Objective: To investigate the effects of Zuogui Jiangtang Yishen Formula (左归降糖益肾方, ZGJTYSF) in regulating the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) signaling axis on pyroptosis in rats with diabetic kidney disease (DKD). Methods: Fifty male specific pathogen-free (SPF) grade Goto-Kakizaki (GK) rats (12 weeks old) were fed a high-fat diet for one month to establish an early DKD model. Model establishment was confirmed when fasting blood glucose (FBG) ≥ 11.1 mmol/L and urinary albumin-to-creatinine ratio (uACR) ≥ 30 mg/g. The successfully modeled early DKD rats were randomly divided by random number table into five groups (n = 10 per group): model group; dapagliflozin group (1.0 mg/kg, by gavage, served as positive control); and low-, medium-, and high-dose of ZGJTYSF groups (4.9, 9.9, and 19.9 g/kg, respectively, by gavage). Age-matched male SPF Wistar rats (n = 10) served as control group. Rats in control and model groups were gavaged with equivalent volumes of distilled water. Treatment lasted 12 weeks. Changes in uACR, FBG, and renal function were observed in all groups. Hematoxylin-eosin (HE), periodic acid-Schiff (PAS), and Masson staining were used to observe renal histopathological changes. Immunohistochemistry was performed to detect the localization and expression of caspase-1, GSDMD, and NLRP3 in rat renal tissues. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) was utilized to detect pyroptosis in renal tissues. Quantitative real-time polymerase chain reaction (qPCR) and Western blot were applied to detect mRNA and protein expression levels of NLRP3, caspase-1, GSDMD, interleukin (IL)-1β, and IL-18. Results: Compared with model group, all doses of ZGJTYSF showed reductions in FBG, with medium- and high-dose of ZGJTYSF groups demonstrating significant decreases at week 8 and 12 (P < 0.05). For uACR, all doses of ZGJTYSF groups exhibited a decreasing trend, with high-dose of ZGJTYSF group being significantly lower than low- and medium-dose of ZGJTYSF groups at week 12 (P < 0.05) and showing no significant difference from dapagliflozin group (P > 0.05). No significant differences in renal function parameters (serum creatinine, blood urea nitrogen, and uric acid) were observed among groups (P > 0.05). Histopathological examination revealed milder glomerular and tubular lesions in both ZGJTYSF groups and dapagliflozin group, with renal pathological changes in high-dose of ZGJTYSF group resembling those in dapagliflozin group. Immunohistochemistry demonstrated significantly reduced expression of caspase-1, GSDMD, and NLRP3 in renal tissues of dapagliflozin group and high-dose of ZGJTYSF group compared with model group (P < 0.05 or P < 0.01), while the differences in low- and medium-dose of ZGJTYSF groups were not statistically significant (P > 0.05). TUNEL assay showed significantly fewer TUNEL-positive cells in renal tissues of dapagliflozin and high-dose of ZGJTYSF groups (P < 0.01), indicating a marked reduction in pyroptotic cells. Molecular analysis revealed that compared with model group, both dapagliflozin and high-dose of ZGJTYSF groups showed significantly downregulated mRNA and protein expression levels of NLRP3, caspase-1, GSDMD, IL-1β, and IL-18 in renal tissues (P < 0.01), while low- and medium-dose of ZGJTYSF groups showed downward trends without statistical significance (P > 0.05). Conclusion ZGJTYSF may inhibit renal pyroptosis by regulating the NLRP3/caspase-1/GSDMD signaling axis, thereby preventing and treating early renal injury in DKD and delaying the onset and progression of DKD.

Approximately 60% of colorectal cancer (CRC) patients exhibit TP53 mutations, which are strongly associated with tumor progression, chemotherapy resistance, and an unfavorable prognosis. However, targeting p53 has historically been challenging, and currently, there are no approved p53-based therapeutics for clinical use worldwide. In this study, we discovered that ubiquitin carboxyl terminal hydrolase L3 (UCHL3) plays a crucial role in high-level glycolysis, enhanced stem-like properties, and 5-fluorouracil (5-FU) chemoresistance in TP53-mutant CRC by exerting its deubiquitinating enzyme activity to stabilize α-enolase (ENO1) protein. Notably, we identified a newly Food and Drug Administration (FDA)-approved drug, pacritinib, that potently suppresses UCHL3 expression by blocking the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway in TP53-mutant CRC. Furthermore, Pacritinib was demonstrated to effectively inhibit glycolysis and improve the sensitivity to 5-FU chemotherapy in TP53-mutant CRC. Our findings suggest that targeting the JAK2-STAT3-UCHL3-ENO1 axis is a promising strategy to suppress glycolysis and enhance the efficacy of 5-FU chemotherapy in TP53-mutant CRC. Pacritinib shows potential for clinical application in the treatment of TP53-mutant CRC.

Objective:To develop a prognostic prediction model for patients with colorectal cancer based on a peripheral blood cell composite score (PBCS) system.Methods:This retrospective observational study included patients who had primary colorectal cancer without distant metastasis, who did not undergo radiotherapy or chemotherapy before surgery, who did not receive leukocyte or platelet-raising therapy within 1 month before surgery, and whose postoperative pathology confirmed colorectal adenocarcinoma with complete tumor resection. Patients with severe anemia, infection, or hematologic diseases before surgery, as well as those with severe heart, lung, or other important organ diseases or concurrent malignant tumors, were excluded. In total, 1021 patients with colorectal cancer who underwent surgical treatment in the Department of Gastrointestinal Surgery of the Fourth Hospital of Hebei Medical University from April 2018 to April 2020 were retrospectively included as the training set (766 patients) and the internal validation set (255 patients). Additionally, using the same criteria, 215 patients with colorectal cancer who underwent surgical treatment in another treatment group from March 2015 to December 2020 were selected as the external validation set. The "surv_cutpoint" function in R software was used to analyze the optimal cut-off values of neutrophils, lymphocytes, and platelets, and a PBCS system was established based on the optimal cut-off values. The scoring rules of the PBCS system were as follows: Neutrophils and platelets below the optimal cut-off value = 1 point, otherwise 0 points; Lymphocytes above the optimal cut-off value = 1 point, otherwise 0 points. The scores of the three cell types were added together to obtain the PBCS. Univariate and multivariate Cox regression analyses were performed to explore the correlation between patients' clinicopathological features and prognosis, and a nomogram was constructed based on the Cox regression analysis to predict patients' prognosis. The accuracy of the nomogram prediction model was validated using the C-index, calibration curve, and decision curve analysis.Results:The optimal cut-off values for neutrophils, lymphocytes, and platelets were 4.40×10 9/L, 1.41×10 9/L, and 355×10 9/L, respectively. The patients were divided into high and low groups according to the optimal cut-off values of these cells. Survival curve analysis showed that a high lymphocyte count (training set: P=0.042, internal validation: P=0.010, external validation: P=0.029), low neutrophil count (training set: P=0.035, internal validation: P=0.001, external validation: P=0.024), and low platelet count (training set: P=0.041, internal validation: P=0.030, external validation: P=0.024) were associated with prolonged overall survival (OS), with statistically significant differences in all cases. Survival analysis of different PBCS groups showed that patients with a high PBCS had longer OS than those with a low PBCS ( P<0.05). Univariate and multivariate Cox regression analysis results showed that aspirin use history, vascular thrombus, neural invasion, CA19-9, N stage, operation time, M stage, and PBCS were independent factors affecting OS (all P<0.05). The PBCS was also an independent factor affecting disease-specific survival ( P<0.05), but not progression-free survival ( P>0.05). The above independent risk or protective factors were included in R software to construct a nomogram for predicting OS. The C-index (0.873), calibration curve, and decision curve analysis (threshold probability: 0.0%–75.2%) all indicated that the nomogram prediction model had good predictive performance for OS. Conclusion:This study demonstrates that the PBCS constructed based on preoperative peripheral blood levels of neutrophils, lymphocytes, and platelets is an independent factor associated with the prognosis of patients with colorectal cancer. The nomogram model constructed based on this score system exhibits good predictive efficacy for the prognosis of these patients.

Primary hepatocellular carcinoma(HCC)is a common malignant tumor in the world,and in China it is the fourth most common malignant tumor and the second cause of cancer mortality.In China,most HCC patients are already in the advanced stage when the clinical diagnosis of HCC is confirmed,and it is impossible to adopt a radical treatment for the patient.At present,transarterial chemoembolization(TACE)has become the mainstream therapeutic option for unresectable HCC,and hepatic arterial perfusion chemotherapy(HAIC),as a new therapeutic option,has attracted extensive attention.This article reviews the research progress in TACE combined with HAIC for the treatment of HCC,and obtains the following conclusions:TACE combined with HAIC has better efficacy than TACE along in patients with unresectable HCC of BCLC stage C,massive HCC,and portal venous invasion,but there is no significant difference in the therapeutic efficacy between TACE combined with HAIC and TACE alone for patients with HCC of BCLC stage A/B.It is expected that this review will provide effective recommendations for treating HCC patients in clinical practice,further standardize TACE treatment and later-stage HAIC treatment,and provide the basis for the design of relevant clinical studies.

Objective:To develop a prognostic prediction model for patients with colorectal cancer based on a peripheral blood cell composite score (PBCS) system.Methods:This retrospective observational study included patients who had primary colorectal cancer without distant metastasis, who did not undergo radiotherapy or chemotherapy before surgery, who did not receive leukocyte or platelet-raising therapy within 1 month before surgery, and whose postoperative pathology confirmed colorectal adenocarcinoma with complete tumor resection. Patients with severe anemia, infection, or hematologic diseases before surgery, as well as those with severe heart, lung, or other important organ diseases or concurrent malignant tumors, were excluded. In total, 1021 patients with colorectal cancer who underwent surgical treatment in the Department of Gastrointestinal Surgery of the Fourth Hospital of Hebei Medical University from April 2018 to April 2020 were retrospectively included as the training set (766 patients) and the internal validation set (255 patients). Additionally, using the same criteria, 215 patients with colorectal cancer who underwent surgical treatment in another treatment group from March 2015 to December 2020 were selected as the external validation set. The "surv_cutpoint" function in R software was used to analyze the optimal cut-off values of neutrophils, lymphocytes, and platelets, and a PBCS system was established based on the optimal cut-off values. The scoring rules of the PBCS system were as follows: Neutrophils and platelets below the optimal cut-off value = 1 point, otherwise 0 points; Lymphocytes above the optimal cut-off value = 1 point, otherwise 0 points. The scores of the three cell types were added together to obtain the PBCS. Univariate and multivariate Cox regression analyses were performed to explore the correlation between patients' clinicopathological features and prognosis, and a nomogram was constructed based on the Cox regression analysis to predict patients' prognosis. The accuracy of the nomogram prediction model was validated using the C-index, calibration curve, and decision curve analysis.Results:The optimal cut-off values for neutrophils, lymphocytes, and platelets were 4.40×10 9/L, 1.41×10 9/L, and 355×10 9/L, respectively. The patients were divided into high and low groups according to the optimal cut-off values of these cells. Survival curve analysis showed that a high lymphocyte count (training set: P=0.042, internal validation: P=0.010, external validation: P=0.029), low neutrophil count (training set: P=0.035, internal validation: P=0.001, external validation: P=0.024), and low platelet count (training set: P=0.041, internal validation: P=0.030, external validation: P=0.024) were associated with prolonged overall survival (OS), with statistically significant differences in all cases. Survival analysis of different PBCS groups showed that patients with a high PBCS had longer OS than those with a low PBCS ( P<0.05). Univariate and multivariate Cox regression analysis results showed that aspirin use history, vascular thrombus, neural invasion, CA19-9, N stage, operation time, M stage, and PBCS were independent factors affecting OS (all P<0.05). The PBCS was also an independent factor affecting disease-specific survival ( P<0.05), but not progression-free survival ( P>0.05). The above independent risk or protective factors were included in R software to construct a nomogram for predicting OS. The C-index (0.873), calibration curve, and decision curve analysis (threshold probability: 0.0%–75.2%) all indicated that the nomogram prediction model had good predictive performance for OS. Conclusion:This study demonstrates that the PBCS constructed based on preoperative peripheral blood levels of neutrophils, lymphocytes, and platelets is an independent factor associated with the prognosis of patients with colorectal cancer. The nomogram model constructed based on this score system exhibits good predictive efficacy for the prognosis of these patients.

Primary hypotension is a common and frequently occurring blood vessel disease,characterized by insidious onset,lingering condition,complex etiology,and diverse symptoms.Its pathogenesis is primarily characterized by deficiency,and its onset involves multiple zang-fu organs.The"yang transforming qi and yin shaping up body"theory is derived from the Huangdi Neijing.This theory summarizes the fundamental laws of the movement and changes in yin and yang.From this perspective,the paper hypothesizes that the basic pathogenesis of primary hypotension stems from an insufficiency of yang in transforming qi and a malfunction of yin in shaping up body.The essence of the condition lies in an overall yang deficiency that fails to provide warmth and transformation,coupled with qi deficiency,which cannot control and regulate bodily functions.This leads to poor blood circulation and inadequate protection,causing yin to malfunction in forming the physical components of the body.As a result,normal physiological functions of the zang-fu organs are disrupted,the production of beneficial physiological substances is obstructed,and metabolic waste products accumulate.The primary therapeutic approach should be focused on tonifying qi and ascending yang;tonifying qi will provide the impetus for blood circulation,whereas ascending yang will facilitate yang transformation qi.The zang-fu organs should also be protected and nourished to ameliorate the internal environment of yang deficiency and yin excess,as well as to eliminate pathological product accumulation to dredge the channels of blood circulation.Using the"yang transforming qi and yin shaping up the body"theory to guide the treatment of primary hypotension can help deepen the understanding of the pathogenesis of this disease and broaden the clinical diagnosis and treatment strategies.

Primary hypotension is a common and frequently occurring blood vessel disease,characterized by insidious onset,lingering condition,complex etiology,and diverse symptoms.Its pathogenesis is primarily characterized by deficiency,and its onset involves multiple zang-fu organs.The"yang transforming qi and yin shaping up body"theory is derived from the Huangdi Neijing.This theory summarizes the fundamental laws of the movement and changes in yin and yang.From this perspective,the paper hypothesizes that the basic pathogenesis of primary hypotension stems from an insufficiency of yang in transforming qi and a malfunction of yin in shaping up body.The essence of the condition lies in an overall yang deficiency that fails to provide warmth and transformation,coupled with qi deficiency,which cannot control and regulate bodily functions.This leads to poor blood circulation and inadequate protection,causing yin to malfunction in forming the physical components of the body.As a result,normal physiological functions of the zang-fu organs are disrupted,the production of beneficial physiological substances is obstructed,and metabolic waste products accumulate.The primary therapeutic approach should be focused on tonifying qi and ascending yang;tonifying qi will provide the impetus for blood circulation,whereas ascending yang will facilitate yang transformation qi.The zang-fu organs should also be protected and nourished to ameliorate the internal environment of yang deficiency and yin excess,as well as to eliminate pathological product accumulation to dredge the channels of blood circulation.Using the"yang transforming qi and yin shaping up the body"theory to guide the treatment of primary hypotension can help deepen the understanding of the pathogenesis of this disease and broaden the clinical diagnosis and treatment strategies.

Primary hypotension is a common and frequently occurring blood vessel disease,characterized by insidious onset,lingering condition,complex etiology,and diverse symptoms.Its pathogenesis is primarily characterized by deficiency,and its onset involves multiple zang-fu organs.The"yang transforming qi and yin shaping up body"theory is derived from the Huangdi Neijing.This theory summarizes the fundamental laws of the movement and changes in yin and yang.From this perspective,the paper hypothesizes that the basic pathogenesis of primary hypotension stems from an insufficiency of yang in transforming qi and a malfunction of yin in shaping up body.The essence of the condition lies in an overall yang deficiency that fails to provide warmth and transformation,coupled with qi deficiency,which cannot control and regulate bodily functions.This leads to poor blood circulation and inadequate protection,causing yin to malfunction in forming the physical components of the body.As a result,normal physiological functions of the zang-fu organs are disrupted,the production of beneficial physiological substances is obstructed,and metabolic waste products accumulate.The primary therapeutic approach should be focused on tonifying qi and ascending yang;tonifying qi will provide the impetus for blood circulation,whereas ascending yang will facilitate yang transformation qi.The zang-fu organs should also be protected and nourished to ameliorate the internal environment of yang deficiency and yin excess,as well as to eliminate pathological product accumulation to dredge the channels of blood circulation.Using the"yang transforming qi and yin shaping up the body"theory to guide the treatment of primary hypotension can help deepen the understanding of the pathogenesis of this disease and broaden the clinical diagnosis and treatment strategies.

Primary hypotension is a common and frequently occurring blood vessel disease,characterized by insidious onset,lingering condition,complex etiology,and diverse symptoms.Its pathogenesis is primarily characterized by deficiency,and its onset involves multiple zang-fu organs.The"yang transforming qi and yin shaping up body"theory is derived from the Huangdi Neijing.This theory summarizes the fundamental laws of the movement and changes in yin and yang.From this perspective,the paper hypothesizes that the basic pathogenesis of primary hypotension stems from an insufficiency of yang in transforming qi and a malfunction of yin in shaping up body.The essence of the condition lies in an overall yang deficiency that fails to provide warmth and transformation,coupled with qi deficiency,which cannot control and regulate bodily functions.This leads to poor blood circulation and inadequate protection,causing yin to malfunction in forming the physical components of the body.As a result,normal physiological functions of the zang-fu organs are disrupted,the production of beneficial physiological substances is obstructed,and metabolic waste products accumulate.The primary therapeutic approach should be focused on tonifying qi and ascending yang;tonifying qi will provide the impetus for blood circulation,whereas ascending yang will facilitate yang transformation qi.The zang-fu organs should also be protected and nourished to ameliorate the internal environment of yang deficiency and yin excess,as well as to eliminate pathological product accumulation to dredge the channels of blood circulation.Using the"yang transforming qi and yin shaping up the body"theory to guide the treatment of primary hypotension can help deepen the understanding of the pathogenesis of this disease and broaden the clinical diagnosis and treatment strategies.

Primary hypotension is a common and frequently occurring blood vessel disease,characterized by insidious onset,lingering condition,complex etiology,and diverse symptoms.Its pathogenesis is primarily characterized by deficiency,and its onset involves multiple zang-fu organs.The"yang transforming qi and yin shaping up body"theory is derived from the Huangdi Neijing.This theory summarizes the fundamental laws of the movement and changes in yin and yang.From this perspective,the paper hypothesizes that the basic pathogenesis of primary hypotension stems from an insufficiency of yang in transforming qi and a malfunction of yin in shaping up body.The essence of the condition lies in an overall yang deficiency that fails to provide warmth and transformation,coupled with qi deficiency,which cannot control and regulate bodily functions.This leads to poor blood circulation and inadequate protection,causing yin to malfunction in forming the physical components of the body.As a result,normal physiological functions of the zang-fu organs are disrupted,the production of beneficial physiological substances is obstructed,and metabolic waste products accumulate.The primary therapeutic approach should be focused on tonifying qi and ascending yang;tonifying qi will provide the impetus for blood circulation,whereas ascending yang will facilitate yang transformation qi.The zang-fu organs should also be protected and nourished to ameliorate the internal environment of yang deficiency and yin excess,as well as to eliminate pathological product accumulation to dredge the channels of blood circulation.Using the"yang transforming qi and yin shaping up the body"theory to guide the treatment of primary hypotension can help deepen the understanding of the pathogenesis of this disease and broaden the clinical diagnosis and treatment strategies.