Colorectal cancer(CRC) is a common malignant tumor worldwide. Due to the treatment intolerance and side effects, CRC rank the top among various cancers regarding the incidence and mortality rates. Therefore, exploring new therapies is of great significance for the treatment of CRC. Aerobic glycolysis(AEG) plays an important role in the microenvironment formation, proliferation, metastasis, and recurrence of CRC and other tumor cells. It has been confirmed that intervening in the AEG pathway can effectively curb CRC. The active ingredients and compound prescriptions of traditional Chinese medicine(TCM) can effectively inhibit the proliferation, metastasis, and drug resistance and regulate the apoptosis of tumor cells by modulating AEG-associated transport proteins [eg, glucose transporters(GLUT)], key enzymes [hexokinase(HK) and phosphofructokinase(PFK)], key genes [hypoxia-inducible factor 1(HIF-1) and oncogene(c-Myc)], and signaling pathways(MET/PI3K/Akt/mTOR). Accordingly, they can treat CRC, reduce the recurrence, and improve the prognosis of CRC. Although AEG plays a key role in the development and progression of CRC, the specific mechanisms are not yet fully understood. Therefore, this article delves into the intrinsic connection of the targets and mechanisms of the AEG pathway with CRC from the perspective of tumor cell glycolysis and explores how active ingredients(oxymatrine, kaempferol, and dioscin) and compound prescriptions(Quxie Capsules, Jiedu Sangen Decoction, and Xianlian Jiedu Prescription) of TCM treat CRC by intervening in the AEG pathway. Additionally, this article explores the shortcomings in the current research, aiming to provide reliable targets and a theoretical basis for treating CRC with TCM.
Humans ; Colorectal Neoplasms/genetics* ; Drugs, Chinese Herbal/therapeutic use* ; Glycolysis/drug effects* ; Animals ; Medicine, Chinese Traditional ; Signal Transduction/drug effects*

Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Combined with elastic network model(ENM),the perturbation response scanning(PRS)has emerged as a robust technique for pinpointing allosteric interactions within proteins.Here,we proposed the PRS analysis of drug-target networks(DTNs),which could provide a promising avenue in network medicine.We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework,for drug repurposing of multiple sclerosis(MS).First,the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes.Then,based on topological analysis and functional annotation,the neurotransmission module was identified as the"therapeutic module"of MS.Further,perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis,giving a list of repurposable drugs for MS.Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of se-rotonin 2B receptor(HTR2B).Finally,we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex.These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS.As a useful systematic method,our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Bacterial biofilms gave rise to persistent infections and multi-organ failure, thereby posing a serious threat to human health. Biofilms were formed by cross-linking of hydrophobic extracellular polymeric substances (EPS), such as proteins, polysaccharides, and eDNA, which were synthesized by bacteria themselves after adhesion and colonization on biological surfaces. They had the characteristics of dense structure, high adhesiveness and low drug permeability, and had been found in many human organs or tissues, such as the brain, heart, liver, spleen, lungs, kidneys, gastrointestinal tract, and skeleton. By releasing pro-inflammatory bacterial metabolites including endotoxins, exotoxins and interleukin, biofilms stimulated the body’s immune system to secrete inflammatory factors. These factors triggered local inflammation and chronic infections. Those were the key reason for the failure of traditional clinical drug therapy for infectious diseases.In order to cope with the increasingly severe drug-resistant infections, it was urgent to develop new therapeutic strategies for bacterial-biofilm eradication and anti-bacterial infections. Based on the nanoscale structure and biocompatible activity, nanobiomaterials had the advantages of specific targeting, intelligent delivery, high drug loading and low toxicity, which could realize efficient intervention and precise treatment of drug-resistant bacterial biofilms. This paper highlighted multiple strategies of biofilms eradication based on nanobiomaterials. For example, nanobiomaterials combined with EPS degrading enzymes could be used for targeted hydrolysis of bacterial biofilms, and effectively increased the drug enrichment within biofilms. By loading quorum sensing inhibitors, nanotechnology was also an effective strategy for eradicating bacterial biofilms and recovering the infectious symptoms. Nanobiomaterials could intervene the bacterial metabolism and break the bacterial survival homeostasis by blocking the uptake of nutrients. Moreover, energy-driven micro-nano robotics had shown excellent performance in active delivery and biofilm eradication. Micro-nano robots could penetrate physiological barriers by exogenous or endogenous driving modes such as by biological or chemical methods, ultrasound, and magnetic field, and deliver drugs to the infection sites accurately. Achieving this using conventional drugs was difficult. Overall, the paper described the biological properties and drug-resistant molecular mechanisms of bacterial biofilms, and highlighted therapeutic strategies from different perspectives by nanobiomaterials, such as dispersing bacterial mature biofilms, blocking quorum sensing, inhibiting bacterial metabolism, and energy driving penetration. In addition, we presented the key challenges still faced by nanobiomaterials in combating bacterial biofilm infections. Firstly, the dense structure of EPS caused biofilms spatial heterogeneity and metabolic heterogeneity, which created exacting requirements for the design, construction and preparation process of nanobiomaterials. Secondly, biofilm disruption carried the risk of spread and infection the pathogenic bacteria, which might lead to other infections. Finally, we emphasized the role of nanobiomaterials in the development trends and translational prospects in biofilm treatment.

Benign prostatic hyperplasia(BPH) is a common disease in middle-aged and elderly men, with lower urinary tract symptoms as the main manifestation, severely affecting the quality of life of patients. The pathogenesis of BPH is not yet fully understood, and there are still some challenges and limitations in western medicine treatment for BPH. Therefore, finding new and more effective treatment strategies is urgent. In recent years, many basic and clinical studies have confirmed the important role of traditional Chinese medicine in the treatment of BPH. This article reviews the progress of basic and clinical research in the treatment of BPH with traditional Chinese medicine, and believes that basic research mainly focuses on the active ingredients of Chinese medicine [regulating pathways such as NF-E2-related factor 2(Nrf2)/antioxidant response element(ARE), nuclear factor κB(NF-κB), epidermal growth factor receptor(EGFR)/signal transducer and activator of transcription 3(STAT3), phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)/mammalian target of rapamycin(mTOR), p38 mitogen-activated protein kinase(p38 MAPK)/forkhead box O subtype(FOXO3a), etc.], single Chinese herbs(regulating inflammatory factors, oxidative stress-related proteins, cell cycle-related proteins, and apoptotic factors, etc.), and Chinese herbal compounds and patent medicines [regulating extracellular signal-regulated kinase(ERK1/2), transforming growth factor-β(TGF-β)/Smad, mitogen-activated protein kinase(MAPK), PI3K/Akt, Nrf2, trefoil factor 2(TFF2)/Wnt, interleukin-6(IL-6)/Janus kinase 2(JAK2)/STAT3, hypoxia-inducible factor 1α(HIF-1α)/vascular endothelial growth factor receptor(VEGFR), etc.], and then play a therapeutic role by inhibiting BPH cell proliferation, oxidative stress, inflammatory response, promoting apoptosis, and inhibiting epithelial-mesenchymal transition. Clinical studies mainly focus on internal treatment, external treatment, combined internal and external treatment, and integrated Chinese and western medicine treatment as the main methods, aiming to improve traditional Chinese medicine syndrome scores, prostate symptom scores, residual urine volume, effective bladder volume, sexual quality of life, increase average urine flow rate, maximum urine flow rate, and promote balance of sex hormone secretion. Through this research, it is hoped to provide some reference ideas for clinical research and drug development for BPH.
Prostatic Hyperplasia/metabolism* ; Male ; Humans ; Drugs, Chinese Herbal/therapeutic use* ; Animals ; Signal Transduction/drug effects* ; Medicine, Chinese Traditional ; NF-E2-Related Factor 2/genetics*

The fat mass and obesity-associated protein (FTO) is an RNA demethylase required for catalytic demethylation of N ⁶-methyladenosine (m⁶A); it is highly expressed and functions as an oncogene in acute myeloid leukemia (AML). Currently, the overarching objective of targeting FTO is to precisely inhibit the catalytic activity. Meanwhile, whether FTO degradation also exerts antileukemic effects remains unknown. Herein, we designed the first FTO-targeting proteolysis targeting chimera (PROTAC) degrader QP73 using our FTO inhibitor Dac85-which potently inhibits FTO demethylation in AML cell lines-as a warhead. Notably, QP73 significantly induced FTO degradation in a time-, dose-, and ubiquitin-proteasome system-dependent manner and had superior antiproliferative activities to the FTO inhibitor Dac85 in various AML cell lines. Moreover, QP73 treatment significantly increased m⁶A modification on mRNA, promoted myeloid differentiation, and induced apoptosis of AML cells. Quantitative proteomics analysis showed that QP73 induced complete FTO degradation, upregulating RARA and ASB2 abundance and downregulating CEBPA, MYC, PFKP, and LDHB levels in AML cells. Lastly, QP73 exhibited antileukemic activity by increasing m⁶A modification and decreasing FTO levels in xenograft AML tumors. This proof-of-concept study shows that FTO-targeting PROTAC degraders can regulate the FTO signaling pathway and have potential antileukemia applications.

BACKGROUND: Controversy exists as to the optimal treatment approach for ostial left anterior descending (LAD) or ostial left circumflex artery (LCx) lesions. Drug-coated balloons (DCB) may overcome some of the limitations of drug-eluting stents (DES). Therefore, we investigated the security and feasibility of the DCB policy in patients with ostial LAD or ostial LCx lesions, and compared it with the conventional DES-only strategy. METHODS: We retrospectively enrolled patients with de novo ostial lesions in the LAD or LCx who underwent interventional treatment. They were categorized into two groups based on their treatment approach: the DCB group and the DES group. The treatment strategies in the DCB group involved the use of either DCB-only or hybrid strategies, whereas the DES group utilized crossover or precise stenting techniques. Two-year target lesion revascularization was the primary endpoint, while the rates of major adverse cardiovascular events, cardiac death, target vessel myocardial infarction, and vessel thrombosis were the secondary endpoints. Using propensity score matching, we assembled a cohort with comparable baseline characteristics. To ensure result analysis reliability, we conducted sensitivity analyses, including interaction, and stratified analyses. RESULTS: Among the 397 eligible patients, 6.25% of patients who were planned to undergo DCB underwent DES. A total of 108 patients in each group had comparable propensity scores and were included in the analysis. Two-year target lesion revascularization occurred in 5 patients (4.90%) and 16 patients (16.33%) in the DCB group and the DES group, respectively (odds ratio = 0.264, 95% CI: 0.093-0.752, P = 0.008). Compared with the DES group, the DCB group demonstrated a lower major adverse cardiovascular events rate (7.84% vs. 19.39%, P = 0.017). However, differences with regard to cardiac death, non-periprocedural target vessel myocardial infarction, and definite or probable vessel thrombosis between the groups were non-significant. CONCLUSIONS The utilization of the DCB approach signifies an innovative and discretionary strategy for managing isolated ostial lesions in the LAD or LCx. Nevertheless, a future randomized trial investigating the feasibility and safety of DCB compared to the DES-only strategy specifically for de novo ostial lesions in the LAD or LCx is highly warranted.

Objective: To further elucidate the clinical efficacy and safety of a combination regimen based on the BTK inhibitor zebutanil bridging CD19 Chimeric antigen receptor T cells (CAR-T cells) in the treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) . Methods: Twenty-one patients with high-risk r/r DLBCL were treated with a zanubrutinib-based regimen bridging CAR-T between June 2020 and June 2023 at the Department of Hematology, Tongji Hospital, Tongji University and the Second Affiliated Hospital of Zhejiang University, and the efficacy and safety were retrospectively analyzed. Results: All 21 patients were enrolled, and the median age was 57 years (range: 38-76). Fourteen patients (66.7%) had an eastern cooperative oncology group performance status score (ECOG score) of ≥2. Eighteen patients (85.7%) had an international prognostic index (IPI) score of ≥3. Three patients (14.3%) had an IPI score of 2 but had extranodal infiltration. Fourteen patients (66.7%) had double-expression of DLBCL and seven (33.3%) had TP53 mutations. With a median follow-up of 24.8 (95% CI 17.0-31.6) months, the objective response rate was 81.0%, and 11 patients (52.4%) achieved complete remission. The median progression-free survival (PFS) was 12.8 months, and the median overall survival (OS) was not reached. The 1-year PFS rate was 52.4% (95% CI 29.8% -74.3%), and the 1-year OS rate was 80.1% (95% CI 58.1% -94.6%). Moreover, 18 patients (85.7%) had grade 1-2 cytokine-release syndrome, and two patients (9.5%) had grade 1 immune effector cell-associated neurotoxicity syndrome. Conclusion: Zanubrutinib-based combination bridging regimen of CAR-T therapy for r/r DLBCL has high efficacy and demonstrated a good safety profile.
Humans ; Middle Aged ; Receptors, Chimeric Antigen/therapeutic use* ; Retrospective Studies ; Immunotherapy, Adoptive/adverse effects* ; Lymphoma, Large B-Cell, Diffuse/drug therapy* ; Cell- and Tissue-Based Therapy ; Antigens, CD19/adverse effects*

Objective: To observe the immediate effect of small-angle Tui-Pushing and An-Pressing anti-rotation bone-setting manipulation in improving the correction of braces for adolescent idiopathic scoliosis. Methods: A total of 50 cases of adolescent idiopathic scoliosis were selected and given brace correction first. The whole spine anteroposterior and lateral radiographs were taken, the Cobb angle was measured, and the visual analog scale (VAS) score of pain caused by brace wearing was recorded. After removal of the brace, small-angle Tui-Pushing and An-Pressing anti-rotation bone-setting manipulation was performed once. After treatment, the same brace was put on again to take a whole spine anteroposterior radiograph, the Cobb angle was measured, and the VAS score was recorded. The changes in Cobb angle and VAS score after manipulation were compared, and the immediate efficacy was evaluated. Results: After the manipulation, the Cobb angle was significantly smaller than that before treatment (P<0.01) and the VAS score was significantly lower than that before treatment (P<0.01). Conclusion: Small-angle Tui-Pushing and An-Pressing anti-rotation bone-setting manipulation can improve the immediate efficacy of brace in treating adolescent idiopathic scoliosis and relieve the pain caused by brace wearing at the same time.

OBJECTIVE: To observe the clinical efficacy of transcutaneous electrical acupoint stimulation (TEAS) combined with warm acupuncture in treating breast cancer associated with upper limb lymphedema (BCRL). METHODS: This was a retrospective cohort study using a paired control design. Fifty-two BCRL patients were assigned to the control group (27 cases) and the treatment group (25 cases). The patients in the control group were treated with lymphedema comprehensive detumescence treatment (CDT) for 4 weeks, including systematic therapy composed of manual lymphatic drainage, compression bandage, skincare, and functional exercise. The patients in the treatment group were treated with TEAS combined with warm acupuncture based on the control group methods. Each treatment lasted for 30 min and was applied twice a week for 4 weeks. The arm circumference (AC) of different positions of the affected limb and the degree of swelling of the affected limb were evaluated before the first treatment and after the last treatment. The clinical efficacy was evaluated according to the degree of edema before and after treatment. All adverse events during treatment were recorded. RESULTS: The patients' AC and the swelling feeling of the affected limb in the treatment group and the control group were both reduced compared with those before treatment. Compared with the control group, AC of the wrist joint transverse stria, the midpoint between the wrist joint transverse stria and the elbow joint transverse stria in the treatment group were significantly reduced (P<0.05). The decrease in AC diameter at the midpoint between the elbow joint transverse stria and the axillary transverse stria was the most significant (P<0.01). The swelling degree of the affected limbs in the treatment group was significantly lower than before treatment, and was significantly lower compared with the control group after treatment (P<0.01). The total effective rate was 72% in the treatment group, significantly higher than that in the control group (55.56%, P<0.05). No serious adverse events occured in either group. CONCLUSIONS TEAS combined with warm acupuncture can effectively reduce AC and swelling feeling of the affected limb in patients with BCRL. The effect is better than that of CDT therapy alone. (Registration No. ChiCTR2200062075).
Humans ; Female ; Breast Neoplasms/therapy* ; Acupuncture Points ; Retrospective Studies ; Lymphedema/complications* ; Acupuncture Therapy/adverse effects* ; Upper Extremity ; Treatment Outcome