Search

Background Patients with lymphoma and hepatitis B virus infection need to be treated with both chemotherapy and nucleotide analogues (NAs) therapy. However, the dynamic change of HBV DNA with the increase of chemotherapy cycles is lacking. It is unknown that whether HBV replication markers: quantitative hepatitis B core antibody (qAnti-HBc), HBV RNA, and hepatitis B virus core-related antigen (HBcrAg) are also sensitive to predict HBV reactivation (HBVr). Methods From 29th June 2010 to 6th December 2021, clinical data and serial serum samples were collected from patients with diffuse large B lymphoma and HBV infection. Serum HBV DNA load (real time fluorescent quantitative PCR), qAnti-HBc (developed chemiluminescent particle immunoassay), HBV RNA (simultaneous amplification testing method based on real-time fluorescence detection), and HBcrAg (Lumipulse G HBcrAg assay) were tested and actors related to HBV DNA reactivation were analyzed. Results Under the NAs, load of HBV DNA in 69 HBsAg + lymphoma patients declined from 3.15 (2.13–4.73) lg IU/ml at baseline to 1.00 (1.00-1.75) lg IU/ml at the end of chemotherapy, and further declined to 1.00 (1.00-1.04) lg IU/ml at the end of 24-month follow-up. Serum qAnti-HBc level decreased gradually during chemotherapy in HBsAg + lymphoma patients (F = 7.090, p = 0.009). Serum HBV RNA and HBcrAg levels stayed stabled. Multivariate analysis revealed that a higher level of qAnti-HBc (1.97 ± 1.20 vs. 1.12 ± 0.84 lg IU/ml, OR = 8.367, [95% CI:1.439–48.645], p = 0.018) and a higher level of HBV RNA (1.00 ± 1.13 vs. 0.37 ± 0.80 lg copies/ml, OR = 3.654, [95% CI:1.208–11.048], p = 0.022) were related to HBVr in HBsAg-/anti-HBc + lymphoma patients. Conclusions The HBV DNA load declined by NAs under chemotherapy in lymphoma patients. In HBsAg-/anti-HBc + lymphoma patients, higher level of baseline serum qAnti-HBc and HBV RNA predict the HBVr during chemotherapy.

Glucagon-like peptide-1 (GLP-1) receptor stimulation ameliorates parkinsonian motor and non-motor deficits in both experimental animals and patients; however, the disease-modifying mechanisms of GLP-1 receptor activation have remained unknown. The present study investigated whether exendin-4 (a GLP-1 analogue) can rescue motor deficits and exert disease-modifying effects in a parkinsonian rat model of α-synucleinopathy. This model was established by unilaterally injecting AAV-9-A53T-α-synuclein into the right substantia nigra pars compacta, followed by 4 or 8 weeks of twice-daily intraperitoneal injections of exendin-4 (5 μg/kg/day) starting at 2 weeks after AAV-9-A53T-α-synuclein injections. Positron emission tomography/computed tomography (PET/CT) scanning and immunostaining established that treatment with exendin-4 attenuated tyrosine-hydroxylase-positive neuronal loss and terminal denervation and mitigated the decrease in expression of vesicular monoamine transporter 2 within the nigrostriatal dopaminergic systems of rats injected with AAV-9-A53T-α-synuclein. It also mitigated the parkinsonian motor deficits assessed in behavioral tests. Furthermore, through both in vivo and in vitro models of Parkinson’s disease, we showed that exendin-4 promoted autophagy and mediated degradation of pathological α-synuclein, the effects of which were counteracted by 3-methyladenine or chloroquine, the autophagic inhibitors. Additionally, exendin-4 attenuated dysregulation of the PI3K/Akt/mTOR pathway in rats injected with AAV-9-A53T-α-synuclein. Taken together, our results demonstrate that exendin-4 treatment relieved behavioral deficits, dopaminergic degeneration, and pathological α-synuclein aggregation in a parkinsonian rat model of α-synucleinopathy and that these effects were mediated by enhanced autophagy via inhibiting the PI3K/Akt/mTOR pathway. In light of the safety and tolerance of exendin-4 administration, our results suggest that exendin-4 may represent a promising disease-modifying treatment for Parkinson’s disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13311-021-01018-5.

Background & Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis even cancer, antiviral therapy can reverse liver fibrosis with limited effect, thus we aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with ETV.Methods: Treatment naïve patients with CHB from Oct 1st, 2013 to Dec 31st, 2020 were randomly treated with ETV alone or combined with ALHX (ETV+ALHX). Patients’ demographic, laboratory and liver histology data before and after 78 weeks of treatment were collected. Ishak fibrosis score (F) was used and fibrosis regression means F decreased ≥1 after treatment.Results: In total, 394 patients with a second liver biopsy after treatment were included in per-protocol population: 132 patients in ETV group and 262 patients in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group were significantly higher than ETV group in baseline F≥3 patients: 124/211 (58.8%) verse 45/98 (45.9%), p=0.035. The degradation rate of liver stiffness measurement (LSM) is also consistent with it: 154/262 (73.0%) in ETV+ALHX group and 60/132 (61.2%) in ETV group, p=0.037. Logistic regression analysis showed that combined with ALHX was related to fibrosis regression (OR=1.94, p=0.018), and family history of hepatocellular carcinoma was on the contrary (OR=0.41, p=0.031).Conclusions: ETV combined with ALHX can significantly increase liver fibrosis regression in CHB patients.

α-Synuclein (α-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson’s disease (PD). Studies have shown that α-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro α-syn aggregation, and the amplified fibrils are more potent in inducing endogenous α-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of α-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD α-syn aggregation and suggests potential alteration of α-syn fibrils during the progression of PD clinical phases.Significance StatementIncreasing evidence support different conformational α-syn fibrils in patients with different α-synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is unknown. Here, we show that α-syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous α-syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of α-syn fibrils along with PD progression.

Silent information regulator 1 (Sirt1) is a deacetylase, which plays an important role in the occurrence and development of diabetic nephropathy (DN). Our previous study shows that Yin yang 1 (YY1), a widely expressed zinc finger DNA/RNA-binding transcription factor, is a novel regulator of renal fibrosis in diabetic nephropathy. Since the activity of YY1 is regulated via acetylation and deacetylation modification, this study aimed to explore whether Sirt1-induced deacetylation of YY1 mediated high glucose (HG)-induced renal tubular epithelial–mesenchymal transition (EMT) and renal fibrosis in vivo and in vitro. We first confirmed that Sirt1 expression level was significantly decreased in the kidney of db/db mice and in HG-treated HK-2 cells. Diabetes-induced Sirt1 reduction enhanced the level of YY1 acetylation and renal tubular EMT. Then, we manipulated Sirt1 expression in vivo and in vitro by injecting resveratrol (50 mg·kg −1 ·d −1 . ip) to db/db mice for 2 weeks or application of SRT1720 (2.5 μM) in HG-treated HK-2 cells, we found that activation of Sirt1 reversed the renal tubular EMT and YY1 acetylation induced by HG condition. On the contrary, Sirt1 was knocked down in db/m mice or EX527 (1 μM) was added in HK-2 cells, we found that inhibition of Sirt1 exacerbated renal fibrosis in diabetic mice and enhanced level of YY1 acetylation in HK-2 cells. Furthermore, knockdown of YY1 inhibited the ameliorating effect of resveratrol on renal tubular EMT and renal fibrosis in db/db mice. In conclusion, this study demonstrates that Sirt1 plays an important role in renal tubular EMT of DN through mediating deacetylation of YY1.