Lubricin-Inspired Nanozymes Reconstruct Cartilage Lubrication System with an "In-Out" Strategy.

Lubricin, secreted primarily by chondrocytes, plays a critical role in maintaining the function of the cartilage lubrication system. However, both external factors such as friction and internal factors like oxidative stress can disrupt this system, leading to osteoarthritis. Inspired by lubricin, a lubricating nanozyme, that is, Poly-2-acrylamide-2-methylpropanesulfonic acid sodium salt-grafted aminofullerene, is developed to restore the cartilage lubrication system using an "In-Out" strategy. The "Out" aspect involves reducing friction through a combination of hydration lubrication and ball-bearing lubrication. Simultaneously, the "In" aspect aims to mitigate oxidative stress by reducing free radical, increasing autophagy, and improving the mitochondrial respiratory chain. This results in reduced chondrocyte senescence and increased lubricin production, enhancing the natural lubrication ability of cartilage. Transcriptome sequencing and Western blot results demonstrate that it enhances the functionality of mitochondrial respiratory chain complexes I, III, and V, thereby improving mitochondrial function in chondrocytes. In vitro and in vivo experiments show that the lubricating nanozymes reduce cartilage wear, improve chondrocyte senescence, and mitigate oxidative stress damage, thereby mitigating the progression of osteoarthritis. These findings provide novel insights into treating diseases associated with oxidative stress and frictional damage, such as osteoarthritis, and set the stage for future research and development of therapeutic interventions.

Out-of-Plane Ferroelectricity in Two-Dimensional 1T‴-MoS2 Above Room Temperature.

Two-dimensional (2D) molybdenum disulfide (MoS2), one of the most extensively studied van der Waals (vdW) materials, is a significant candidate for electronic materials in the post-Moore era. MoS2 exhibits various phases, among which the 1T‴ phase possesses noncentrosymmetry. 1T‴-MoS2 was theoretically predicted to be ferroelectric a decade ago, but this has not been experimentally confirmed until now. Here, we have prepared high-purity 2D 1T‴-MoS2 crystals and experimentally confirmed the room-temperature out-of-plane ferroelectricity. The noncentrosymmetric crystal structure in 2D 1T‴-MoS2 was convinced by atomically resolved transmission electron microscopic imaging and second harmonic generation (SHG) measurements. Further, the ferroelectric polarization states in 2D 1T‴-MoS2 can be switched using piezoresponse force microscopy (PFM) and electrical gating in field-effect transistors (FETs). The ferroelectric-to-paraelectric transition temperature is measured to be about 350 K. Theoretical calculations have revealed that the ferroelectricity of 2D 1T‴-MoS2 originates from the intralayer charge transfer of S atoms within the layer. The discovery of intrinsic ferroelectricity in the 1T‴ phase of MoS2 further enriches the properties of this important vdW material, providing more possibilities for its application in the field of next-generation electronic devices.

Effects of omalizumab on lung function in patients with moderate-to-severe allergic asthma: a systematic review and meta-analysis.

BACKGROUND: With the rise of targeted treatments for asthma, treatment with omalizumab is a new option. OBJECTIVES: To assess the improvement of pulmonary function with additional omalizumab treatment in patients (⩾6 years old) with moderate-to-severe allergic asthma. DATA SOURCES AND METHODS: Observational studies of randomized controlled trials of add-on omalizumab for the treatment of patients with moderate-to-severe allergic asthma, published from the establishment till August 2022, were retrieved from WAN FANG DATA, PubMed, CNKI, Embase, Cochrane, and Web of Science databases. Data extraction and quality evaluation were performed on the literature that met the inclusion criteria, using RevMan 5.3 to analyze the data. RESULTS: A total of 11 randomized controlled clinical trials were included, involving a total of 3578 patients with asthma, 1856 patients in the omalizumab group, and 1722 patients in the control group. The improvement in Forced expiratory volume in 1 s as a percentage of predicted normal and Forced expiratory volume in 1 s was more pronounced in the omalizumab-treated group [MD = 3.91, 95% confidence interval (CI): 1.89-5.94, p = 0.0002; MD = 0.09, 95% CI: 0.05-0.13, p < 0.0001], while the improvement in Morning Peak expiratory flow rate was not statistically different between the two groups (MD = 3.64, 95% CI: -22.17-29.45, p = 0.78). CONCLUSION: Additional omalizumab treatment showed some improvement in lung function in patients with moderate-to-severe asthma. TRIAL REGISTRATION: PROSPERO ID:CRD42022378498.

Improvement of lung function in asthmatic patients with additional omalizumabIn this paper, by screening clinical trials related to the treatment of patients with moderate and severe asthma with omalizumab plus, we extracted indicators related to lung function for meta-analysis and found that in patients with moderate to severe asthma, the addition of omalizumab can improve lung function to a certain extent and delay the worsening of lung function.

Synthesis of component-controllable monolayer MoxW(1-x)S2ySe2(1-y) alloys with continuously tunable band gap and carrier type.

Alloying can effectively modify electronic and optical properties of two-dimensional (2D) transition metal dichalcogenides (TMDs). However, efficient and simple methods to synthesize atomically thin TMD alloys need to be further developed. In this study, we synthesized 25 monolayer MoxW(1-x)S2ySe2(1-y) alloys by using a new liquid phase edge epitaxy (LPEE) growth method with high controllability. This straightforward approach can be used to obtain monolayer materials and operates on a self-limiting growth mechanism. The process allows the liquid solution to come into contact with the two-dimensional grains only at their edges, resulting in epitaxy confined only along the in-plane direction, which produces exclusively monolayer epitaxy. By controlling the weight ratio of MoS2/WSe2 (MoSe2/WS2), 25 monolayer MoxW(1-x)S2ySe2(1-y) alloys with different atomic ratios can be obtained on sapphire substrates, with band gap ranging from WS2 (1.55 eV) to MoSe2 (1.99 eV) and a continuously broad spectrum ranging from 623 nm to 800 nm. By adjusting the alloy composition, the carrier type and carrier mobility of alloy-based field-effect transistors can be modulated. In particular, the adjustable conductivity of MoxW(1-x)S2ySe2(1-y) alloys from n-type to bipolar type is achieved for the first time. This general synthetic strategy provides a foundation for the development of monolayer TMD alloys with multiple components and various 2D materials.

Prevalence and associations of sarcopenia, obesity and sarcopenic obesity in end-stage knee osteoarthritis patients.

OBJECTIVE: To identify the prevalence of obesity, sarcopenia, sarcopenic obesity in end-stage knee osteoarthritis (KOA) patients and analyze influences of obesity and sarcopenia in the progression of KOA. METHODS: A cross-sectional study was carried out among end-stage KOA patients who consecutively admitted to Orthopedic Department for TKA. We suppose that the level of decreased physical activities would be influenced by unilateral or bilateral KOA. Patient information, albumin, hemoglobin, pace, step frequency, number of comorbid conditions were collected. Bioelectrical impedance analyzer was used to analyze body composition. Obesity, sarcopenia, sarcopenic obesity rate were analyzed with accepted diagnosis criteria. Correlations between body mass index (BMI) or age and fat mass (FM), appendicular skeletal muscle mass (ASM) were analyzed. RESULTS: 138 patients (male 30, female 108) in southwest of China including 67 patients with unilateral KOA and 71 patients with bilateral KOA were analyzed. No statistic difference was found in mean albumin, prealbumin and hematocrystallin, body composition values and number of comorbid conditions. We found that BMI was positively correlated with FM (Male: R2 = 0.7177, p < 0.0001, Female: R2 = 0.8898, p < 0.0001), ASM (Male: R2 = 0.2640, p = 0.0037, Female: R2 = 0.2102, p < 0.0001), FM index (FMI) (Male: R2 = 0.6778, p < 0.0001, Female: R2 = 0.8801, p < 0.0001), and ASM index (ASMI) (Male: R2 = 0.3600, p = 0.0005, Female: R2 = 0.4208, p < 0.0001) in end-stage KOA patients. However, age was not obviously correlated with FM or FMI (Male: FM, R2 = 0.006911, p = 0.3924; FMI, R2 = 0.7554, p = 0.0009196; Female: FM, R2 = 0.001548, p = 0.8412; FMI, R2 = 0.002776, p = 0.7822). And slightly negatively correlated with ASM (Male: R2 = 0.05613, p = 0.0136, Female: R2 = 0.01327, p = 0.5433) and ASMI (Male: R2 = 0.02982, p = 0.3615; Female: R2 = 0.03696, p = 0.0462). The prevalence of obesity, sarcopenia and obesity sarcopenia differs according to different diagnosis criteria. No difference in the occurrence rate of obesity was found between bilateral KOA and unilateral KOA patients, and occurrence rates of sarcopenia and sarcopenic obesity were statistically higher in bilateral KOA than that in unilateral KOA patients. CONCLUSIONS: Obesity, sarcopenia and sarcopenic obesity are highly prevalent in end-stage KOA patients, sarcopenic obesity are more prevalent in bilateral KOA patients than that in unilateral KOA patients.

Osteoarthritis: The Most Common Joint Disease and Outcome of Sports Injury.

Osteoarthritis (OA) is the most common joint disease and affects an estimated 240 million people worldwide [...].

LncRNA H19 mediates BMP9-induced angiogenesis in mesenchymal stem cells by promoting the p53-Notch1 angiogenic signaling axis.

BMP9 mediated osteogenic differentiation mechanisms of MSCs were widely explored, however, mechanisms of BMP9-induced angiogenesis still need to be clarified. We previously characterized that Notch1 promoted BMP9-induced osteogenesis-angiogenesis coupling process in mesenchymal stem cells (MSCs). Here, we explored the underlying mechanisms of lncRNA H19 (H19) mediated regulation of BMP9-induced angiogenesis through activating Notch1 signaling. We demonstrated that basal expression level of H19 was high in MSCs, and silencing H19 attenuates BMP9-induced osteogenesis and angiogenesis of MSCs both in vitro and in vivo. Meanwhile, we identified that BMP9-induced production of CD31+ cells was indispensable for BMP9-induced bone formation, and silencing H19 dramatically blocked BMP9-induced production of CD31+ cells. In addition, we found that down-regulation of H19 inhibited BMP9 mediated blood vessel formation and followed subsequent bone formation in vivo. Mechanistically, we clarified that H19 promoted p53 phosphorylation by direct interacting and phosphorylating binding, and phosphorylated p53 potentiated Notch1 expression and activation of Notch1 targeting genes by binding on the promoter area of Notch1 gene. These findings suggested that H19 regulated BMP9-induced angiogenesis of MSCs by promoting the p53-Notch1 angiogenic signaling axis.

Long noncoding RNA (lncRNA) H19: An essential developmental regulator with expanding roles in cancer, stem cell differentiation, and metabolic diseases.

Recent advances in deep sequencing technologies have revealed that, while less than 2% of the human genome is transcribed into mRNA for protein synthesis, over 80% of the genome is transcribed, leading to the production of large amounts of noncoding RNAs (ncRNAs). It has been shown that ncRNAs, especially long non-coding RNAs (lncRNAs), may play crucial regulatory roles in gene expression. As one of the first isolated and reported lncRNAs, H19 has gained much attention due to its essential roles in regulating many physiological and/or pathological processes including embryogenesis, development, tumorigenesis, osteogenesis, and metabolism. Mechanistically, H19 mediates diverse regulatory functions by serving as competing endogenous RNAs (CeRNAs), Igf2/H19 imprinted tandem gene, modular scaffold, cooperating with H19 antisense, and acting directly with other mRNAs or lncRNAs. Here, we summarized the current understanding of H19 in embryogenesis and development, cancer development and progression, mesenchymal stem cell lineage-specific differentiation, and metabolic diseases. We discussed the potential regulatory mechanisms underlying H19's functions in those processes although more in-depth studies are warranted to delineate the exact molecular, cellular, epigenetic, and genomic regulatory mechanisms underlying the physiological and pathological roles of H19. Ultimately, these lines of investigation may lead to the development of novel therapeutics for human diseases by exploiting H19 functions.

Corrigendum to "Sox9 augments BMP2-induced chondrogenic differentiation by downregulating Smad7 in mesenchymal stem cells (MSCs)" [Genes & Diseases 4 (2017) 229-239].

[This corrects the article DOI: 10.1016/j.gendis.2017.10.004.].

Van der Waals Ferroelectric Semiconductor Field Effect Transistor for In-Memory Computing.

In-memory computing is a highly efficient approach for breaking the bottleneck of von Neumann architectures, i.e., reducing redundant latency and energy consumption during the data transfer between the physically separated memory and processing units. Herein we have designed a in-memory computing device, a van der Waals ferroelectric semiconductor (InSe) based metal-oxide-ferroelectric semiconductor field-effect transistor (MOfeS-FET). This MOfeS-FET integrates memory and logic functions in the same material, in which the out-of-plane (OOP) ferroelectric polarization in InSe is used for data storage and the semiconducting property is used for the logic computation. The MOfeS-FET shows a long retention time with high on/off ratios (>106), high program/erase (P/E) ratios (103), and stable cyclic endurance. Moreover, inverter, programmable NAND, and NOR Boolean logic operations with nonvolatile storage of the results have all been demonstrated using our approach. These findings highlight the potential of van der Waals ferroelectric semiconductor-based MOfeS-FETs in the in-memory computing and their potential of achieving size scaling beyond Moore's law.

AMPK activator decelerates osteoarthritis development by inhibition of ß-catenin signaling in chondrocytes.

Background: Osteoarthritis (OA) is a common degenerative joint disease with significant negative impact on the quality of life. It has been reported that abnormal upregulation of ß-catenin signaling could lead to OA development; however, the upstream regulatory mechanisms of ß-catenin signaling have not been determined. Methods: Primary rat chondrocytes and ATDC5 chondrocyte cell line were stimulated with AKT2 and treated with or without metformin, an adenosine 5'-monophosphate-activated protein kinase (AMPK) activator. Westerrn blot analysis, luciferase reporter assay and immunofluorescent (IF) staining were performed to examine changes in ß-cateninS552 phosphorylation and ß-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes. Results: We found that metformin inhibited ß-cateninS552 phosphorylation in ATDC5 cells and in primary chondrocytes in a time-dependent manner. Metformin inhibited ß-catenin nuclear translocation and ß-catenin reporter activity. In addition, metformin also attenuated the expression of ß-catenin downstream target genes. We also demonstrated that metformin inhibited ß-cateninS552 phosphorylation in articular cartilage in mice. Conclusion: These findings suggest that metformin may exert its chondro-protective effect at least in part through the inhibition of ß-catenin signaling in chondrocytes. The translational potential of this article: This study demonstrated the interaction between AMPK and ß-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.

PI3K-Akt signaling regulates BMP2-induced osteogenic differentiation of mesenchymal stem cells (MSCs): A transcriptomic landscape analysis.

Bone morphogenetic protein 2 (BMP2) effectively induced mesenchymal stem cells (MSCs) osteogenic differentiation hold great potential for bone tissue engineering. However, a global mechanistic view of BMP2-induced osteogenic differentiation of MSCs remains to be fully elucidated. Here, human umbilical cord-derived MSCs (UC-MSCs) were induced with BMP2, three days and five days later, total RNA were extracted and subjected to RNA-sequencing (RNA-Seq) followed with bioinformatic analysis. Osteogenic differentiation abilities were evaluated with Alkaline phosphatase (ALP) staining and osteogenic differentiation marker expression at both mRNA and protein levels. We identified that adenoviral vectors effectively transduced in UC-MSCs and expressed BMP2 in high efficiency. Both on day 3 and day 5, differentially expressed genes (DEGs) were highly enriched in PI3K-Akt signaling pathway. As for the common DEGs among total BMP2 group vs control group, BMP2 (day 3) versus control (day 3) and BMP2 (day 5) versus control (day 5), there were 105 DGEs and highly enriched in PI3K-Akt signaling pathway. Finally, we found that PI3K-Akt signaling inhibitor dramatically inhibited BMP2-iduced osteogenic differentiation of UC-MSCs. We firstly identified that PI3K-Akt signaling pathway plays a pivotal role in BMP2-induced osteogenic differentiation of MSCs, which may apply a new perspective for BMP2 based bone tissue engineering.

A retrospective study of deltoid ligament repair versus syndesmotic fixation in lateral malleolus fracture combined with both deltoid ligament injury and inferior tibiofibular syndesmotic disruption.

Background: To compare clinical outcomes of deltoid ligament repair versus syndesmotic fixation in lateral malleolus fracture combined with both deltoid ligament injury and inferior tibiofibular syndesmotic disruption. Methods: Patients diagnosed with lateral malleolus fracture combined with both deltoid ligament injury and inferior tibiofibular syndesmotic disruption who received open reduction and internal fixation (ORIF) were retrospectively reviewed. Seventy-eight patients were enrolled into the study, including 40 patients treated with lateral malleolus fracture ORIF and trans-syndesmotic fixation, and 38 patients treated with lateral malleolus fracture ORIF and deltoid ligament repair. Basic information and pre- and postoperative radiological materials were reviewed. Visual analog pain scale (VAS) score, Olerud-Molander score, and the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale were used for evaluating pain control and functional recovery postoperatively at different time points. Results: No complication was reported in both groups. In the trans-syndesmotic fixation group, all patients received syndesmotic screw removal 6-8 weeks postoperatively. The Olerud-Molander score and AOFAS Ankle-Hindfoot Scale in the deltoid ligament repair group were higher than the trans-syndesmotic fixation group 3 months after operation. No statistical difference was found between the two groups in VAS score from 1 to 12 months postoperatively. Conclusions: Lateral malleolus fracture ORIF and deltoid ligament repair is an effective method for lateral malleolus fracture combined with both deltoid ligament injury and inferior tibiofibular syndesmotic disruption. Compared with trans-syndesmotic fixation, deltoid ligament repair holds the advantage of not needing surgical removal of inferior tibiofibular screws postoperatively.

Frailty affects prognosis in patients with colorectal cancer: A systematic review and meta-analysis.

Background: The prevalence of colorectal cancer has remained high. Most patients have already developed into the middle and advanced stage when they are diagnosed with colorectal cancer, and a small number of them are accompanied by metastasis. In recent years, frailty has been recognized as an important factor affecting the prognosis of colorectal cancer. The aim of this study was to assess the value of frailty on prognosis in patients with colorectal cancer after treatment. Method: We systematically searched PubMed, Embase, Web Of Science databases up until March2022. A total of 18 studies were retrieved that met the inclusion criteria, including 9 prospective studies and 9 retrospective studies. Frailty screening tools, proportion of frail patients, and outcomes of colorectal cancer patients after treatment were recorded. Result: 18 studies were included with a total of 352,535 participants. Regardless of differences in frailty screening and treatment approaches, outcomes for frailty patients were less favorable in all studies. Compared with the non-frail group, the frail group had higher mortality, more serious complications, more postoperative blood transfusions and delirium, and more support outside the home. Conclusion: Although there is no uniform standard for frailty screening, assessing the frailty of colorectal cancer patients is of great significance for predicting prognosis of patients after treatment.

The natural product salicin alleviates osteoarthritis progression by binding to IRE1α and inhibiting endoplasmic reticulum stress through the IRE1α-IκBα-p65 signaling pathway.

Despite the high prevalence of osteoarthritis (OA) in older populations, disease-modifying OA drugs (DMOADs) are still lacking. This study was performed to investigate the effects and mechanisms of the small molecular drug salicin (SA) on OA progression. Primary rat chondrocytes were stimulated with TNF-α and treated with or without SA. Inflammatory factors, cartilage matrix degeneration markers, and cell proliferation and apoptosis markers were detected at the mRNA and protein levels. Cell proliferation and apoptosis were evaluated by EdU assays or flow cytometric analysis. RNA sequencing, molecular docking and drug affinity-responsive target stability analyses were used to clarify the mechanisms. The rat OA model was used to evaluate the effect of intra-articular injection of SA on OA progression. We found that SA rescued TNF-α-induced degeneration of the cartilage matrix, inhibition of chondrocyte proliferation, and promotion of chondrocyte apoptosis. Mechanistically, SA directly binds to IRE1α and occupies the IRE1α phosphorylation site, preventing IRE1α phosphorylation and regulating IRE1α-mediated endoplasmic reticulum (ER) stress by IRE1α-IκBα-p65 signaling. Finally, intra-articular injection of SA-loaded lactic-co-glycolic acid (PLGA) ameliorated OA progression by inhibiting IRE1α-mediated ER stress in the OA model. In conclusion, SA alleviates OA by directly binding to the ER stress regulator IRE1α and inhibits IRE1α-mediated ER stress via IRE1α-IκBα-p65 signaling. Topical use of the small molecular drug SA shows potential to modify OA progression.

Shear-responsive boundary-lubricated hydrogels attenuate osteoarthritis.

Lipid-based boundary layers formed on liposome-containing hydrogels can facilitate lubrication. However, these boundary layers can be damaged by shear, resulting in decreased lubrication. Here, a shear-responsive boundary-lubricated drug-loaded hydrogel is created by incorporating celecoxib (CLX)-loaded liposomes within dynamic covalent bond-based hyaluronic acid (HA) hydrogels (CLX@Lipo@HA-gel). The dynamic cross-linked network enables the hydrogel to get restructured in response to shear, and the HA matrix allows the accumulation of internal liposome microreservoirs on the sliding surfaces, which results in the formation of boundary layers to provide stable lubrication. Moreover, hydration shells formed surrounding the hydrogel can retard the degradation process, thus helping in sustaining lubrication. Furthermore, in vitro and in vivo experiments found that CLX@Lipo@HA-gels can maintain anabolic-catabolic balance, alleviate cartilage wear, and attenuate osteoarthritis progression by delivering CLX and shear-responsive boundary lubrication. Overall, CLX@Lipo@HA-gels can serve as shear-responsive boundary lubricants and drug-delivery vehicles to alleviate friction-related diseases like osteoarthritis.

High-Performance Photodetectors Based on the 2D SiAs/SnS2 Heterojunction.

Constructing 2D heterojunctions with high performance is the critical solution for the optoelectronic applications of 2D materials. This work reports on the studies on the preparation of high-quality van der Waals SiAs single crystals and high-performance photodetectors based on the 2D SiAs/SnS2 heterojunction. The crystals are grown using the chemical vapor transport (CVT) method and then the bulk crystals are exfoliated to a few layers. Raman spectroscopic characterization shows that the low wavenumber peaks from interlayer vibrations shift significantly along with SiAs' thickness. In addition, when van der Waals heterojunctions of p-type SiAs/n-type SnS2 are fabricated, under the source-drain voltage of -1 V-1 V, they exhibit prominent rectification characteristics, and the ratio of forwarding conduction current to reverse shutdown current is close to 102, showing a muted response of 1 A/W under excitation light of 550 nm. The light responsivity and external quantum efficiency are increased by 100 times those of SiAs photodetectors. Our experimental results enrich the research on the IVA-VA group p-type layered semiconductors.

Pre-Emptive Antifibrinolysis: Its Role and Efficacy in Hip Fracture Patients Undergoing Total Hip Arthroplasty.

BACKGROUND: We aimed to determine the efficacy of pre-emptive antifibrinolysis with tranexamic acid (TXA) in decreasing hidden blood loss (HBL) in the elderly hip fracture patients. METHODS: Ninety-six elderly hip fracture patients receiving hip arthroplasty were randomized to receive 100 mL of normal saline (group A) or 1.5 g of TXA (group B) intravenously q12 hours from postadmission day 1 (PAD1) to the day before surgery. Both groups were treated with 1.5 g of TXA q12 hours from postoperative day 1 (POD1) to POD3. HBL was calculated by formulas and recorded as the primary outcome. RESULTS: In overall analyses, no difference was found in HBL, while the decline of hemoglobin (ΔHb), allogeneic blood transfusion (ABT) rate, fibrinogen degradation product (FDP-on PAD2, PAD3, POD1, and POD2), and d-dimer (D-D-on PAD2, PAD3, and POD1) were lower in group B. In subgroup analyses for patients receiving intervention within 72 hours of injury, group B had lower postoperative HBL, ΔHb, ABT rate, FDP, and D-D levels (on PAD2, PAD3, POD1, and POD2). For patients receiving intervention over 72 hours after injury, no difference was detected in perioperative HBL, ΔHb, and ABT rate between the 2 groups. The FDP and D-D levels were lower in group B on PAD2 and PAD3. No difference was found in coagulation parameters, wound complications, venous thromboembolism rate, and 90-day mortality in all analyses. CONCLUSION: Early administration (within 72 hours of injury) of multidose of TXA is effective in reducing perioperative HBL in elderly hip fracture patients. Delayed use (over 72 hours after injury) of TXA was not beneficial.

Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.

OBJECTIVE: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and Panax ginseng has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota. DESIGN: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed. RESULTS: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of Teff cells after combination treatment. Besides, the microbial analysis indicated that the abundance of Parabacteroides distasonis and Bacteroides vulgatus was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders. CONCLUSION: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.