Drawing on recent advances in modern fascial anatomy and biomechanics， this paper interprets the biomechanical implications of yin-yang balance at the physical level from the perspective of holistic force lines. It posits that holistic force lines represent the functional expression of mechanical load transmission and integration within the myofascial network； the channel sinews system and myofascial chains exhibit significant similarities in terms of their distribution， functional attributes， and principles of holistic regulation， and can thus be understood as structural-functional carriers of yin-yang balance. Accordingly， this paper provides a biomechanical interpretation of the yin-yang relationship from four aspects， including interdependence， mutual restriction， dynamic balance through waxing and waning， and mutual transformation， proposing that in a healthy state， the body relies on the continuous integration， distribution， and readjustment of the myofascial tension network to maintain overall coordination， whereas disease states are often associated with compensatory transmission of local tension abnormalities along holistic force lines， the accumulation of imbalances， and structural rigidity. The holistic force-line perspective provides a biomechanical explanatory framework for the theory of yin-yang balance and offers a new theoretical basis for clinical diagnosis and treatment to shift from empirical holistic balancing toward holistic force-line balancing based on posture， function， and tension transmission pathways.

ObjectiveTo study the effect and mechanism of Shentong Zhuyutang in treating intervertebral disc degeneration （IDD） in rats. MethodsIn the cell experiment， male rats were administrated with normal saline or low-， medium-， and high-dose （3.38， 6.75，13.5 g·kg^-1， respectively） Shentong Zhuyutang by gavage， respectively， and serum samples were collected after 7 days of continuous administration. Another 10 male rats were selected for the isolation of nucleus pulposus cells. The cell model of IDD was established by treatment with interleukin （IL）-1β. The modeled cells were then treated with Shentong Zhuyutang-containing serum and the ferroptosis inhibitor ferrostatin-1 （Fer-1）， respectively， to investigate the effects of Shentong Zhuyutang-containing serum on the proliferation and ferroptosis of nucleus pulposus cells. To study the role of silent information regulator 1 （SIRT1）/nuclear factor erythroid 2-related factor 2 （Nrf2） in the regulation of ferroptosis in nucleus pulposus cells by Shentong Zhuyutang-containing serum， this study treated the cells with the SIRT1 inhibitor Ex 527 and the Nrf2 inhibitor ML385， respectively， in addition to the treatment with IL-1β and high-dose Shentong Zhuyutang-containing serum. The cell-counting kit-8 （CCK-8） assay and EdU staining were employed to measure the cell viability and proliferation， respectively. The Fe²⁺， glutathione （GSH）， and malondiadehyde （MDA） levels were measured by colorimetric assay. Western blot was employed to determine the protein levels of glutathione peroxidase 4 （GPX4）， acyl-CoA synthetase long-chain family 4 （ACSL4）， Collagen Ⅱ， Aggrecan， SIRT1， and Nrf2. Immunofluorescence was used detect SIRT1 expression. In the animal experiment， male rats were treated with anulus puncture for the modeling of IDD. Rats were randomly assigned into sham operation， model， Shentong Zhuyutang-containing serum （13.5 g·kg^-1）， and positive control （nimesulide dispersible tablets， 0.18 mg·kg^-1） groups. Rats in the drug intervention groups were administrated with corresponding agents at 1 mL·kg^-1， and those in the sham operation and model groups were administrated with equal volumes of normal saline， once daily for 28 consecutive days. At the end of the last administration， the histopathological changes in the intervertebral discs of rats were observed by hematoxylin-eosin staining and scored by the Masuda method. Western blot was employed to determine the protein levels of SIRT1， Nrf2， GPX4， and Collagen Ⅱ in the nucleus pulposus tissue. ResultsCompared with the control group， the IL-1β group of nucleus pulposus cells showed elevated levels of Fe²⁺， MDA， and ACSL4 （P<0.05）， decreased cell viability， lowered GSH level， and down-regulated protein levels of GPX4， Collagen Ⅱ， and Aggrecan （P<0.05）. Shentong Zhuyutang-containing serum and Fer-1 reversed the effects of IL-1β on the viability and ferroptosis of nucleus pulposus cells and up-regulated the protein levels of Collagen Ⅱ and Aggrecan in nucleus pulposus cells （P<0.05）. Compared with the control group， the IL-1β group showcased down-regulated expression of Sirt1 and Nrf2 in nucleus pulposus cells （P<0.05）. Compared with the IL-1β group， the high-dose Shentong Zhuyutang-containing serum+IL-1β group showed up-regulated expression of SIRT1 and Nrf2 in nucleus pulposus cells （P<0.05）. Compared with the high-dose Shentong Zhuyutang-containing serum+IL-1β group， the ML385 group showed down-regulated protein levels of Nrf2 and GPX4， lowered GSH level， and elevated Fe²⁺ and MDA levels （P<0.05）. In addition， the Ex 527 group showed down-regulated protein levels of SIRT1， Nrf2， and GPX4 （P<0.05）. The results of the animal experiment showed that compared with the sham operation group， the model group had severe degeneration of the intervertebral disc tissue with increased pathological score， up-regulated protein level of ACSL4 （P<0.05）， and down-regulated protein levels of SIRT1， Nrf2， GPX4， and Collagen Ⅱ （P<0.05）. Compared with the model group， the Shentong Zhuyutang group showed alleviated IDD with declined pathological score， down-regulated protein level of ACSL4 （P<0.05）， and up-regulated protein levels of SIRT1， Nrf2， GPX4， and Collagen Ⅱ （P<0.05）. ConclusionShentong Zhuyutang may activate the SIRT1/Nrf2 signaling pathway to inhibit the ferroptosis of nucleus pulposus cells， thereby delaying the process of IDD in rats.

Background Exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with the development of metabolic syndrome (MS). However, the role of amino acids in PAH-induced MS remains unclear. Objective To explore the impact of PAHs exposure on the incidence of MS among coking workers, and to determine potential modifying effect of amino acid on this relationship. Methods Unmatched nested case-control design was adopted and the baseline surveys of coking workers were conducted in two plants in Taiyuan in 2017 and 2019, followed by a 4-year follow-up. The cohort comprised 667 coking workers. A total of 362 participants were included in the study, with 84 newly diagnosed cases of MS identified as the case group and 278 as the control group. Urinary levels of 11 PAH metabolites and plasma levels of 17 amino acids were measured by ultrasensitive performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Logistic regression was used to estimate the association between individual PAH metabolites and MS. Stratified by the median concentration of amino acids, Bayesian kernel machine regression (BKMR) model was employed to assess the mixed effects of PAHs on MS. Due to the skewed data distribution, all PAH metabolites and amino acids in the analysis were converted by natural logarithm ln (expressed as lnv). Results The median age of the 362 participants was 37 years, and 83.2% were male. Compared to the control group, the case group exhibited higher concentrations of urinary 2-hydroxyphenanthrene (2-OHPhe), 9-hydroxyphenanthrene (9-OHPhe), and hydroxyphenanthrene (OHPhe) (P=0.005, P=0.049, and P=0.004, respectively), as well as elevated levels of plasma branched chain amino acid (BCAA) and aromatic amino acid (AAA) (P<0.05). After being adjusted for confounding factors, for every unit increase in lnv_2-OHPhe in urine, the OR (95%CI) of MS was 1.57 (1.11, 2.26), and for every unit increase in lnv_OHPhe, the OR (95%CI) of MS was 1.82 (1.16, 2.90). Tyrosine, leucine, and AAA all presented a significant nonlinear correlation with MS. At low levels, tyrosine, leucine, and AAA did not significantly increase the risk of MS, but at high levels, they increased the risk of MS. In the low amino acid concentration group, as well as in the low BCAA and low AAA concentration groups, it was found that compared to the PAH metabolite levels at the 50th percentile (P₅₀), the log-odds of MS when the PAH metabolite levels was at the 75th percentile (P₇₅) were 0.158 (95%CI: 0.150, 0.166), 0.218 (95%CI: 0.209, 0.227), and 0.262 (95% CI: 0.241, 0.282), respectively, However, no correlation between PAHs and MS was found in the high amino acid concentration group. Conclusion Amino acids modify the effect of PAHs exposure on the incidence of MS. In individuals with low plasma amino acid levels, the risk of developing MS increases with higher concentrations of mixed PAH exposure. This effect is partly due to the low concentrations of BCAA and AAA.

BACKGROUND: It is inaccurate to reflect the level of dust exposure through working years. Furthermore, identifying a predictive indicator for lung function decline is significant for coal miners. The study aimed to explored whether club cell secretory protein (CC16) levels can reflect early lung function changes. METHODS: The cumulative respiratory dust exposure (CDE) levels of 1,461 coal miners were retrospectively assessed by constructed a job-exposure matrix to replace working years. Important factors affecting lung function and CC16 were selected by establishing random forest models. Subsequently, the potential of CC16 to reflect lung injury was explored from multiple perspectives. First, restricted cubic spline (RCS) models were used to compare the trends of changes in lung function indicators and plasma CC16 levels after dust exposure. Then mediating analysis was performed to investigate the role of CC16 in the association between dust exposure and lung function decline. Finally, the association between baseline CC16 levels and follow-up lung function was explored. RESULTS: The median CDE were 35.13 mg/m³-years. RCS models revealed a rapid decline in forced vital capacity (FVC), forced expiratory volume in the first second (FEV₁), and their percentages of predicted values when CDE exceeded 25 mg/m³-years. The dust exposure level (<5 mg/m³-years) causing significant changes in CC16 was much lower than the level (25 mg/m³-years) that caused changes in lung function indicators. CC16 mediated 11.1% to 26.0% of dust-related lung function decline. Additionally, workers with low baseline CC16 levels experienced greater reductions in lung function in the future. CONCLUSIONS CC16 levels are more sensitive than lung indicators in reflecting early lung function injury and plays mediating role in lung function decline induced by dust exposure. Low baseline CC16 levels predict poor future lung function.
Uteroglobin/blood* ; Humans ; Dust/analysis* ; Occupational Exposure/analysis* ; Male ; Middle Aged ; Adult ; Retrospective Studies ; Lung Injury/chemically induced* ; Coal Mining ; Biomarkers/blood* ; China/epidemiology* ; Air Pollutants, Occupational ; Female

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy predominantly managed via chemotherapy. Our clinical sample analysis revealed a significant correlation between elevated CD24 expression in TNBC tumor cells and patient survival rates. We developed a novel antibody-drug conjugate (ADC), named HN03, consisting of an antibody with engineered cysteines for site-specific conjugation with a low toxic nitric oxide (NO) precursor as its payload through a novel Pt(IV)-mediated bioorthogonal self-cleavable linker. HN03 specifically targets tumor cells expressing high levels of CD24, concurrently generating cisplatin and releasing NO upon activation. HN03 also exhibited potent in vitro and in vivo antitumor activity. It significantly reduced tumor growth at various doses, prevented tumor metastasis, with markedly lower toxicity than traditional chemotherapy agents. We found that a key mechanism of its action involved inducing apoptosis and endoplasmic reticulum stress, substantially decreasing the number of M2-type macrophages. Overall, HN03 stands out as a promising therapeutic option for TNBC, offering a targeted treatment with reduced side effects and the potential for improved outcomes. Furthermore, using Pt(IV) in the linker and an NO precursor as the payload enhances the versatility of the Antibody-NO donor Conjugate (ANC), offering new avenues for the design of the next generation of ADCs.

OBJECTIVE: This study aims to elucidate the therapeutic potential of osthole for the treatment of atopic dermatitis (AD), focusing on its ability to alleviate chronic pruritus (CP) and the underlying molecular mechanisms. METHODS: In this study, we investigated the anti-inflammatory effects of osthole in both a 2,4-dichloronitrobenzene (DNCB)-induced AD mouse model and tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) stimulated huma immortalized epidermal (HaCaT) cells. The anti-itch effect of osthole was specifically assessed in the AD mouse model. Using methods such as hematoxylin and eosin (HE) staining, enzyme-linked immunosorbent assay (ELISA), western blot (WB), quantitative real-time PCR (qRT-PCR), and immunofluorescence staining. RESULTS: Osthole improved skin damage and clinical dermatitis scores, reduced scratching bouts, and decreased epidermal thickness AD-like mice. It also reduced the levels of interleukin (IL)-31 and IL-31 receptor A (IL-31 RA) in both skin tissues and HaCaT cells. Furthermore, Osthole suppressed the protein expression levels of phosphor-p65 (p-p65) and phosphor-inhibitor of nuclear factor kappa-Bα (p-IκBα). Meanwhile, it increased the protein expression levels of peroxisome proliferator-activated receptor α (PPARα) and PPARγ in HaCaT cells. CONCLUSION These findings indicated that osthole effectively inhibited CP in AD by activating PPARα, PPARγ, repressing the NF-κB signaling pathway, as well as the expression of IL-31 and IL-31 RA.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

Metastasis remains the primary cause of cancer-related mortality worldwide. Circulating tumor cells (CTCs) represent critical targets for metastasis prevention and treatment. Traditional Chinese medicine may prevent lung cancer metastasis through long-term intervention in CTC activity. Tiao-Shen-Zhi-Ai Formular (TSZAF) represents a Chinese medicine compound prescription utilized clinically for lung cancer treatment. This study combined three principal active ingredients from TSZAF into a novel TSZAF monomer combination (TSZAF mc) to investigate its anti-metastatic effects and mechanisms. TSZAF mc demonstrated significant inhibition of proliferation, migration, and invasion in CTC-TJH-01 and LLC cells, while inducing cellular apoptosis in vitro. Moreover, TSZAF mc substantially inhibited LLC cell growth and metastasis in vivo. Mechanistically, TAZSF mc significantly suppressed the Wnt/β-catenin signaling pathway and CXCL5 expression in lung cancer cells and tissues. Additionally, TAZSF mc notably reduced neutrophil infiltration in metastatic lesions. These findings indicate that TSZAF mc inhibits lung cancer growth and metastasis by suppressing the Wnt/β-catenin signaling pathway and reducing CXCL5 secretion, thereby decreasing neutrophil recruitment and infiltration. TSZAF mc demonstrates potential as an effective therapeutic agent for lung cancer metastasis.
Lung Neoplasms/genetics* ; Wnt Signaling Pathway/drug effects* ; Animals ; Humans ; Drugs, Chinese Herbal/pharmacology* ; Mice ; Neoplasm Metastasis/prevention & control* ; Cell Proliferation/drug effects* ; Cell Line, Tumor ; Neutrophil Infiltration/drug effects* ; Down-Regulation/drug effects* ; Cell Movement/drug effects* ; beta Catenin/genetics* ; Apoptosis/drug effects* ; Mice, Inbred C57BL ; Male ; Neoplastic Cells, Circulating/drug effects*

Objective To analyze the dosimetric differences between Monaco Monte Carlo(MC)algorithm and Pinnacle collapse cone convolution(CCC)algorithm for the same machine model using the 6 MV flatten-filter free(FFF)mode,thus providing a reference for the clinical application of these two treatment planning systems.Methods According to the MPPG5 and TRS430 reports,the acceptance and commissioning of Monaco MC algorithm model and Pinnacle CCC algorithm model in Department of Radiation Oncology,Shenzhen Hospital,Cancer Hospital of Chinese Academy of Medical Sciences were performed.A retrospectively analysis was conducted on 30 cases,including 10 cases of nasopharyngeal cancer,6 cases of lung cancer,4 cases of esophageal cancer,and 10 cases of cervical cancer.For each case,a 6 MV FFF plan was designed in Pinnacle using CCC algorithm.A 2.5 mm dose grid was selected for plan optimization and dose calculation.The plan was then exported to Monaco,where dose to medium was calculated using MC algorithm and a 2.5 mm dose grid with a 1%uncertainty for each control point.Both calculations in Pinnacle and Monaco took into account the impact of the treatment couch and immobilization devices on dose attenuation.The dose differences to the target volumes and major organs at risk between Pinnacle and Monaco for 3 different body parts including the head,chest and abdomen were compared.Results(1)For nasopharyngeal cancer,compared with Pinnacle CCC algorithm,Monaco MC algorithm lowered the Vpd of PTVp,PTVn,PTVrpn,PTV1 and PTV2 by 9.98%,2.64%,15.0%,1.93%and 8.01%,elevated the Dmax of PTVp,PTVn and PTVrpn by 2.98%,5.62%and 2.39%,increased the Dmean of PTVn and PTV1 by 1.87%and 0.72%,respectively;and the Dmax of the brainstem,the Dmax of the optic chiasm,and the Dmean of the right parotid gland were 3.83%lower,7.03%higher and 1.32%higher in Monaco MC algorithm as compared with Pinnacle CCC algorithm,respectively.(2)For lung cancer and esophageal cancer,Monaco MC algorithm showed increases of 2.37%,4.18%,15.30%,6.36%and 1.04%in the Dmax of PGTV,the V20,V5 and Dmean of lungs,and the V30 of heart as compared with Pinnacle CCC algorithm,respectively.(3)For cervical cancer,the Vpd of PTV_LR,Dmax of PTV_LR,the V40 of the rectum,the Dmax of the small intestine,and the Dmean of humeral head were 7.70%lower,3.70%higher,4.31%lower,3.05%higher and 2.07%higher in Monaco MC algorithm than in Pinnacle CCC algorithm,respectively.These differences were statistically significant(P<0.05).Conclusion For the above 3 treatment sites,significant differences are found in dose calculations for target areas and organs at risk between Monaco MC algorithm and Pinnacle CCC algorithm for the same treatment plan.Attention should be paid to the differences in dose algorithms for different treatment planning systems in clinical applications,which may have impacts on patient survival rates and organ toxicity.

BACKGROUND:Inflammation and apoptosis play key roles in the pathological process of cervical spondylotic myelopathy.Previous studies have shown that Pueraria lobata decoction has favorable therapeutic effects on cervical spondylotic myelopathy.OBJECTIVE:To investigate the effects and mechanism of Pueraria lobata decoction in neuroinflammatory response and apoptosis in rats with cervical spondylotic myelopathy.METHODS:Sixty Sprague-Dawley rats were randomly divided into six groups:a normal group,a sham-operated group,a model group,and three groups that received low,medium,and high doses of Pueraria lobata decoction.An animal model of cervical spondylotic myelopathy was constructed through compression of the spinal cord with water-absorbing and expanding material.Gastric administration of Pueraria lobata decoction(4.86,9.72,and 19.44 g/kg)was given in the three Pueraria lobata decoction groups 2 weeks after surgery,and the resting groups were given saline by gavage,once daily for 4 weeks.Motor function evaluation(Basso-Beattie-Bresnahan score)was performed in rats on days 1,7,14,21 and 28 after drug administration.At 4 weeks after drug administration,hematoxylin-eosin staining was used to observe the pathomorphologic changes in spinal cord tissue;immunofluorescence double staining was used for the detection of microglial cell polarization in spinal cord tissue;quantitative fluorescence PCR was used to detect the changes in the expression of interleukin-6 and interleukin-1β mRNA;western blot assay was used to detect the protein expression of p-NF-κB p65,NF-κB p65,NLRP3,ASC,Cleaved Caspase-1,Bax,Bcl-2,Cleaved Caspase-3,NOX4,p-Drp1,Drp1,and Mfn2 in spinal cord tissues;TUNEL assay was used to detect apoptosis in spinal cord tissues;and DHE staining was used to detect reactive oxygen species levels in rat spinal cord tissues.RESULTS AND CONCLUSION:(1)Compared with the normal and sham-operated groups,reduced Basso-Beattie-Bresnahan scores were observed in the model group(P<0.05),spinal cord neurons were crumpled and malformed with vacuolike changes.The Basso-Beattie-Bresnahan scores in the low-,medium-and high-dose Pueraria lobata decoction groups were significantly higher than those in the model group(P<0.05),and spinal cord neuronal damage reduced significantly.(2)Compared with the normal and sham-operated groups,there were elevated levels of Iba-1 and inducible nitric oxide synthase proteins and increased interleukin-6 and interluekin-1β mRNA expression in the spinal cord tissue of rats in the model group(P<0.05).The expression levels of Iba-1,inducible nitric oxide synthase,p-NF-κB,NLRP3,ASC and cleaved caspase-1 proteins as well as interleukin-6 and interleukin-1β mRNAs in the spinal cord tissues of rats in the low-,medium-and high-dose Pueraria lobata decoction groups were reduced compared with those in the model group(P<0.05).(3)Compared with the normal and sham-operated groups,the rate of TUNEL-positive cells and the levels of Bax and cleaved caspase-3 proteins were increased in the spinal cord tissues of rats in the model group(P<0.05),while the expression of Bcl-2 protein was reduced(P<0.05).Compared with the model group,the above indexes were significantly improved in the low-,medium-and high-dose Pueraria lobata decoction groups.(4)Compared with the normal and sham-operated groups,the model group exhibited increased levels of reactive oxygen species,along with elevated expression of NOX4 and p-Drp1 proteins(P<0.05)and reduced expression of Mfn2 protein(P<0.05)in the rat spinal crod tissue.Compared with the model group,the low-,medium-,and high-dose Pueraria lobata decoction groups exhibited reduced levels of reactive oxygen species,as well as decreased expression of NOX4 and p-Drp1 proteins(P<0.05)and increased expression of Mfn2 protein(P<0.05)in the rat spinal cord tissue.To conclude,Pueraria lobata decoction inhibits neuroinflammatory responses and neuronal apoptosis in the rat model of cervical spondylotic myelopathy,and the mechanism of action may be related to the regulation of the NOX4/reactive oxygen species/DRP1 signaling pathway.