Enhancing circuit stability under growth feedback with supplementary repressive regulation.

The field of synthetic biology and biosystems engineering increasingly acknowledges the need for a holistic design approach that incorporates circuit-host interactions into the design process. Engineered circuits are not isolated entities but inherently entwined with the dynamic host environment. One such circuit-host interaction, 'growth feedback', results when modifications in host growth patterns influence the operation of gene circuits. The growth-mediated effects can range from growth-dependent elevation in protein/mRNA dilution rate to changes in resource reallocation within the cell, which can lead to complete functional collapse in complex circuits. To achieve robust circuit performance, synthetic biologists employ a variety of control mechanisms to stabilize and insulate circuit behavior against growth changes. Here we propose a simple strategy by incorporating one repressive edge in a growth-sensitive bistable circuit. Through both simulation and in vitro experimentation, we demonstrate how this additional repressive node stabilizes protein levels and increases the robustness of a bistable circuit in response to growth feedback. We propose the incorporation of repressive links in gene circuits as a control strategy for desensitizing gene circuits against growth fluctuations.

Proteome characterization of liver-kidney comorbidity after microbial sepsis.

Sepsis is a life-threatening condition that occurs when the body responds to an infection but subsequently triggers widespread inflammation and impaired blood flow. These pathologic responses can rapidly cause multiple organ dysfunction or failure either one by one or simultaneously. The fundamental common mechanisms involved in sepsis-induced multiple organ dysfunction remain unclear. Here, employing quantitative global and phosphoproteomics, we examine the liver's temporal proteome and phosphoproteome changes after moderate sepsis induced by cecum ligation and puncture. In total, 4593 global proteins and 1186 phosphoproteins according to 3275 phosphosites were identified. To characterize the liver-kidney comorbidity after sepsis, we developed a mathematical model and performed cross-analyses of liver and kidney proteome data obtained from the same set of mice. Beyond immune response, we showed the commonly disturbed pathways and key regulators of the liver-kidney comorbidity are linked to energy metabolism and consumption. Our data provide open resources to understand the communication between the liver and kidney as they work to fight infection and maintain homeostasis.

Influence of tumor thrombus morphology on the surgical complexity in renal cell carcinoma with inferior vena cava tumor thrombus: a single-center, large-sample study from China.

BACKGROUND: The morphology of tumor thrombus varies from person to person and it may affect surgical methods and tumor prognosis. However, studies on the morphology of tumor thrombus are limited. The purpose of our study was to evaluate the impact of tumor thrombus morphology on surgical complexity. METHODS: We retrospectively reviewed the clinical data of 229 patients with renal cell carcinoma combined with inferior vena cava (IVC) tumor thrombus who underwent surgical treatment at Peking University Third Hospital between January 2014 and December 2021. The patients were divided into floating morphology (107 patients) and filled morphology (122 patients) tumor thrombi groups. Chi-square and Mann-Whitney U tests were used for categorical and continuous variables, respectively. Postoperative complications were evaluated using the Clavien-Dindo surgical complication classification method. RESULTS: Patients with filled morphology tumor thrombus required more surgical techniques than those with floating morphology tumor thrombus, which was reflected in more open surgeries (P < 0.001), more IVC interruptions (P <0.001), lesser use of the delayed occlusion of the proximal inferior vena cava (DOPI) technique (P < 0.001), and a greater need for cut-off of the short hepatic vein (P < 0.001) and liver dissociation (P = 0.001). Filled morphology significantly increased the difficulty of surgery in patients with renal cell carcinoma with tumor thrombus, reflected in longer operation time (P < 0.001), more surgical blood loss (P <0.001), more intra-operative blood transfusion (P < 0.001), and longer postoperative hospital stay (P < 0.001). Filled morphology tumor thrombus also led to more postoperative complications (53% vs. 20%; P < 0.001). CONCLUSION: Compared with floating morphology thrombus, filled morphology thrombus significantly increased the difficulty of surgery in patients with renal cell carcinoma with IVC tumor thrombus.

Emergence of qualitative states in synthetic circuits driven by ultrasensitive growth feedback.

The mutual interactions between the synthetic gene circuits and the host growth could cause unexpected outcomes in the dynamical behaviors of the circuits. However, how the steady states and the stabilities of the gene circuits are affected by host cell growth is not fully understood. Here, we developed a mathematical model for nonlinear growth feedback based on published experimental data. The model analysis predicts that growth feedback could significantly change the qualitative states of the system. Bistability could emerge in a circuit without positive feedback, and high-order multistability (three or more steady states) arises in the self-activation and toggle switch circuits. Our results provide insight into the potential effects of ultrasensitive growth feedback on the emergence of qualitative states in synthetic circuits and the corresponding underlying mechanism.

Growth Feedback Confers Cooperativity in Resource-Competing Synthetic Gene Circuits.

Modularity is a key concept in designing synthetic gene circuits, as it allows for constructing complex molecular systems using well-characterized building blocks. One of the major challenges in this field is that these modular components often do not function as expected when assembled into larger circuits. One of the major issues is caused by resource competition, where multiple genes in the circuit compete for the same limited cellular resources, such as transcription factors and ribosomes. In addition, the mutual inhibition between synthetic gene circuits and cell growth results in growth feedback that significantly impacts its host-circuit dynamics. However, the complexity of the gene circuit dynamics under intertwined resource competition and growth feedback is not fully understood. This study developed a theoretical framework to examine the dynamics of synthetic gene circuits by considering both growth feedback and resource competition. Our results suggest a cooperative behavior between resource-competing gene circuits under growth feedback. Cooperation or competition is non-monotonically determined by the metabolic burden threshold. These two diverse effects could lead to the activation or deactivation of one circuit by the other. Lastly, the cooperativity mediated by growth feedback can attenuate the winner-takes-all resource competition. These findings show that coupling growth feedback and resource competition plays a crucial role in the dynamics of the host-circuit system, and understanding its effects helps control unexpected gene expression behaviors.

[Clinicopathologic features and prognosis of young renal tumors with tumor thrombus].

OBJECTIVE: To retrospectively analyze clinical data of patients under 40 years old who underwent surgical treatment for renal tumors with tumor thrombus from January 2016 to December 2022 at Peking University Third Hospital, and to evaluate the surgical effect and investigate the relationship between clinicopathological characteristics and prognosis. METHODS: The clinical data of 17 young patients with renal tumor thrombus were retrospectively analyzed, and the clinicopathological features and prognosis were summarized. The patients were grouped according to the presence or absence of symptoms, 2017 American Joint Committee on Cancer (AJCC) clinical stage, and postoperative combined adjuvant therapy. Kaplan-Meier method was used to plot the survival curve, and Log-rank test was used to compare the differences in postoperative survival time and progression-free survival time between the different groups. The relationship between clinicopathological features and prognosis was analyzed. RESULTS: All the 17 patients received venous tumor thrombectomy, including 16 patients (94.1%) who underwent radical nephrectomy and 1 patient (5.9%) who underwent partial nephrectomy. Twelve patients (70.6%) had symptoms and 5 (29.4%) had no symptoms before operation. A total of 17 renal tumors were observed, with 2 patients (11.8%) identified as benign and 15 patients (88.2%) classified as malignant. Among the malignant tumors, 1 patient (6.7%) was diagnosed as clear cell carcinoma, while the remaining 14 patients (93.3%) were categorized as non-clear cell carcinoma. In terms of tumor stage, 8 patients (53.3%) were classified as stage Ⅲ according to the AJCC classification, while 7 patients (46.7%) were categorized as stage Ⅳ. Additionally, 6 patients (40%) received multiple adjuvant therapy, while 9 patients (60%) did not undergo such treatment. The follow-up period ranged from 2 to 78 months, with a median follow-up of 41 months. During this time, 3 patients (20%) died. The median survival time after surgery was 39.0 (2.3, 77.8) months, and the progression-free survival time was 16.4 (2.3, 77.8) months. There was no significant difference in postoperative survival time and progression-free survival time among young patients with renal tumor with tumor thrombus, based on the presence of symptoms before surgery (P=0.307, P=0.302), clinical stage of AJCC (P=0.340, P=0.492), and postoperative adjuvant therapy (P=0.459, P=0.253) group. CONCLUSION: The pathological types of young patients with renal tumor with tumor thrombus are more complex and varied due to symptoms, and the proportion of non-clear cell carcinoma in malignant tumor with tumor thrombus is higher. Symptomatic and non-clear cell carcinoma may be potentially associated with poor prognosis. Surgical operation combined with adjuvant therapy is a relatively safe and effective treatment for young patients with renal tumor and tumor thrombus.

[Risk factors for massive hemorrhage after radical nephrectomy and removal of venous tumor thrombus].

OBJECTIVE: To investigate and analyze the risk factors of massive hemorrhage in patients with renal cell carcinoma and venous tumor thrombus undergoing radical nephrectomy and removal of venous tumor thrombus. METHODS: From January 2014 to June 2020, 241 patients with renal cancer and tumor thrombus in a single center of urology at Peking University Third Hospital were retrospectively analyzed. All patients underwent radical nephrectomy and removal of venous tumor thrombus. The relevant preoperative indicators, intraoperative conditions, and postoperative data were statistically analyzed by using statistical software of SPSS 18.0. The main end point of the study was intraoperative bleeding volume greater than 2 000 mL. Logistic regression analysis was used to determine the relevant influencing factors. First, single factor Logistic regression was used for preliminary screening of influencing factors, and variables with single factor Logistic regression analysis P < 0.05 were included in multivariate Logistic regression. In all statistical analyses, P < 0.05 is considered statistically significant. RESULTS: Among the 241 patients included, there were 60 cases of massive hemorrhage, 48 males and 12 females, with a median age of 62 years. The number of non-massive hemorrhage was 181. There were 136 males and 45 females, with a median age of 59 years. Univariate analysis showed that the clinical symptoms (both systemic and local symptoms, OR 2.794, 95%CI 1.087-7.181, P=0.033), surgical approach (open surgery, OR 9.365, 95%CI 4.447-19.72, P < 0.001), Mayo grade (Mayo 3-4, OR 5.257, 95%CI 2.806-10.886, P < 0.001), American Society of Anesthesiologists (ASA) score (ASA level 3, OR 2.842, 95%CI 1.338-6.036, P=0.007), preoperative hemoglobin (OR 0.978, 95%CI 0.965-0.991, P=0.001), preoperative platelet count (OR 0.996, 95%CI 0.992-1.000, P=0.037), maximum tumor thrombus width (OR 1.061, 95%CI 1.033-1.091, P < 0.001), Complicated with bland thrombus (OR 4.493, 95%CI 2.264-8.915, P < 0.001), adrenalectomy (OR 3.101, 95%CI 1.614-5.958, P=0.001), segmental resection of the inferior vena cava (OR 2.857, 95%CI 1.395-5.852, P=0.004). There was a statistically significant difference in these aspects(P < 0.05). Multivariate Logistic regression analysis showed that there was a statistically significant difference in surgical approach (open surgery, OR 6.730, 95%CI 2.947-15.368;P < 0.001), Mayo grade (Mayo 3-4, OR 2.294, 95%CI 1.064-4.948, P=0.034), Complicated with bland thrombus (OR 3.236, 95%CI 1.492-7.020, P=0.003). CONCLUSION: Combining the results of univariate and multivariate Logistic regression analysis, the surgical approach, Mayo grade, and tumor thrombus combined with conventional thrombus were associated risk factors for massive hemorrhage during surgery for renal cell carcinoma with tumor thrombus. Patients who undergo open surgery, high Mayo grade, and tumor thrombus combined with conventional thrombus are at a relatively higher risk of massive hemorrhage.

[Treatment outcome of laparoscopic partial nephrectomy in patients with renal tumors of moderate to high complexity].

OBJECTIVE: To investigate the treatment outcome of laparoscopic partial nephrectomy in the patients with renal tumors of moderate to high complexity (R.E.N.A.L. score 7-10). METHODS: In the study, 186 patients with a renal score of 7-10 renal tumors who underwent laparoscopic partial nephrectomy in Peking University Third Hospital from February 2016 to April 2021 were selected. Laparoscopic partial nephrectomy was performed after examination. The patients were followed-up, and their postoperative hemoglobin, creatinine, complications, and length of hospital stay recorded. The data were represented by mean±standard deviation or median (range). RESULTS: There were 128 males and 58 females in this group, aged (54.6±12.8) years, with body mass index of (25.4 ± 3.4) kg/m2; The tumors were located in 95 cases on the left and 91 cases on the right, with maximum diameter of (3.1±1.2) cm. The patient's preoperative hemoglobin was (142.9±15.8) g/L, and blood creatinine was 78 µmol/L (47-149 µmol/L). According to preoperative CT images, the R.E.N.A.L. score was 7 points for 43 cases, 8 points for 67 cases, 9 points for 53 cases, and 10 points for 23 cases. All the ope-rations were successfully completed, with 12 cases converted to open surgery. The operation time was 150 minutes (69-403 minutes), the warm ischemic time was 25 minutes (3-60 minutes), and the blood loss was 30 mL (5-1 500 mL). There were 9 cases of blood transfusions, with a transfusion volume of 800 mL (200-1 200 mL). Postoperative hemoglobin was (126.2±17.0) g/L. The preoperative crea-tinine was 78 µmol/L (47-149 µmol/L), the postoperative creatinine was 83.5 µmol/L (35-236 µmol/L), the hospital stay was 6 days (3-26 days), and surgical results achieved "the trifecta" in 87 cases (46.8%). In the study, 167 cases were followed up for 12 months (1-62 months), including 1 case with recurrence and metastasis, 4 cases with metastasis, and 2 cases with other tumors (1 case died). CONCLUSION: Laparoscopic partial nephrectomy is safe and effective in the treatment of renal tumors with R.E.N.A.L. score of 7-10. Based on the complexity of the tumor, with the increase of difficulty, the warm ischemia time and operation time tend to increase gradually, while "the trifecta" rate gradually decreases. The complications of this operation are less, and the purpose of preserving renal function to the greatest extent is achieved.

The role of prophylactic antibiotics in elective inguinal tension-free hernia repair: A systematic review and meta-analysis.

Whether to use antibiotics to prevent surgical site infection in elective inguinal tension-free hernia repair has been controversial. To systematically evaluate the effect of prophylactic antibiotic application in elective inguinal tension-free hernia repair, we identified all published randomised controlled trials of the effect of prophylactic antibiotic application on elective inguinal tension-free hernia repair were collected by computer retrieval from the China National Knowledge Infrastructure; VIP Database; Wanfang Database; China Biomedical Literature Database; and PubMed, EMBASE and Cochrane Library databases. Meta-analysis was performed by RevMan 5.3 software. The meta-analysis showed that the total incidence of surgical site infections [P = 0.003] and the incidence of superficial surgical site infections [P = 0.004] in the antibiotic group (AG) were lower than those in the non-antibiotic group (NAG). There was no significant difference in the total incidence of postoperative infections [P = 0.06], deep surgical site infections [P = 0.26] and seroma [P = 0.52] between the AG and the NAG. Based on current evidence, the application of prophylactic antibiotics in elective inguinal tension-free hernia repair can prevent the total incidence of surgical site infections and that of superficial surgical site infections but cannot prevent the total incidence of postoperative infection events, incidence of deep surgical site infections and incidence of seroma.

Topology-dependent interference of synthetic gene circuit function by growth feedback.

Growth-mediated feedback between synthetic gene circuits and host organisms leads to diverse emerged behaviors, including growth bistability and enhanced ultrasensitivity. However, the range of possible impacts of growth feedback on gene circuits remains underexplored. Here we mathematically and experimentally demonstrated that growth feedback affects the functions of memory circuits in a network topology-dependent way. Specifically, the memory of the self-activation switch is quickly lost due to the growth-mediated dilution of the circuit products. Decoupling of growth feedback reveals its memory, manifested by its hysteresis property across a broad range of inducer concentration. On the contrary, the toggle switch is more refractory to growth-mediated dilution and can retrieve its memory after the fast-growth phase. The underlying principle lies in the different dependence of active and repressive regulations in these circuits on the growth-mediated dilution. Our results unveil the topology-dependent mechanism on how growth-mediated feedback influences the behaviors of gene circuits.

Control of tissue homeostasis, tumorigenesis, and degeneration by coupled bidirectional bistable switches.

The Hippo-YAP/TAZ signaling pathway plays a critical role in tissue homeostasis, tumorigenesis, and degeneration disorders. The regulation of YAP/TAZ levels is controlled by a complex regulatory network, where several feedback loops have been identified. However, it remains elusive how these feedback loops contain the YAP/TAZ levels and maintain the system in a healthy physiological state or trap the system in pathological conditions. Here, a mathematical model was developed to represent the YAP/TAZ regulatory network. Through theoretical analyses, three distinct states that designate the one physiological and two pathological outcomes were found. The transition from the physiological state to the two pathological states is mechanistically controlled by coupled bidirectional bistable switches, which are robust to parametric variation and stochastic fluctuations at the molecular level. This work provides a mechanistic understanding of the regulation and dysregulation of YAP/TAZ levels in tissue state transitions.

A plausible accelerating function of intermediate states in cancer metastasis.

Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process and plays an essential role in development, tissue regeneration, and cancer metastasis. Interestingly, EMT is not a binary process but instead proceeds with multiple partial intermediate states. However, the functions of these intermediate states are not fully understood. Here, we focus on a general question about how the number of partial EMT states affects cell transformation. First, by fitting a hidden Markov model of EMT with experimental data, we propose a statistical mechanism for EMT in which many unobservable microstates may exist within one of the observable macrostates. Furthermore, we find that increasing the number of intermediate states can accelerate the EMT process and that adding parallel paths or transition layers may accelerate the process even further. Last, a stabilized intermediate state traps cells in one partial EMT state. This work advances our understanding of the dynamics and functions of EMT plasticity during cancer metastasis.

What can single-molecule Fano resonance tell?

In this work, we showcase applications of single-molecule Fano resonance (SMFR) measurements beyond the determination of molecular excitonic energy and associated dipole orientation. We use the SMFR measurement to probe the local influence of a man-made single chlorine vacancy on the molecular transition of a single zinc phthalocyanine, which clearly reveals the lifting-up of the double degeneracy of the excited states due to defect-induced configurational changes. Furthermore, time-trace SMFR measurements at different excitation voltages are used to track the tautomerization process in a free-base phthalocyanine. Different behaviors in switching between two inner-hydrogen configurations are observed with decreasing voltages, which helps to reveal the underlying tautomerization mechanism involving both the molecular electronic excited states and vibrational excited states in the ground state.

Investigating epithelial-to-mesenchymal transition with integrated computational and experimental approaches.

The transition between epithelial and mesenchymal (EMT) is a fundamental cellular process that plays critical roles in development, cancer metastasis, and tissue wound healing. EMT is not a binary process but involves multiple partial EMT states that give rise to a high degree of cell state plasticity. Here, we first reviewed several studies on theoretical predictions and experimental verification of these intermediate states, the role of partial EMT on kidney fibrosis development, and how quantitative signaling information controls cell commitment to partial or full EMT upon transient signals. Next, we summarized existing knowledge and open questions on the coupling between EMT and other biological processes, such as the cell cycle, epigenetic regulation, stemness, and apoptosis. Taken together, EMT is a model system that has attracted increasing interests for quantitative experimental and theoretical studies.

Disseminated cysticercosis in China with complex and variable clinical manifestations: a case series.

BACKGROUND: Cysticercosis is an emerging and neglected tropical disease (NTD) that poses a serious public health concern worldwide. Disseminated cysticercosis (DCC) is an uncommon manifestation of cysticercosis, also found in China. CASE PRESENTATION: We report three cases of DCC in patients living in China, with different clinical and radiological presentations. All three patients had DCC with active ocular cysticercosis, including one patient with widespread DCC caused by direct ingestion of Taenia solium eggs. The intravitreal cysticercus cyst in this patient was completely extracted entirely by 23-gauge pars plana vitrectomy, and the cyst was oval in shape on the flat mount preparation. CONCLUSION: The clinical presentation of DCC is highly sophisticated. The diagnosis depended on the typical radiological presentations, biopsy and flat mount preparations of the cyst.

Achieving diverse and monoallelic olfactory receptor selection through dual-objective optimization design.

Multiple-objective optimization is common in biological systems. In the mammalian olfactory system, each sensory neuron stochastically expresses only one out of up to thousands of olfactory receptor (OR) gene alleles; at the organism level, the types of expressed ORs need to be maximized. Existing models focus only on monoallele activation, and cannot explain recent observations in mutants, especially the reduced global diversity of expressed ORs in G9a/GLP knockouts. In this work we integrated existing information on OR expression, and constructed a comprehensive model that has all its components based on physical interactions. Analyzing the model reveals an evolutionarily optimized three-layer regulation mechanism, which includes zonal segregation, epigenetic barrier crossing coupled to a negative feedback loop that mechanistically differs from previous theoretical proposals, and a previously unidentified enhancer competition step. This model not only recapitulates monoallelic OR expression, but also elucidates how the olfactory system maximizes and maintains the diversity of OR expression, and has multiple predictions validated by existing experimental results. Through making an analogy to a physical system with thermally activated barrier crossing and comparative reverse engineering analyses, the study reveals that the olfactory receptor selection system is optimally designed, and particularly underscores cooperativity and synergy as a general design principle for multiobjective optimization in biology.

[Multiple primary neoplasms with renal neurilemmoma: a case report and literature review].

Multiple primary neoplasms are not common, those containing renal neurilemoma are even more rare. Our study involves the diagnosis and treatment of a female patient with multiple primary neoplasms with renal neurilemoma. She was previously diagnosed with left ovarian dermoid cyst, right posterior mediastinal neurilemmoma, left forearm neurilemmoma, and papillary thyroid carcinoma, underwent operation treatment. Physical examination reveals a left renal mass with a left adrenal tumor a month before, and underwent retroperitoneal laparoscopic left adrenal nodule resection and left partial nephrectomy. Operation was successful, without conversions to open. Artery occlusion time was 18 min, and blood loss was 20 mL. Post operation pathologic result shows a left renal cellular leiomyoma neurilemmoma with focal cystic change, and tumor diameter was about 3 cm. Immunohistochemistry reports S-100 (+), Ki-67 (15%+), and short-term follow-up without recurrence. In our case of study, even though the tumors were heterochronism, they were both treated with surgical resection. Renal neurilemoma is benign. Laparoscopic partial nephrectomy is not only minimally invasive, fast in recovery, but most importantly preserves renal tissue to the largest extent. It can prevent preoperative pathological uncertainty, which often undergoes radical nephrectomy.

[Protective effect of phloroglucinol on renal ischemia and reperfusion injury].

OBJECTIVE: To investigate the effect and mechanisms of Phloroglucinol (PG) on renal ischemia and reperfusion injury (IRI). METHODS: Forty-eight male Wistar rats were divided into 3 groups (16 rats per group): sham operated, saline-treated I/R (I/R), and PG-treated I/R (PG). I/R model: After removing the right kidney, renal I/R injury was induced by clamping the left renal artery for 45 min followed by reperfusion. The rats were administered with PG (30 mg/kg, intraperitoneally) or saline 15 min before renal ischemia. The blood and kidneys were harvested 6 and 24 h after reperfusion. Renal function and histologic changes of serum creatinine (SCr) and blood urea nitrogen(BUN)were assessed. Malondialdehyde (MDA),catalase (CAT),superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)were measured. Nuclear factor-kapa B (NF-κB) and caspase-3 in the kidneys were also measured. RESULTS: SCr and BUN were (103.9±10.4) µmol/L and (15.2±1.0) mmol/L in I/R group, and (81.8±13.4) µmol/L and (11.5±1.2) mmol/L in PG group 6 h after reperfusion. SCr and BUN were (154.9±12.1) µmol/L and (28.1±1.4) mmol/L in I/R group, (103.8±5.9) µmol/L and (16.0±1.0) mmol/L in PG group 24 h after reperfusion.PG treatment significantly attenuated renal dysfunction and histologic damage caused by I/R injury (P<0.05).The I/R-induced elevation in kidney MDA level decreased, where as reduced kidney SOD,CAT and GSH-Px were increased. What is more, the apoptotic tubular cells, the levels of active caspase-3,and active nuclear factor kappa B dramatically decreased after PG treatment. CONCLUSION: PG protects murine kidney I/R injury by suppressing oxidative stress, inflammation, and cell apoptosis.

Statistical mechanics model for the dynamics of collective epigenetic histone modification.

Epigenetic histone modifications play an important role in the maintenance of different cell phenotypes. The exact molecular mechanism for inheritance of the modification patterns over cell generations remains elusive. We construct a Potts-type model based on experimentally observed nearest-neighbor enzyme lateral interactions and nucleosome covalent modification state biased enzyme recruitment. The model can lead to effective nonlocal interactions among nucleosomes suggested in previous theoretical studies, and epigenetic memory is robustly inheritable against stochastic cellular processes.

Berberine ameliorates renal interstitial fibrosis induced by unilateral ureteral obstruction in rats.

AIM: To investigate the potential effects of berberine on renal interstitial fibrosis (RIF) of obstructed kidneys in a unilateral ureteral obstruction (UUO) rat model. METHODS: Forty-eight rats were randomly divided into three groups: sham-operated, vehicle-treated UUO, and berberine-treated UUO. Rats were gavaged with berberine (200 mg/kg per day) or vehicle. Eight randomly chosen rats in each group were kiled and specimens were collected at day 14 after UUO. Physiological parameters and histological changes were assessed, RIF was evaluated using Masson's trichrome and Sirius red staining, oxidative stress and inflammation markers were determined, transforming growth factor ß1 (TGF-ß1), phosphorylated Smad3 (pSmad3) and α-smooth muscle actin (α-SMA) were measured using immunohistochemistry or western blotting analysis. The obstruction was relieved at day 14 by percutaneous nephrostomy in the remaining UUO rats. The resistive index of left kidneys was undertaken by coloured Doppler flow imaging at day 14 before nephrostomy and day 7 after the relief. RESULTS: Berberine treatment significantly attenuated RIF induced by UUO. The UUO-induced reduction in kidney superoxide dismutase and catalase activities increased, whereas elevated kidney malondialdehyde level markedly decreased. Berberine treatment significantly ameliorated UUO-induced inflammation, and decreased TGF-ß1, pSmad3 and α-SMA expression of UUO kidneys. Moreover, berberine treatment significantly suppressed the increase of resistive index compared with UUO group at day 14 after UUO as well as day 7 after the relief of obstruction. CONCLUSION: Berberine treatment ameliorates RIF in a UUO rat model by inhibition of oxidative stress, inflammatory responses, and TGF-ß1/pSmad3 signalling.