstrated that CM3-SII could directly bind to Niemann-Pick C1-like 1 with high affinity. The triglyceride-lowering mechanisms of CM3-SII were related to its downregulation of sterol regulatory element-binding protein 1c and upregulation of peroxisome proliferator-activated receptor α. Importantly, CM3-SII increased the abundance of Actinobacteria and Faecalibaculum and the ratio of Bacteroidetes/Firmicutes. Thus, CM3-SII attenuated hyperlipidemia by modulating the expression of multiple molecules involved in lipid metabolism and the gut microbiota.

Chinese Expert Consensus on the Use of Biologics in Patients with Chronic Rhinosinusitis (2022, Zhuhai).

BACKGROUND: Chronic rhinosinusitis (CRS) is a common inflammatory disease in otolaryngology, mainly manifested as nasal congestion, nasal discharge, facial pain/pressure, and smell disorder. CRS with nasal polyps (CRSwNP), an important phenotype of CRS, has a high recurrence rate even after receiving corticosteroids and/or functional endoscopic sinus surgery. In recent years, clinicians have focused on the application of biological agents in CRSwNP. However, it has not reached a consensus on the timing and selection of biologics for the treatment of CRS so far. SUMMARY: We reviewed the previous studies of biologics in CRS and summarized the indications, contraindications, efficacy assessment, prognosis, and adverse effects of biologics. Also, we evaluated the treatment response and adverse reactions of dupilumab, omalizumab, and mepolizumab in the management of CRS and made recommendations. KEY MESSAGES: Dupilumab, omalizumab, and mepolizumab have been approved for the treatment of CRSwNP by the US Food and Drug Administration. Type 2 and eosinophilic inflammation, need for systemic steroids or contraindication to systemic steroids, significantly impaired quality of life, anosmia, and comorbid asthma are required for the use of biologics. Based on current evidence, dupilumab has the prominent advantage in improving quality of life and reducing the risk of comorbid asthma in CRSwNP among the approved monoclonal antibodies. Most patients tolerate biological agents well in general with few major or severe adverse effects. Biologics have provided more options for severe uncontrolled CRSwNP patients or patients who refuse to have surgery. In the future, more novel biologics will be assessed in high-quality clinical trials and applied clinically.