AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin-based chemotherapy. As a plasma membrane adhesion molecule, amphoterin-induced gene and ORF-2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin-induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin-induced activation of (caspase-8 and caspase-9)/caspase-3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME-mediated pyroptosis.

Fluorescence Enhancement of Adamantane-Modified Dyes in Aqueous Solution via Supramolecular Interaction with Methyl-ß-cyclodextrin and Their Application in Cell Imaging.

The fluorescence of functional dyes was generally quenched in aqueous solution, which hindered their application in water-bearing detections. In this work, a novel strategy based on host-guest interaction was provided for the purpose of fluorescence enhancement in aqueous solution and cell imaging. Three adamantane-modified fluorescent dyes (Coum-Ad, NP-Ad, NR-Ad) with coumarin, 1,8-naphthalimide and Nile Red as fluorophores were initially designed and prepared. The ((adamantan-1-yl)methyl)amino group, as the auxochrome of those dyes, complexed with methylated ß-cyclodextrin (M-ß-CD) via supramolecular interaction, and then fluorescent supramolecular nanoparticles (FSNPs) were formed by self-assembly in water. The inclusion equilibrium constant (K) could be as high as 3.94×104  M-1 . With the addition of M-ß-CD, fluorescence quantum yields of these dyes were separately improved to 69.8 %, 32.9 % and 41.3 %. Inspired by the above satisfactory results, six adamantane-modified probes organelle-NPAds with organelle-targeting capability were further obtained. As the formation of hydrogen bonds between organelle-NPAd2 and M-ß-CD verified by theoretical calculation, K of organelle-NPAd2 (5.13×104  M-1 ~4.53×105  M-1 ) with M-ß-CD was higher than that of organelle-NPAd1 (1.15×104  M-1 ~3.66×104  M-1 ) and their fluorescence quantum yields increased to 32.8 %~83.6 % in aqueous solution. In addition, fluorescence enhancement was realized in cell imaging with the addition of M-ß-CD.

Viscosity probes towards different organelles with red emission based on an identical hemicyanine structure.

A series of viscosity probes targeting different organelles were obtained using a single hemicyanine dye as the matrix structure. Specifically, probes 1a-d were obtained by introducing four amines (6-amino-2H-chromen-2-one, N-(2-aminoethyl)-4-methylbenzenesulfonamide, dodecan-1-amine and N,N diphenylbenzene-1,4-diamine) into the indole hemicyanine dye of the carboxylic acid with a D-π-A structure. Their maximum absorption wavelengths were in the range 570-586 nm and they had relatively large molar absorption coefficients, while their maximum emission wavelengths in the red light region were in the range 596-611 nm. Moreover, their fluorescence intensity in glycerol was 35-184 times higher than that in phosphate buffer solution (PBS). The lg(Fl) and lg η of probes 1a-d showed good linearity with high correlation coefficients according to the Förster-Hoffman equation. In addition, cell staining experiments demonstrated that 1a-c could target lysosomes, endoplasmic reticulum and mitochondria, respectively. They could also undergo viscosity-detectable changes in the corresponding organelles under the action of the corresponding ion carriers.

Integrative phosphatidylcholine metabolism through phospholipase A2 in rats with chronic kidney disease.

Dysregulation in lipid metabolism is the leading cause of chronic kidney disease (CKD) and also the important risk factors for high morbidity and mortality. Although lipid abnormalities were identified in CKD, integral metabolic pathways for specific individual lipid species remain to be clarified. We conducted ultra-high-performance liquid chromatography-high-definition mass spectrometry-based lipidomics and identified plasma lipid species and therapeutic effects of Rheum officinale in CKD rats. Adenine-induced CKD rats were administered Rheum officinale. Urine, blood and kidney tissues were collected for analyses. We showed that exogenous adenine consumption led to declining kidney function in rats. Compared with control rats, a panel of differential plasma lipid species in CKD rats was identified in both positive and negative ion modes. Among the 50 lipid species, phosphatidylcholine (PC), lysophosphatidylcholine (LysoPC) and lysophosphatidic acid (LysoPA) accounted for the largest number of identified metabolites. We revealed that six PCs had integral metabolic pathways, in which PC was hydrolysed into LysoPC, and then converted to LysoPA, which was associated with increased cytosolic phospholipase A2 protein expression in CKD rats. The lower levels of six PCs and their corresponding metabolites could discriminate CKD rats from control rats. Receiver operating characteristic curves showed that each individual lipid species had high values of area under curve, sensitivity and specificity. Administration of Rheum officinale significantly improved impaired kidney function and aberrant PC metabolism in CKD rats. Taken together, this study demonstrates that CKD leads to PC metabolism disorders and that the dysregulation of PC metabolism is involved in CKD pathology.

Cucurbit[7]uril as the host of adamantane-modified dyes for fluorescence enhancement in aqueous environments.

Taking advantage of the excellent host-guest complexation ability between an auxochrome (adamantane group) and CB[7], the fluorescence emission performance of dyes in water was effectively improved with the addition of two equivalents of CB[7], which provided an efficient method for increasing fluorescence intensity in aqueous environments. Furthermore, these dyes with the host were successfully used in cell imaging.

Deciphering the role of lipoproteins and lipid metabolic alterations in ageing and ageing-associated renal fibrosis.

Fibrosis is the ultimate pathological feature of many chronic diseases, and ageing a major risk factor for fibrotic diseases. Current therapies are limited to those that reduce the rate of functional decline in patients with mild to moderate disease, but few interventions are available to specifically target the pathogenesis of fibrosis. In this context, new treatments that can significantly improve survival time and quality of life for these patients are urgently needed. In this review, we outline both the synthesis and metabolism of lipids and lipoproteins associated with ageing-associated renal fibrosis and the prominent contribution of lipids and lipidomics in the discovery of biomarkers that can be used for the prevention, diagnosis, and treatment of renal ageing and fibrosis. Next, we describe the effect of dyslipidaemia on ageing-related renal fibrosis and the pathophysiological changes in the kidney caused by dyslipidaemia. We then summarize the enzymes, transporters, transcription factors, and RNAs that contribute to dysregulated lipid metabolism in renal fibrosis and discuss their role in renal fibrosis in detail. We conclude by discussing the progress in research on small molecule therapeutic agents that prevent and treat ageing and ageing-associated renal fibrosis by modulating lipid metabolism. A growing number of studies suggest that restoring aberrant lipid metabolism may be a novel and promising therapeutic strategy to combat ageing and ageing-associated renal fibrosis.

Shenkang injection improves chronic kidney disease by inhibiting multiple renin-angiotensin system genes by blocking the Wnt/ß-catenin signalling pathway.

Chronic kidney disease (CKD) is a major worldwide public health problem. The increase in the number of patients with CKD and end-stage kidney disease requesting renal dialysis or transplantation will progress to epidemic proportions in the next several decades. Although blocking the renin-angiotensin system (RAS) has been used as a first-line standard therapy in patients with hypertension and CKD, patients still progress towards end-stage kidney disease, which might be closely associated with compensatory renin expression subsequent to RAS blockade through a homeostatic mechanism. The Wnt/ß-catenin signalling pathway is the master upstream regulator that controls multiple intrarenal RAS genes. As Wnt/ß-catenin regulates multiple RAS genes, we inferred that this pathway might also be implicated in blood pressure control. Therefore, discovering new medications to synchronously target multiple RAS genes is necessary and essential for the effective treatment of patients with CKD. We hypothesized that Shenkang injection (SKI), which is widely used to treat CKD patients, might ameliorate CKD by inhibiting the activation of multiple RAS genes via the Wnt/ß-catenin signalling pathway. To test this hypothesis, we used adenine-induced CKD rats and angiotensin II (AngII)-induced HK-2 and NRK-49F cells. Treatment with SKI inhibited renal function decline, hypertension and renal fibrosis. Mechanistically, SKI abrogated the increased protein expression of multiple RAS elements, including angiotensin-converting enzyme and angiotensin II type 1 receptor, as well as Wnt1, ß-catenin and downstream target genes, including Snail1, Twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1 and fibroblast-specific protein 1, in adenine-induced rats, which was verified in AngII-induced HK-2 and NRK-49F cells. Similarly, our results further indicated that treatment with rhein isolated from SKI attenuated renal function decline and epithelial-to-mesenchymal transition and repressed RAS activation and the hyperactive Wnt/ß-catenin signalling pathway in both adenine-induced rats and AngII-induced HK-2 and NRK-49F cells. This study first revealed that SKI repressed epithelial-to-mesenchymal transition by synchronously targeting multiple RAS elements by blocking the hyperactive Wnt/ß-catenin signalling pathway.

Placental weight and size in relation to fetal growth restriction: a case-control study.

OBJECTIVE: Reductions in placental weight and size have been associated with reduced fetal growth. However, few studies have examined the association of placental weight and size with the risk of fetal growth restriction (FGR). METHODS: We enrolled 121 mother-newborn pairs, including 54 FGR cases and 67 healthy controls, from our previous case-control study. The weight, surface area, and thickness of the placenta were measured by medical professionals. RESULTS: Reduced placental weight and surface area were found to be associated with decreased birth weight. A 10-unit decrement in placental weight (g) and surface area (cm2) was associated with 33.9 (ß = 33.9, 95% CI, 22.1-45.7) and 24.3 (ß = 24.3, 95% CI, 11.2-37.5) g decrease in birth weight, respectively. Those associations varied by infant gender and the magnitudes of effect were larger among male fetuses. Moreover, reduced placental weight and surface area were associated with increased odds of FGR. A 10-unit decrease in placental weight and surface area were associated with 21% (OR = 1.21, 95% CI, 1.08-1.44) and 19% (OR = 1.19, 95% CI, 1.06-1.41) increase in the odds of FGR. CONCLUSIONS: Our results suggest that fetuses with lower placental weight and smaller surface area are at higher risk of developing FGR.

Shenkang Injection and Its Three Anthraquinones Ameliorates Renal Fibrosis by Simultaneous Targeting IƙB/NF-ƙB and Keap1/Nrf2 Signaling Pathways.

Oxidative stress and inflammation are important and critical mediators in the development and progression of chronic kidney disease (CKD) and its complications. Shenkang injection (SKI) has been widely used to treat patients with CKD. Although the anti-oxidative and anti-inflammatory activity was involved in SKI against CKD, its bioactive components and underlying mechanism remain enigmatic. A rat model of adenine-induced chronic renal failure (CRF) is associated with, and largely driven by, oxidative stress and inflammation. Hence, we identified the anti-oxidative and anti-inflammatory components of SKI and further revealed their underlying mechanism in the adenine-induced CRF rats. Compared with control rats, the levels of creatinine, urea, uric acid, total cholesterol, triglyceride, and low-density lipoprotein cholesterol in serum were significantly increased in the adenine-induced CRF rats. However, treatment with SKI and its three anthraquinones including chrysophanol, emodin, and rhein could reverse these aberrant changes. They could significantly inhibit pro-fibrotic protein expressions including collagen I, α-SMA, fibronectin, and vimentin in the kidney tissues of the adenine-induced CRF rats. Of note, SKI and rhein showed the stronger inhibitory effect on these pro-fibrotic protein expressions than chrysophanol and emodin. Furthermore, they could improve dysregulation of IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways. Chrysophanol and emodin showed the stronger inhibitory effect on the NF-κB p65 protein expression than SKI and rhein. Rhein showed the strongest inhibitory effect on p65 downstream target gene products including NAD(P)H oxidase subunits (p47phox, p67phox, and gp91phox) and COX-2, MCP-1, iNOS, and 12-LO in the kidney tissues. However, SKI and rhein showed the stronger inhibitory effect on the significantly downregulated anti-inflammatory and anti-oxidative protein expression nuclear Nrf2 and its target gene products including HO-1, catalase, GCLC, and NQO1 in the Keap1/Nrf2 signaling pathway than chrysophanol and emodin. This study first demonstrated that SKI and its major components protected against renal fibrosis by inhibiting oxidative stress and inflammation via simultaneous targeting IƙB/NF-ƙB and Keap1/Nrf2 signaling pathways, which illuminated the potential molecular mechanism of anti-oxidative and anti-inflammatory effects of SKI.

A new 3-benzylchroman derivative from Sappan Lignum (Caesalpinia sappan).

3'-Deoxy-4-O-methylepisappanol, a new 3-benzylchroman derivative, was isolated from Sappan Lignum, together with thirteen known chemical compounds identified as protosappanin A, sappanchalcone, sappanone B, palmitic acid, (+)-(8S,8'S)-bisdihydrosiringenin, brazilein, 3-deoxysappanchalcone, (+)-lyoniresinol, 3-deoxysappanone B, protosappanin B, isoprotosappanin B, 3'-O-methylbrazilin and brazilin, respectively. Among these known compounds, this is the first time that (+)-(8S,8'S)-bisdihydrosiringenin was obtained from the family Caesalpiniaceae.

[Clinical observation on catgut implantation at Shu- and Mu-acupoints for treatment of premature ovarian failure].

OBJECTIVE: To observe clinical therapeutic effect of catgut implantation at Shu- and Mu-acupoints of liver, spleen and kidney on premature ovarian failure. METHODS: One hundred and thirty-two cases of premature ovarian failure were randomly divided into a catgut implantation group and a medication group, 66 cases in each group. The catgut implantation group were treated by catgut implantation at She- and Mu-acupoints of liver, spleen and kidney, and the medication group were treated with oral administration of Estradiol Valerate 2 mg, qd, for 20 days, and 10 days later, Medroxyprogesterone Acetate 4 mg was added, b. i. d, for 10 days, averaging 6 months of medication. The therapeutic effects and changes of serum follicle-stimulating hormone (FSH) and estradiol (E2) were observed in the two groups. RESULTS: After treatment, serum FSH and E2 significantly improved in the two groups (P<0.01), with the serum E2 in the catgut implantation group increased more significantly than that in the medication group (P<0.01). The cured rate and the total effective rate were 84.9% and 97.0% in the catgut implantation group and 31.8% and 84.8% in the medication group, the cured rate in the catgut implantation group being better than that in the medication group (P<0.05). Ten month later, the therapeutic effect in the catgut implantation group was kept. CONCLUSION: Catgut implantation at Shu- and Me-acupoints of liver, spleen and kidney has a good therapeutic effect on premature ovarian failure with no side effect.

[Comparative observation on acupuncture and western medicine for treatment of minimal brain dysfunction].

OBJECTIVE: To compare the therapeutic effects of acupuncture and western medicine on minimal brain dysfunction (MBD) and to search for a clinically effective therapy for MBD. METHODS: Sixty-eight cases were randomly divided into an acupuncture group and a western medicine group, 34 cases in each group. The acupuncture group were treated by acupuncture at Dazhui (GV 14) and Shenque (CV 8), and the western medicine group by taking Haloperidol orally. One month constituted one course. After treatment, the total effective rate and scores of Connell's scale for diagnosis and behavior of MBD were compared between the two groups. RESULTS: The total effective rate and the score after treatment were 97.1% and 10 +/- 0.37 in the acupuncture group and 82.4% and 15 +/- 0.93 in the western medicine group, with a very significant difference between the two groups (P < 0.01, P < 0.000 5), the acupuncture group being better than the western medicine group. Follow-up survey for 2-10 months showed the effects of the acupuncture group still were kept. CONCLUSION: Acupuncture at Dazhui (GV 14) and Shenque (CV 8) can effectively cure MBD.