The Dunhuang manuscript Fuxing Jue takes the "Tangye Jingfa Tu" as the core of its theory on prescription and compatibility. Its medication principles mainly include the "five elements principle of tonifying and purging" and the "five elements principle of elimination and transformation". Based on the differentiation of deficiency and excess in the five Zang organs， it flexibly applies medicinal properties， usage， and flavor transformation for tonifying and purging， forming its unique method of medication and compatibility. In Taiyin disease， "fullness syndrome" often occurs together with "diarrhea"， and these two conditions also serve as the primary indications for the middle-regulating formulas. Among them， Lizhong Wan （Tang） mainly address Taiyin deficiency. The three Xiexin Tang （Banxia Xiexin Tang， Gancao Xiexin Tang， Shengjiang Xiexin Tang） address Taiyin deficiency accompanied by pathogenic excess. The Sini Tangand Tongmai Sini Tang primarily treat dysfunction of the liver， spleen， and kidney with impaired opening and closing of Taiyin， manifesting as diarrhea. The medicinal flavors of middle-regulating formulas are pungent， sweet， and bitter， acting directly on the spleen of Taiyin. The pungent flavor induces purging of the spleen， sweet flavor tonifies the spleen， and bitter flavor eliminates lumps. When the constituent medicinal units of middle-regulating formulas are unified， the ratio of pungent to sweet flavors reflects the tonic and purgative strength of the formula. In addition， the two decoction methods， "short-term decoction to extract Qi" and "long-term decoction to extract flavor"， also influence the formula's tonifying and purgative effects. Based on the composition of flavors and special decoction methods， this article discusses the differences in the use of middle-regulating formulas for treating "“fullness syndrome" versus "diarrhea". Dysfunction of the spleen can give rise to various diseases. Therefore， middle-regulating formulas are not limited to treating "deficiency， cold， and dampness" syndromes. Later generations of physicians further modified Lizhong Tang to treat "excess， heat， and dryness" syndromes， laying a solid foundation for more flexible and effective clinical application of middle-regulating formulas.

The Dunhuang manuscript Fuxing Jue takes the "Tangye Jingfa Tu" as the core of its theory on prescription and compatibility. Its medication principles mainly include the "five elements principle of tonifying and purging" and the "five elements principle of elimination and transformation". Based on the differentiation of deficiency and excess in the five Zang organs， it flexibly applies medicinal properties， usage， and flavor transformation for tonifying and purging， forming its unique method of medication and compatibility. In Taiyin disease， "fullness syndrome" often occurs together with "diarrhea"， and these two conditions also serve as the primary indications for the middle-regulating formulas. Among them， Lizhong Wan （Tang） mainly address Taiyin deficiency. The three Xiexin Tang （Banxia Xiexin Tang， Gancao Xiexin Tang， Shengjiang Xiexin Tang） address Taiyin deficiency accompanied by pathogenic excess. The Sini Tangand Tongmai Sini Tang primarily treat dysfunction of the liver， spleen， and kidney with impaired opening and closing of Taiyin， manifesting as diarrhea. The medicinal flavors of middle-regulating formulas are pungent， sweet， and bitter， acting directly on the spleen of Taiyin. The pungent flavor induces purging of the spleen， sweet flavor tonifies the spleen， and bitter flavor eliminates lumps. When the constituent medicinal units of middle-regulating formulas are unified， the ratio of pungent to sweet flavors reflects the tonic and purgative strength of the formula. In addition， the two decoction methods， "short-term decoction to extract Qi" and "long-term decoction to extract flavor"， also influence the formula's tonifying and purgative effects. Based on the composition of flavors and special decoction methods， this article discusses the differences in the use of middle-regulating formulas for treating "“fullness syndrome" versus "diarrhea". Dysfunction of the spleen can give rise to various diseases. Therefore， middle-regulating formulas are not limited to treating "deficiency， cold， and dampness" syndromes. Later generations of physicians further modified Lizhong Tang to treat "excess， heat， and dryness" syndromes， laying a solid foundation for more flexible and effective clinical application of middle-regulating formulas.

Based on the theory of "disease of both blood and water" in Essentials from the Golden Cabinet （《金匮要略》）， and in combination with the dynamic syndrome evolution of heart failure with preserved ejection fraction （HFpEF）， this paper systematically clarifies the pathomechanism of HFpEF， characterized by yang deficiency as the root， blood stasis as the pivotal factor and water retention as the manifestation. Accordingly， the therapeutic principles have been proposed， which are warming yang and banking up original qi to consolidate the root， activating blood and unblocking collaterals to smooth the mechanism， and promoting urination and regulating pivot to remove the branch. On this basis， a compound formula structure of "one monarch， one minister and one assistant" is established， forming an integrated intervention strategy that synergistically combines the three methods of warming yang， activating blood， and promoting urination through combined classical formulas. Zhenwu Decoction （真武汤）， which warms yang and dissolves rheum， is used to consolidate the root and directly target the source of yang deficiency， serving as the monarch； Guizhi Fuling Pills （桂枝茯苓丸）， which activates blood， promotes urination and unblocks the pivot， assists in interrupting the binding of blood stasis and water retention， serving as the minister； Tingli Dazao Xiefei Decoction （葶苈大枣泻肺汤）， which regulates qi， disperses retained fluids， and eliminates the manifestation， alleviates acute water-retention symptoms， serving as the assistant. This compound formula is warming without being drying， diuretic without being drastic， and dispels stasis without consuming blood， thereby achieving the therapeutic effects of warming yang， activating blood， and promoting urination.

To explore the advantages of traditional Chinese medicine （TCM） and integrative TCM-Western medicine approaches in the treatment of diabetic microvascular complications （DMC）， refine key pathophysiological insights and treatment principles， and promote academic innovation and strategic research planning in the prevention and treatment of DMC. The 38th session of the Expert Salon on Diseases Responding Specifically to Traditional Chinese Medicine， hosted by the China Association of Chinese Medicine， was held in Beijing， 2024. Experts in TCM， Western medicine， and interdisciplinary fields convened to conduct a systematic discussion on the pathogenesis， diagnostic and treatment challenges， and mechanism research related to DMC， ultimately forming a consensus on key directions. Four major research recommendations were proposed. The first is addressing clinical bottlenecks in the prevention and control of DMC by optimizing TCM-based evidence evaluation systems. The second is refining TCM core pathogenesis across DMC stages and establishing corresponding "disease-pattern-time" framework. The third is innovating mechanism research strategies to facilitate a shift from holistic regulation to targeted intervention in TCM. The fourth is advancing interdisciplinary collaboration to enhance the role of TCM in new drug development， research prioritization， and guideline formulation. TCM and integrative approaches offer distinct advantages in managing DMC. With a focus on the diseases responding specifically to TCM， strengthening evidence-based support and mechanism interpretation and promoting the integration of clinical care and research innovation will provide strong momentum for the modernization of TCM and the advancement of national health strategies.

Abdominal aortic aneurysm (AAA) is a deadly condition of the aorta, carrying a significant risk of death upon rupture. Currently, there is a dearth of efficacious pharmaceutical interventions to impede the advancement of AAA and avert it from rupturing. Here, we investigated dihydromyricetin (DHM), one of the predominant bioactive flavonoids in Ampelopsis grossedentata (A. grossedentata), as a potential agent for inhibiting AAA. DHM effectively blocked the formation of AAA in angiotensin II-infused apolipoprotein E-deficient (ApoE^-/-) mice. A combination of network pharmacology and whole transcriptome sequencing analysis revealed that DHM's anti-AAA action is linked to heme oxygenase (HO)-1 (Hmox-1 for the rodent gene) and hypoxia-inducible factor (HIF)-1α in vascular smooth muscle cells (VSMCs). Remarkably, DHM caused a robust rise (∼10-fold) of HO-1 protein expression in VSMCs, thereby suppressing VSMC inflammation and oxidative stress and preserving the VSMC contractile phenotype. Intriguingly, the therapeutic effect of DHM on AAA was largely abrogated by VSMC-specific Hmox1 knockdown in mice. Mechanistically, on one hand, DHM increased the transcription of Hmox-1 by triggering the nuclear translocation and activation of HIF-1α, but not nuclear factor erythroid 2-related factor 2 (NRF2). On the other hand, molecular docking, combined with cellular thermal shift assay (CETSA), isothermal titration calorimetry (ITC), drug affinity responsive target stability (DARTS), co-immunoprecipitation (Co-IP), and site mutant experiments revealed that DHM bonded to HO-1 at Lys243 and prevented its degradation, thereby resulting in considerable HO-1 buildup. In summary, our findings suggest that naturally derived DHM has the capacity to markedly enhance HO-1 expression in VSMCs, which may hold promise as a therapeutic strategy for AAA.

Although clinical evidence suggests that nonalcoholic fatty liver disease is an established major risk factor for heart failure, it remains unexplored whether sleep disorder-caused hepatic damage contributes to the development of cardiovascular disease (CVD). Here, our findings revealed that sleep fragmentation (SF) displayed notable hepatic detrimental phenotypes, including steatosis and oxidative damage, along with significant abnormalities in cardiac structure and function. All these pathological changes persisted even after sleep recovery for 2 consecutive weeks or more, displaying memory properties. Mechanistically, persistent higher expression of nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4) in the liver was the key initiator of SF-accelerated damage phenotypes. SF epigenetically controlled the acetylation of histone H3 lysine 27 (H3K27ac) enrichment at the Nox4 promoter and markedly increased Nox4 expression in liver even after sleep recovery. Moreover, fine coordination of the circadian clock and hepatic damage was strictly controlled by BMAL1-dependent Sirtuin 1 (Sirt1) transcription after circadian misalignment. Accordingly, genetic manipulation of liver-specific Nox4 or Sirt1, along with pharmacological intervention targeting NOX4 (GLX351322) or SIRT1 (Resveratrol), could effectively erase the epigenetic modification of Nox4 by reducing the H3K27ac level and ameliorate the progression of liver pathology, thereby counteracting SF-evoked sustained CVD. Collectively, our findings may pave the way for strategies to mitigate myocardial injury from persistent hepatic detrimental memory in diabetic patients.

A major obstacle in type 2 diabetes mellitus (T2DM) is sleep fragmentation (SF), which negatively affects testicular function. However, the underlying mechanisms remain to be elucidated. In this study, we demonstrate that SF induces testicular damage through a mechanism involving lipid metabolism, specifically mediated by melatonin (MEL) receptor 1a (MT1). T2DM mice with SF intervention displayed several deleterious phenotypes such as apoptosis, deregulated lipid metabolism, and impaired testicular function. Unexpectedly, sleep recovery (SR) for 2 consecutive weeks could not completely abrogate SF's detrimental effects on lipid deposition and testicular function. Interestingly, MEL and MT1 agonist 2-iodomelatonin (2IM) effectively improved lipid homeostasis, highlighting MEL/2IM as a promising therapeutic drug for SF-trigged testicular damage. Mechanistically, MEL and 2IM activated FGFR1 and sequentially restrained the crosstalk and physical interaction between TAB1 and TAK1, which ultimately suppressed the phosphorylation of TAK1 to block lipid deposition and cell apoptosis caused by SF. The ameliorating effect of MEL/2IM was overtly nullified in Fgfr1 knockout (Fgfr1-KO ^+/- ) diabetic mice. Meanwhile, testicular-specific overexpression of Tak1 abolished the protective effect of FGF1^mut on diabetic mouse testis. Our findings offer valuable insights into the molecular mechanisms underlying the testicular pathogenesis associated with SF and propose a novel therapeutic approach for addressing male infertility in T2DM.

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [¹⁵N₂]-cystine and [¹³C₅]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

OBJECTIVE: To investigate the feasibility and prognostic implications of assessing volume status during early fluid resuscitation in septic patients based on estimated plasma volume status (ePVS). METHODS: A prospective study was conducted. Patients with sepsis admitted to intensive care unit (ICU) of the First Affiliated Hospital of Kunming Medical University from March to December in 2023 were enrolled. The general information and laboratory indicators at ICU admission were recorded, and ePVS, sequential organ failure assessment (SOFA) score, acute physiology and chronic health status evaluation II (APACHE II) score were calculated. The vital signs, arterial blood gas analysis and volume status related indicators before liquid resuscitation (T0h) and 3 hours (T3h) and 6 hours (T6h) of fluid resuscitation were recorded. The diameter and variability of the inferior vena cava (IVC) were measured by ultrasound, and ePVS, percentage change value of estimated plasma volume status (ΔePVS%), difference in central venous-to-arterial partial pressure of carbon dioxide (Pcv-aCO₂), and lactate clearance rate (LCR) were calculated. Patients were divided into sepsis group and septic shock group based on the diagnosis at ICU admission, and septic patients were subdivided into survival group and death group based on their 28-day survival status. The differences in clinical data between the groups were compared. The correlation between ePVS or ΔePVS% and volume status related indicators during early liquid resuscitation was analyzed by Spearman rank sum correlation test. The predictive value of each variable for 28-day survival in patients with sepsis was analyzed by receiver operator characteristic curve (ROC curve), and 28-day death risk factors were analyzed by Logistic regression method. RESULTS: Fifty-four septic patients were enrolled in the final analysis, including 17 with sepsis and 37 with septic shock; 34 survived at 28 days and 20 died, with a 28-day survival rate of 63.0%. Compared with the sepsis group, the septic shock group had a lower venous ePVS at ICU admission [dL/g: 4.96 (3.67, 7.15) vs. 7.55 (4.36, 10.07), P < 0.05]. Compared with the death group, the survival group had higher T6h arterial and venous ΔePVS%, and albumin [Alb; T6h arterial ΔePVS% (%): 11.57% (-1.82%, 31.35%) vs. 0.48% (-5.67%, 6.02%), T6h venous ΔePVS%: 9.62% (3.59%, 25.75%) vs. 1.52% (-9.65%, 7.72%), Alb (g/L): 27.57±4.15 vs. 23.77±6.97, all P < 0.05], lower SOFA score, APACHE II score, AST, T0h Lac, and T3h and T6h norepinephrine dosage [SOFA score: 9.00 (8.00, 10.00) vs. 11.50 (9.25, 14.50), APACHE II score: 18.00 (14.75, 21.25) vs. 25.50 (21.00, 30.00), AST (U/L): 34.09 (23.20, 56.64) vs. 79.24 (25.34, 196.59), T0h Lac (mmol/L): 1.75 (1.40, 2.93) vs. 3.25 (2.33, 5.30), norepinephrine dosage (mg): 0.98 (< 0.01, 3.10) vs. 4.60 (1.05, 8.55) at T3h, 1.82 (0.38, 5.30) vs. 8.20 (2.80, 17.73) at T6h, all P < 0.05]. While there were no significantly differences in other basic data and ePVS at all of the time points before and after resuscitation between the two groups. Correlation analysis showed that T6h venous ePVS was significantly positively correlated with T6h IVC variability in septic patients (r = 0.360, P < 0.05), T0h arterial ePVS was significantly negatively correlated with T3h and T6h liquid intake volume (r₁ = -0.367, r₂ = -0.280, both P < 0.05), and venous ePVS at ICU admission was significantly positively correlated with NT-proBNP at ICU admission (r = 0.409, P < 0.05). T6h venous ΔePVS% was significantly positively correlated with T3h liquid intake volume and T6h LCR (r₁ = 0.286, r₂ = 0.286, both P < 0.05), and significantly negatively correlated with T6h urine volume and T6h change value of Pcv-aCO₂ (ΔPcv-aCO₂; r₁ = -0.321, r₂ = -0.371, both P < 0.05). ROC curve analysis showed that the area under the ROC curve (AUC) of T6h venous ΔePVS% for predicting 28-day survival in septic patients was 0.726 [95% confidence interval (95%CI) was 0.578-0.875, P = 0.006], with a sensitivity of 82.4%, a specificity of 60.0%, and an optimal cut-off value of 3.09%. Binary multifactorial Logistic regression analysis showed that an increase in T6h venous ΔePVS% was a protective factor for 28-day death in patients with sepsis on early fluid resuscitation [odds ratio (OR) = 0.900, 95%CI was 0.834-0.972, P = 0.007]. CONCLUSIONS ePVS may have potential for assessing the volume status of septic patients during early fluid resuscitation. The ΔePVS% during early fluid resuscitation may help to identify septic patients with a poor prognosis.
Humans ; Prognosis ; Fluid Therapy ; Sepsis/physiopathology* ; Prospective Studies ; Plasma Volume ; Intensive Care Units ; Resuscitation ; Male ; Female ; Middle Aged ; Shock, Septic/therapy*

OBJECTIVE: To evaluate the effectiveness of tibial nerve transection with epineurial suture and division of the common plantar digital nerve branches in the treatment of congenital macrodactyly in children. METHODS: A retrospective analysis was conducted on clinical data from 9 children with congenital macrodactyly who met the selection criteria and were admitted between January 2018 and December 2024. The cohort included 4 boys and 5 girls, aged 1-6 years (median, 3 years). Syndactyly of the second and third toes was present in 2 patients. Hypertrophy distribution was as follows: 1 case of single-ray involvement, 4 of double-ray, 1 of triple-ray, 1 of quadruple-ray, and 2 of quintuple-ray. Preoperatively, 7 cases exhibited limitations in both active and passive flexion and extension of the affected toes; in 2 cases, active movement was restricted while passive motion remained intact. All 9 children were unable to wear standard-sized footwear for the unaffected foot. Six presented with a limp, and 3 had difficulty walking. All 9 cases were moderate to severe progressive macrodactyly, and the growth rate of the affected foot was significantly faster than that of the healthy side. Six cases had undergone prior surgical interventions at other institutions, but disease progression continued postoperatively. All 9 patients underwent tibial nerve transection with epineurial suture and selective division of the common plantar digital nerve branches. At last follow-up, the foot growth rate was calculated (compared with that immediately after operation), and the changes of plantar pain sensation in the affected foot were detected before operation, immediately after operation, and at last follow-up, and the surgical efficacy was evaluated based on improvements in shoe fit and gait function. RESULTS: All 9 children were followed up 6-36 months, with an average of 18 months. All the incisions healed by first intention, and no infection or plantar ulceration occurred. At last follow-up, the growth rate of the affected foot was 0.10 (0.04, 0.14) cm/month, which was significantly slower than that of the healthy foot [0.14 (0.08, 0.18) cm/month] ( Z=3.951, P<0.001). Preoperatively, plantar pain sensation was absent in all cases; it was restored immediately after operation. At last follow-up, 6 patients had absent pain sensation, 2 had partial preservation (involving certain toes and central plantar regions), and 1 patient (with 3-year follow-up) exhibited regained sensation in multiple plantar areas. Gait improved in most cases, in which 8 children achieved normal ambulation, while 1 continued to limp due to leg-length discrepancy. Surgical efficacy were rated as excellent in 1 case, good in 7, and fair in 1. CONCLUSION Tibial nerve transection with epineurial suture combined with selective division of the common plantar digital nerve branches effectively reduces the growth rate of congenital macrodactyly in children, has minimal impact on plantar sensory function, and does not result in plantar ulcers or impaired ambulation.
Humans ; Male ; Female ; Child, Preschool ; Child ; Retrospective Studies ; Infant ; Tibial Nerve/surgery* ; Toes/surgery* ; Treatment Outcome ; Suture Techniques ; Fingers/surgery* ; Foot/innervation* ; Limb Deformities, Congenital