Penthorum chinense Pursh inhibits ferroptosis in cellular and Caenorhabditis elegans models of Alzheimer's disease.

BACKGROUND: Ferroptosis, a unique type of cell death triggered by iron-dependent lipid peroxidation, plays a critical role in the pathogenesis of Alzheimer's disease (AD), a debilitating condition marked by memory loss and cognitive impairment due to the accumulation of beta-amyloid (Aß) and hyperphosphorylated Tau protein. Increasing evidence suggests that inhibitors of ferroptosis could be groundbreaking in the treatment of AD. METHOD: In this study, we established in vitro ferroptosis using erastin-, RSL-3-, hemin-, and iFSP1-induced PC-12 cells. Using MTT along with Hoechst/PI staining, we assessed cell viability and death. To determine various aspects of ferroptosis, we employed fluorescence probes, including DCFDA, JC-1, C11 BODIPY, Mito-Tracker, and PGSK, to measure ROS production, mitochondrial membrane potential, lipid peroxidation, mitochondrial morphology, and intracellular iron levels. Additionally, Western blotting, biolayer interferometry technology, and shRNA were utilized to investigate the underlying molecular mechanisms. Furthermore, p-CAX APP Swe/Ind- and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, along with Caenorhabditis elegans (C. elegans) strains CL4176, CL2331, and BR5270, were employed to examine ferroptosis in AD models. RESULTS: Here, we conducted a screening of our natural medicine libraries and identified the ethanol extract of Penthorum chinense Pursh (PEE), particularly its ethyl acetate fraction (PEF), displayed inhibitory effects on ferroptosis in cells. Specifically, PEF inhibited the generation of ROS, lipid peroxidation, and intracellular iron levels. Furthermore, PEF demonstrated protective effects against H2O2-induced cell death, ROS production, and mitochondrial damage. Mechanistic investigations unveiled PEF's modulation of intracellular iron accumulation, GPX4 expression and activity, and FSP1 expression. In p-CAX APP Swe/Ind and pRK5-EGFP-Tau P301L overexpressing PC-12 cells, PEF significantly reduced cell death, as well as ROS and lipid peroxidase production. Moreover, PEF ameliorated paralysis and slowing rate in Aß and Tau transgenic C. elegans models, while inhibiting ferroptosis, as evidenced by decreased DHE intensity, lipid peroxidation levels, iron accumulation, and expression of SOD-3 and gst-4. CONCLUSION: Our findings highlight the suppressive effects of PEF on ferroptosis in AD cellular and C. elegans models. This study helps us better understand how ferroptosis affects AD and emphasizes the potential of PCP as a candidate for AD intervention.

Targeting autophagy to discover the Piper wallichii petroleum ether fraction exhibiting antiaging and anti-Alzheimer's disease effects in Caenorhabditis elegans.

BACKGROUND: With population aging, the incidence of aging-related Alzheimer's disease (AD) is increasing, accompanied by decreased autophagy activity. At present, Caenorhabditis elegans (C. elegans) is widely employed to evaluate autophagy and in research on aging and aging-related diseases in vivo. To discover autophagy activators from natural medicines and investigate their therapeutic potential in antiaging and anti-AD effects, multiple C. elegans models related to autophagy, aging, and AD were used. METHOD: In this study, we employed the DA2123 and BC12921 strains to discover potential autophagy inducers using a self-established natural medicine library. The antiaging effect was evaluated by determining the lifespan, motor ability, pumping rate, lipofuscin accumulation of worms, and resistance ability of worms under various stresses. In addition, the anti-AD effect was examined by detecting the paralysis rate, food-sensing behavior, and amyloid-ß and Tau pathology in C. elegans. Moreover, RNAi technology was used to knock down the genes related to autophagy induction. RESULTS: We discovered that Piper wallichii extract (PE) and the petroleum ether fraction (PPF) activated autophagy in C. elegans, as evidenced by increased GFP-tagged LGG-1 foci and decreased GFP-p62 expression. In addition, PPF extended the lifespan and enhanced the healthspan of worms by increasing body bends and pumping rates, decreasing lipofuscin accumulation, and increasing resistance to oxidative, heat, and pathogenic stress. Moreover, PPF exhibited an anti-AD effect by decreasing the paralysis rate, improving the pumping rate and slowing rate, and alleviating Aß and Tau pathology in AD worms. However, the feeding of RNAi bacteria targeting unc-51, bec-1, lgg-1, and vps-34 abolished the antiaging and anti-AD effects of PPF. CONCLUSION: Piper wallichii may be a promising drug for antiaging and anti-AD. More future studies are also needed to identify autophagy inducers in Piper wallichii and clarify their molecular mechanisms.

Evaluation of chemical similarity among rhizome, pseudo stem and leaf of Musa basjoo by UPLC-ELSD fingerprint combined with chemo metrics methods.

Rhizoma Musa (the Rhizome of Musa basjoo Sied.et Zucc.) is used as a traditional medical herb of Miao nationality in Guizhou province, in China. It has the efficacy of clearing heat and detoxifying, quenching thirst, diuresis, etc. Modern pharmacological studies have shown that it has hypoglycemic, inhibition of α-glucosidase, and anti-inflammatory activity. However, when the rhizomes of Musa basjoo are dug up, the rhizomes are unable regenerate, and the pseudostem and leaf are discarded, which not only pollutes the environment, but also causes a huge waste of herb resources. In this study, a UPLC-ELSD fingerprint analysis with chemometric method was applied for the evaluation of chemical similarity among rhizome, pseudostem and leaf of Musa Basjoo. The results indicated that the combined method could efficiently analyze and compare the chemical similarity among rhizome, pseudostem, and leaf of Musa Basjoo. The proposed method provides the foundation for the resource substitution of the rhizome, pseudostem, and leaf of Musa Basjoo.

[The characteristics of anorectal manometry in Parkinson's disease with constipation and functional constipation].

OBJECTIVE: To investigate the discrepancy of anorectal function in patients of Parkinson's disease (PD) with constipation and functional constipation (FC). METHODS: Fifteen consecutive male PD patients with constipation and 45 male FC patients were recruited for the study. All subjects underwent colonoscopy or barium enema in order to exclude organic colon diseases. Every patient underwent anorectal manometry and was categorized into subgroups of either dyssynergia defecation (F3a) or inadequate defecatory propulsion (F3b). RESULTS: The ages of PD with constipation and FC patients were (70 ± 11) and (68 ± 11) years old respectively. The rectal resting pressure in PD with constipation was higher than that in FC group without statistical significance [9.0(4.0, 15.0) mm Hg vs 6.0(3.0, 9.5) mm Hg, P = 0.082, 1 mm Hg = 0.133 kPa]. The anal resting pressure in PD group was not different from FC group [(51.2 ± 17.2) mm Hg vs (59.7 ± 20.4) mm Hg, P = 0.152]. During anal squeezing, the maximal contraction pressure and area under the squeeze curve in PD with constipation group were both significantly lower than FC patients [maximal contraction pressure: (136.9 ± 43.8) mm Hg vs (183.0 ± 62.1) mm Hg, P = 0.010; area under the squeeze curve: (823.5 ± 635.7) mm Hg·s vs (1392.4 ± 939.9) mm Hg·s, P = 0.033]. During forced defecation, both of the defecation rectal pressure and defecation anal pressure in PD with constipation group were significantly lower than that of FC patients [22.0(15.0, 30.0) vs 42.0(31.0, 55.0) mm Hg, P = 0.000; and (46.3 ± 23.3) vs (77.9 ± 35.1) mm Hg, P = 0.002]. The proportions of F3a subtype were 10/15 and 46.7% (21/45) in PD with constipation and FC patients respectively. There was no significant difference in the constituent ratio (P = 0.120). Initial rectal sensory volumes were (91.3 ± 56.9) ml and (67.2 ± 38.9) ml in PD with constipation and FC patients respectively. Even both volumes were higher than the normal controls, there was no significant difference between the two groups (P = 0.074). CONCLUSIONS: Both PD with constipation and FC patients have abnormal anorectal motility and sensation comparing to the FC group, the parameters of anal contraction and defecation are significantly lower, F3b is dominant, and rectal sensory threshold is higher in PD with constipation patients. These parameters could possibly characterize the anorectal manometry for PD with constipation patients, which is helpful to understand the pathogenesis of PD and differentiate from other diseases.

Xylocoside G reduces amyloid-ß induced neurotoxicity by inhibiting NF-κB signaling pathway in neuronal cells.

Amyloid-ß (Aß) peptide, which can invoke a cascade of inflammatory responses, is considered to play a causal role in the development and progress of Alzheimer's disease (AD). Xylocoside G (XG) is an active compound isolated from a traditional Chinese medicinal plant, Itoa orientalis. We have previously reported that XG has neuroprotective effects, of which the mechanism is yet unknown. In this study, we investigated the possible mechanisms underlying neuroprotection of XG against Aß-induced toxicity in SH-SY5Y cells and primary neurons. Pretreatment with XG significantly attenuated the cell viability reduction induced by Aß exposure in a dose dependent manner which was testified by 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase release assay. In addition, pretreatment with XG countered the effect of Aß on Bax and Bcl-2 expression and repressed Aß-induced caspase-3 activation, suggesting that the neuroprotective effect of XG is associated with apoptosis regulation. Neuroinflammation has been implicated in Aß-induced neuronal death. XG significantly attenuated Aß-stimulated release of inflammatory factors such as tumor necrosis factor-α, interleukin-1ß, and prostaglandin E2. It also downregulated the expression of cyclooxygenase-2 in SH-SY5Y cells. Further molecular mechanism studies demonstrated that XG inhibited Aß-induced NF-κB p65 translocation, which was probably the result of inhibition of JNK phosphorylation but not ERK or p38 MAPK pathway by XG. This is the first study to demonstrate that XG protects SH-SY5Y cells against Aß-induced inflammation and apoptosis by down-regulating NF-κB signaling pathways.