Sarsasapogenin regulates the immune microenvironment through MAPK/NF-kB signaling pathway and promotes functional recovery after spinal cord injury.

Spinal cord injury (SCI) occurs as a result of traumatic events that damage the spinal cord, leading to motor, sensory, or autonomic function impairment. Sarsasapogenin (SA), a natural steroidal compound, has been reported to have various pharmacological applications, including the treatment of inflammation, diabetic nephropathy, and neuroprotection. However, the therapeutic efficacy and underlying mechanisms of SA in the context of SCI are still unclear. This research aimed to investigate the therapeutic effects and mechanisms of SA against SCI by integrating network pharmacology analysis and experimental verification. Network pharmacology results suggested that SA may effectively treat SCI by targeting key targets such as TNF, RELA, JUN, MAPK14, and MAPK8. The underlying mechanism of this treatment may involve the MAPK (JNK) signaling pathway and inflammation-related signaling pathways such as TNF and Toll-like receptor signaling pathways. These findings highlight the therapeutic potential of SA in SCI treatment and provide valuable insights into its molecular mechanisms of action. In vivo experiments confirmed the reparative effect of SA on SCI in rats and suggested that SA could repair SCI by modulating the immune microenvironment. In vitro experiments further investigated how SA regulates the immune microenvironment by inhibiting the MAPK/NF-kB pathways. Overall, this study successfully utilized a combination of network pharmacology and experimental verification to establish that SA can regulate the immune microenvironment via the MAPK/NF-kB signaling pathway, ultimately facilitating functional recovery from SCI. Furthermore, these findings emphasize the potential of natural compounds from traditional Chinese medicine as a viable therapy for SCI treatment.

Ozone therapy (O2-O3) alleviates the progression of early intervertebral disc degeneration via the inhibition of oxidative stress and the interception of the PI3K/Akt/NF-κB signaling pathway.

Intervertebral disc degeneration (IDD) stands for the most frequent cause of low back pain. Finding a cure for this disease is an important challenge as current conservative treatments and surgical interventions fail to bring a solution to this disease. Ozone therapy (O2-O3) has yielded outstanding outcomes in intervertebral disc pathology. The ozone's efficacy in the treatment of IDD remains unconfirmed. This study aimed to assess the effectiveness of intradiscal ozone injection on IDD induced in a rat. Effects of ozone therapy on the viability of nucleus pulposus cells were evaluated by CCK-8 assays. Macrophage immunoreactivity was detected by immunohistochemical, the expression of collagen type II was evaluated by western blot, and measurement of oxidative stress parameters was realized. Molecular docking studies were carried out in order to predict the interaction formed between O3 and the target enzymes, on the one hand, O3 with PI3K and, on the other hand, O3 with COX-2. IRM, X-ray, hematoxylin-eosin, and bleu alcian staining were realized to assess the therapeutic impacts of ozone in the puncture-induced rat model of IDD. In vivo, O3 ameliorated the IDD in the early stage of this disease. It was also displayed in molecular docking that O3 might bind to PI3K to suppress the PI3K/Akt/NF-κB signaling pathway. This study's results show that the O3 should be administered at the low grade of IDD and at an early stage because it cannot restore the advanced inflammatory alteration of the IVD. Our results corroborated also that O3 inhibits the progression of IDD via the PI3K/Akt/NF-κB signaling pathway, which supports O3 as an effective therapeutic option for treating IDD.

Insights into the mechanisms of diabetic wounds: pathophysiology, molecular targets, and treatment strategies through conventional and alternative therapies.

Diabetes mellitus is a prevalent cause of mortality worldwide and can lead to several secondary issues, including DWs, which are caused by hyperglycemia, diabetic neuropathy, anemia, and ischemia. Roughly 15% of diabetic patient's experience complications related to DWs, with 25% at risk of lower limb amputations. A conventional management protocol is currently used for treating diabetic foot syndrome, which involves therapy using various substances, such as bFGF, pDGF, VEGF, EGF, IGF-I, TGF-ß, skin substitutes, cytokine stimulators, cytokine inhibitors, MMPs inhibitors, gene and stem cell therapies, ECM, and angiogenesis stimulators. The protocol also includes wound cleaning, laser therapy, antibiotics, skin substitutes, HOTC therapy, and removing dead tissue. It has been observed that treatment with numerous plants and their active constituents, including Globularia Arabica, Rhus coriaria L., Neolamarckia cadamba, Olea europaea, Salvia kronenburgii, Moringa oleifera, Syzygium aromaticum, Combretum molle, and Myrtus communis, has been found to promote wound healing, reduce inflammation, stimulate angiogenesis, and cytokines production, increase growth factors production, promote keratinocyte production, and encourage fibroblast proliferation. These therapies may also reduce the need for amputations. However, there is still limited information on how to prevent and manage DWs, and further research is needed to fully understand the role of alternative treatments in managing complications of DWs. The conventional management protocol for treating diabetic foot syndrome can be expensive and may cause adverse side effects. Alternative therapies, such as medicinal plants and green synthesis of nano-formulations, may provide efficient and affordable treatments for DWs.

Can curcumin supplementation break the vicious cycle of inflammation, oxidative stress, and uremia in patients undergoing peritoneal dialysis?

BACKGROUND & AIMS: Turmeric (a source of curcumin) is an excellent food to modulate oxidative stress, inflammation, and gut dysbiosis in patients with chronic kidney disease (CKD). However, no studies report the benefits of curcumin in patients undergoing peritoneal dialysis (PD). This study aims to evaluate the effects of curcuminoid supplementation on oxidative stress, inflammatory markers, and uremic toxins originating from gut microbiota in patients with CKD undergoing PD. METHODS: This longitudinal, randomized, single-blind, placebo-controlled trial evaluated 48 patients who were randomized into two groups: Curcumin (three capsules of 500 mg of Curcuma longa extract, with 98.42 % total curcuminoids) or placebo (three capsules of 500 mg of starch) for twelve weeks. In the peripheral blood mononuclear cells (PBMCs), the transcriptional expression levels of Nrf2, HOX-1 and NF-κB were evaluated by quantitative real-time PCR. Oxidative stress was evaluated by malondialdehyde (MDA) and total Thiol (T-SH). TNF-α and IL-6 plasma levels were measured by ELISA. P-cresyl sulphate plasma level, a uremic toxin, was evaluated by high-performance liquid chromatography (HPLC) with fluorescent detection. RESULTS: Twenty-four patients finished the study: 10 in the curcumin group (57.5 ± 11.6 years) and 14 in the placebo group (56.5 ± 10.0 years). The plasma levels of MDA were reduced after 12 weeks in the curcumin group (p = 0.01), while the placebo group remained unchanged. However, regarding the difference between the groups at the endpoint, no change was observed in MDA. Still, there was a trend to reduce the p-CS plasma levels in the curcumin group compared to the placebo group (p = 0.07). Likewise, the concentrations of protein thiols, mRNA expression of Nrf2, HOX-1, NF-κB, and cytokines plasma levels did not show significant changes. CONCLUSION: Curcuminoid supplementation for twelve weeks attenuates lipid peroxidation and might reduce uremic toxin in patients with CKD undergoing PD. This study was registered on Clinicaltrials.gov as NCT04413266.

Capsicum annuum var. abbreviatum Induces a Macrophage M2-Like Phenotype Mediated by Nrf2/HO-1 in LPS-Stimulated Macrophages.

Capsicum annuum var. abbreviatum (CAAE), which is in the genus Capsicum L. (Solanaceae), was found to be richer in polyphenols and flavonoids than other prevalent peppers of Capsicum annuum var. angulosum and Capsicum annuum. L. Yet, it is still unclear how CAAE reduces inflammation. In this study, we used the lipopolysaccharide-stimulated RAW264.7 macrophage cell line and bone marrow-derived macrophages to assess its anti-inflammatory activities. Initially, we discovered that CAAE decreased the levels of nitric oxide and inducible nitric oxide synthase. In addition, CAAE decreased the intracellular reactive oxygen species levels and increased the nuclear factor-erythroid 2-related factor 2 and heme oxygenase-1 compared with the phenotype of M2 macrophages. CAAE inhibited the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases, c-Jun N-terminal kinases, and p38 MAPKs. CAAE also inhibited the translocation of nuclear factor kappa B into nuclear, hence preventing the production of proinflammatory cytokines. Therefore, we suggest that CAAE might have potential as a candidate therapeutic agent for inflammatory diseases.

Sulforaphane Supplementation Did Not Modulate NRF2 and NF-kB mRNA Expressions in Hemodialysis Patients.

BACKGROUND: Patients with chronic kidney disease (CKD) have reduced expression of erythroid nuclear factor-related factor 2 (NRF2) and increased nuclear factor κB (NF-κB). "Food as medicine" has been proposed as an adjuvant therapeutic alternative in modulating these factors. No studies have investigated the effects of sulforaphane (SFN) in cruciferous vegetables on the expression of these genes in patients with CKD. OBJECTIVE: The study aimed to evaluate the effects of SFN on the expression of NRF2 and NF-κB in patients on hemodialysis (HD). DESIGN AND METHODS: A randomized, double-blind, crossover study was performed on 30 patients on regular HD. Fourteen patients were randomly allocated to the intervention group (1 sachet/day of 2.5 g containing 1% SFN extract with 0.5% myrosinase) and 16 patients to the placebo group (1 sachet/day of 2.5 g containing corn starch colored with chlorophyll) for 2 months. After a washout period of 2 months, the groups were switched. NRF2 and NF-κB mRNA expression was evaluated by real-time quantitative polymerase chain reaction, and tumor necrosis factor alpha and interleukin-6 levels were quantified by enzyme-linked immunosorbent assay. Malondialdehyde was evaluated as a marker of lipid peroxidation. RESULTS: Twenty-five patients (17 women, 55 [interquartile range = 19] years and 55 [interquartile range = 74] months on HD) completed the study. There was no significant difference concerning the expression of mRNA NRF2 (P = .915) and mRNA NF-κB (P = .806) after supplementation with SFN. There was no difference in pro-inflammatory and oxidative stress biomarkers. CONCLUSION: 150 µmol of SFN for 2 months had no antioxidant and anti-inflammatory effect in patients with CKD undergoing HD.

Intestinal Microbiota and Metabolomics Reveal the Role of Auricularia delicate in Regulating Colitis-Associated Colorectal Cancer.

BACKGROUND: The edible fungus Auricularia delicate (ADe) is commonly employed in traditional medicine for intestinal disorders; however, its inhibitory effect on colitis-associated colorectal cancer (CAC) and the underlying mechanisms remain unexplored. (2) Methods: The inhibitory effect of ADe on CAC was investigated using a mouse model induced by azoxymethane/dextran sulfate sodium. RESULTS: ADe effectively suppressed the growth and number of intestinal tumors in mice. Intestinal microbiota analyses revealed that ADe treatment increased Akkermansia and Parabacteroides while it decreased Clostridium, Turicibacter, Oscillospira, and Desulfovibrio. ADe regulated the levels of 2'-deoxyridine, creatinine, 1-palmitoyl lysophosphatidylcholine, and choline in serum. Furthermore, the levels of these metabolites were associated with the abundance of Oscillospira and Paraacteroides. ADe up-regulated the free fatty acid receptor 2 and ß-Arrestin 2, inhibited the nuclear factor kappa B (NF-κB) pathway, and significantly attenuated the levels of inflammatory cytokines, thereby mitigating the inflammatory in CAC mice. CONCLUSIONS: The protective effect of ADe in CAC mice is associated with the regulation of intestinal microbiota, which leads to the inhibition of NF-kB pathway and regulation of inflammation.

Ethanol extract of Paridis rhizoma attenuates carrageenan-induced paw swelling in rats by inhibiting the production of inflammatory factors.

CONTEXT: Inflammation has been identified as a key factor contributing to the development of numerous diseases. Several anti-inflammatory drugs have been developed to treat inflammation-related diseases. However, some of such drugs are associated with varying degrees of side effects. Therefore, it is imperative to develop new anti-inflammatory drugs with reducing side effects for the treatment of inflammation-related diseases. Natural anti-inflammatory drugs have emerged as an important area of research in recent years. The study was to determine the anti-inflammatory mechanism of Paridis rhizoma extract (PRE) in rat models of acute inflammation induced by carrageenan and RAW264.7 cells models induced by lipopolysaccharide (LPS). MATERIALS AND METHODS: PRE was investigated using the carrageenan-induced paw oedema model on rats in vivo. Histopathology examined the extent of inflammatory infiltration and tissue damage. The effect of PRE on the levels of specific cytokines was determined using enzyme-linked immunosorbent assay (ELISA). The Cell Counting Kit (CCK)-8 assay evaluated the cytotoxic effects of PRE on Raw264.7 cells. The mRNA expression levels of cytokines were quantified using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR). Western blot measured TNF-α, IL6, TLR4, p-P65, p-IKB, HO1, SOD1 and SOD2. Fluorescence measured the cellular levels of reactive oxygen species (ROS). RESULTS: PRE treatment reduced interstitial edema and structural damage in a dose-dependent manner in vivo. PRE inhibited inflammatory responses in vivo and in vitro, as evidenced by the decreased expression of inflammatory factors, production of ROS, and increased expression of SOD1, SOD2, and HO1. Moreover, PRE inhibited the activity of the nuclear factor kappa B (NF-kB) pathway. CONCLUSION: The anti-inflammatory activity and potential mechanism of PRE were demonstrated according to the results. PRE reduced LPS-induced inflammation in RAW264.7 cells by inhibiting the NF-KB signaling pathway and ROS production in vitro. PRE alleviated interstitial edema and structural damage in the carrageenan-induced paw edema model on rats in vivo. This study provided an idea for future development of PR-based anti-inflammatory drugs.

Effect of acupuncture on arthritic pathological injury in rats with type â ¡ collagen-induced rheumatoid arthritis. / é’ˆåˆºæ”¹å–„â ¡åž‹èƒ¶åŽŸè›‹ç™½è¯±å¯¼æ€§å ³èŠ‚ç‚Žå¤§é¼ ç‚Žæ€§ååº”çš„æœºåˆ¶ç ”ç©¶.

OBJECTIVES: To observe the effect of acupuncture stimulation of "Yanglingquan"(GB34), "Zusanli"(ST36) and "Xuanzhong" (GB39) on arthritis index (AI), joint synovial membrane pathology, serum-related immunoinflammatory factors, and expressions of tumor suppressor gene mt-p53, nuclear factor kappa B (NF-κB) and peroxisome proliferator activated receptor gamma (PPARγ) in knee joint synovial tissue of rats with type Ⅱ collagen-induced arthritis (CIA), so as to explore its possible mechanisms underlying improvement of rheumatoid arthritis (RA). METHODS: Male SD rats were used in the present study. The CIA model was established by subcutaneous injection of collagen emulsion (200 µL/rat) in the tail root region on the first day and repeat (100 µL/rat) once on the 9th day. Eighteen successful CIA rats were randomized into model, medication and acupuncture groups, with 6 rats in each group. Other 6 normal rats were used as the normal control group. For rats of the medication group, leflunomide (1.9 mg/kg) was administrated by gavage, once a day, and for rats of the acupuncture group, manual acupuncture stimulation was applied to bilateral GB34, ST36, GB39 for 30 min, once a day, for 12 weeks. The arthritis index (AI) score (0-4 points) was evaluated once every week. The contents of IL-6, IL-17 and TNF-α in the serum were determined by ELISA. Histopathological changes of the ankle joint were observed by H.E. staining. The protein and mRNA expression levels of mt-p53, NF-κB p65, and PPARγ in the knee joint synovial tissue were determined by Western blot and quantitative real time PCR, separately. RESULTS: Compared with the normal control group, the AI scores at different time-points after modeling, contents of serum TNF-α, IL-6 and IL-17, expression levels of mt-p53, NF-κB p65, PPARγ proteins and mRNAs were significantly increased in the model group (P<0.01, P<0.05). In comparison with the model group, the AI scores at the 10th week in the medication group and at the 3rd, 9th and 10th week in the acupuncture group, contents of serum TNF-α, IL-6 and IL-17, and the expression levels of mt-p53 and NF-κB p65 proteins in both medication and acupuncture groups, as well as mt-p53 and NF-κB p65 mRNAs in the medication group were apparently decreased (P<0.01, P<0.05), while the expression levels of PPARγ protein in both medication and acupuncture group and PPARγ mRNA in the medication group were significantly up-regulated (P<0.05, P<0.01). No significant differences were found between the acupuncture and medication groups in down-regulating the AI score and serum TNF-α, IL-6 and IL-17 contents. The effect of acupuncture was weaker than that of medication in down-regulating the expression of mt-p53 and NF-κB p65 proteins and mRNAs and in up-regulating PPARγ mRNA (P<0.01). H.E. results showed ankle cartilage hyperplasia, reduced joint cavity, mild fibroproliferation and inflammatory cell infiltration in the surrounding soft tissue of the ankle joint in rats of the model group, which was milder in both medication and acupuncture groups. CONCLUSIONS: Acupuncture stimulation can improve the degree of joint inflammation and swelling in CIA rats, which may be related to its effects in inhibiting the overexpression of immunoinflammatory factors in serum and regulating expression of mt-p53, NF-κB p65, PPARγ mRNAs and proteins in the synovial tissue.

Network pharmacology-based exploration identified the antiviral efficacy of Quercetin isolated from mulberry leaves against enterovirus 71 via the NF-κB signaling pathway.

Introduction: Mulberry leaf (ML) is known for its antibacterial and anti-inflammatory properties, historically documented in "Shen Nong's Materia Medica". This study aimed to investigate the effects of ML on enterovirus 71 (EV71) using network pharmacology, molecular docking, and in vitro experiments. Methods: We successfully pinpointed shared targets between mulberry leaves (ML) and the EV71 virus by leveraging online databases. Our investigation delved into the interaction among these identified targets, leading to the identification of pivotal components within ML that possess potent anti-EV71 properties. The ability of these components to bind to the targets was verified by molecular docking. Moreover, bioinformatics predictions were used to identify the signaling pathways involved. Finally, the mechanism behind its anti-EV71 action was confirmed through in vitro experiments. Results: Our investigation uncovered 25 active components in ML that targeted 231 specific genes. Of these genes, 29 correlated with the targets of EV71. Quercetin, a major ingredient in ML, was associated with 25 of these genes. According to the molecular docking results, Quercetin has a high binding affinity to the targets of ML and EV71. According to the KEGG pathway analysis, the antiviral effect of Quercetin against EV71 was found to be closely related to the NF-κB signaling pathway. The results of immunofluorescence and Western blotting showed that Quercetin significantly reduced the expression levels of VP1, TNF-α, and IL-1ß in EV71-infected human rhabdomyosarcoma cells. The phosphorylation level of NF-κB p65 was reduced, and the activation of NF-κB signaling pathway was suppressed by Quercetin. Furthermore, our results showed that Quercetin downregulated the expression of JNK, ERK, and p38 and their phosphorylation levels due to EV71 infection. Conclusion: With these findings in mind, we can conclude that inhibiting the NF-κB signaling pathway is a critical mechanism through which Quercetin exerts its anti-EV71 effectiveness.

Evaluating Prophylactic Effect of Bovine Colostrum on Intestinal Barrier Function in Zonulin Transgenic Mice: A Transcriptomic Study.

The intestinal barrier comprises a single layer of epithelial cells tightly joined to form a physical barrier. Disruption or compromise of the intestinal barrier can lead to the inadvertent activation of immune cells, potentially causing an increased risk of chronic inflammation in various tissues. Recent research has suggested that specific dietary components may influence the function of the intestinal barrier, potentially offering a means to prevent or mitigate inflammatory disorders. However, the precise mechanism underlying these effects remains unclear. Bovine colostrum (BC), the first milk from cows after calving, is a natural source of nutrients with immunomodulatory, anti-inflammatory, and gut-barrier fortifying properties. This novel study sought to investigate the transcriptome in BC-treated Zonulin transgenic mice (Ztm), characterized by dysbiotic microbiota, intestinal hyperpermeability, and mild hyperactivity, applying RNA sequencing. Seventy-five tissue samples from the duodenum, colon, and brain of Ztm and wild-type (WT) mice were dissected, processed, and RNA sequenced. The expression profiles were analyzed and integrated to identify differentially expressed genes (DEGs) and differentially expressed transcripts (DETs). These were then further examined using bioinformatics tools. RNA-seq analysis identified 1298 DEGs and 20,952 DETs in the paired (Ztm treatment vs. Ztm control) and reference (WT controls) groups. Of these, 733 DEGs and 10,476 DETs were upregulated, while 565 DEGs and 6097 DETs were downregulated. BC-treated Ztm female mice showed significant upregulation of cingulin (Cgn) and claudin 12 (Cldn12) duodenum and protein interactions, as well as molecular pathways and interactions pertaining to tight junctions, while BC-treated Ztm males displayed an upregulation of transcripts like occludin (Ocln) and Rho/Rac guanine nucleotide exchange factor 2 (Arhgf2) and cellular structures and interfaces, protein-protein interactions, and organization and response mechanisms. This comprehensive analysis reveals the influence of BC treatment on tight junctions (TJs) and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway gene expressions. The present study is the first to analyze intestinal and brain samples from BC-treated Ztm mice applying high-throughput RNA sequencing. This study revealed molecular interaction in intestinal barrier function and identified hub genes and their functional pathways and biological processes in response to BC treatment in Ztm mice. Further research is needed to validate these findings and explore their implications for dietary interventions aimed at improving intestinal barrier integrity and function. The MGH Institutional Animal Care and Use Committee authorized the animal study (2013N000013).

Bioactive glass in the treatment of ulcerative colitis to regulate the TLR4 / MyD88 / NF-κB pathway.

Ulcerative colitis (UC) is a chronic and recurrent intestinal disease of unknown aetiology, and the few treatments approved for UC have serious side effects. In this study, a new type of uniformly monodispersed calcium-enhanced radial mesoporous micro-nano bioactive glass (HCa-MBG) was prepared for UC treatment. We established cellular and rat UC models to explore the effects and mechanism of HCa-MBG and traditional BGs (45S5, 58S) on UC. The results showed that BGs significantly reduced the cellular expression of several inflammatory factors, such as IL-1ß, IL-6, TNF-α and NO. In the animal experiments, BGs were shown to repair the DSS-damaged colonic mucosa. Moreover, BGs downregulated the mRNA levels of the inflammatory factors IL-1ß, IL-6, TNF-α and iNOS, which were stimulated by DSS. BGs were also found to manage the expression of key proteins in NF-kB signal pathway. However, HCa-MBG was more effective than traditional BGs in terms of improving UC clinical manifestations and reducing the expression of inflammatory factors in rats. This study confirmed for the first time that BGs can be used as an adjuvant drug in UC treatment, thereby preventing UC progression.

Pinellia ternata (Thunb.) Breit. attenuates the allergic airway inflammation of cold asthma via inhibiting the activation of TLR4-medicated NF-kB and NLRP3 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Pinellia ternata (Thunb.) Breit. (PT) has been demonstrated to be effective against the allergic airway inflammation (AAI) in clinical practices, especially in cold asthma (CA). Until now, the active ingredients, protective effect, and possible mechanism of PT against CA remain unknown. AIM OF THE STUDY: The aim of this investigation was to examine the therapeutic impact and elucidate the underlying mechanism of PT on the AAI of CA. METHODS: The compositions of PT water extract were determined via the UPLC-Q-TOF-MS/MS. The ovalbumin (OVA) and cold-water baths were used to induce CA in female mice. Morphological characteristic observations, expectorant effect, bronchial hyperreactivity (BHR), excessive mucus secretion, and inflammatory factors were used to uncover the treatment effect of PT water extract. In addition, the mucin 5AC (MUC5AC) mRNA and protein levels and the aquaporin 5 (AQP5) mRNA and protein levels were detected via qRT-PCR, immunohistochemistry (IHC), and western blotting. Moreover, the protein expressions associated with the TLR4, NF-κB, and NLRP3 signaling pathway were monitored by western blot analysis. RESULTS: Thirty-eight compounds were identified from PT water extract. PT showed significant therapeutic effects on mice with cold asthma in terms of expectorant activity, histopathological changes, airway inflammation, mucus secretion, and hyperreactivity. PT exhibited good anti-inflammatory effects in vitro and in vivo. The expression levels of MUC5AC mRNA and protein decreased significantly, while AQP5 expression levels increased significantly in the lung tissues of mice after administration with PT as compared to mice induced by CA. Furthermore, the protein expressions of TLR4, p-iκB, p-p65, IL-1ß, IL-18, NLRP3, cleaved caspase-1, and ASC were markedly reduced following PT treatment. CONCLUSIONS: PT attenuated the AAI of CA by modulating Th1- and Th2-type cytokines. PT could inhibit the TLR4-medicated NF-kB signaling pathway and activate the NLRP3 inflammasome to reduce CA. This study provides an alternative therapeutic agent of the AAI of CA after administration with PT.

l-carnitine: Nutrition, pathology, and health benefits.

Carnitine is a medically needful nutrient that contributes in the production of energy and the metabolism of fatty acids. Bioavailability is higher in vegetarians than in people who eat meat. Deficits in carnitine transporters occur as a result of genetic mutations or in combination with other illnesses such like hepatic or renal disease. Carnitine deficit can arise in diseases such endocrine maladies, cardiomyopathy, diabetes, malnutrition, aging, sepsis, and cirrhosis due to abnormalities in carnitine regulation. The exogenously provided molecule is obviously useful in people with primary carnitine deficits, which can be life-threatening, and also some secondary deficiencies, including such organic acidurias: by eradicating hypotonia, muscle weakness, motor skills, and wasting are all improved l-carnitine (LC) have reported to improve myocardial functionality and metabolism in ischemic heart disease patients, as well as athletic performance in individuals with angina pectoris. Furthermore, although some intriguing data indicates that LC could be useful in a variety of conditions, including carnitine deficiency caused by long-term total parenteral supplementation or chronic hemodialysis, hyperlipidemias, and the prevention of anthracyclines and valproate-induced toxicity, such findings must be viewed with caution.

Momordica cochinchinensis (Gac) Seed Extracts Induce Apoptosis and Necrosis in Melanoma Cells.

Momordica cochinchinensis is a herbal medicine used throughout Asia and this study investigated the antimelanoma potentials and molecular mechanisms of M. cochinchinensis seed with emphasis on extraction to optimise bioactivity. Overall, the aqueous extract was superior, with a wider diversity and higher concentration of proteins and peptides that was more cytotoxic to the melanoma cells than other extraction solvents. The IC50 of the aqueous extract on melanoma cells were similar to treatment with current anticancer drugs, vemurafenib and cisplatin. This cytotoxicity was cancer-specific with lower cytotoxic effects on HaCaT epidermal keratinocytes. Cytotoxicity correlated with MAPK signalling pathways leading to apoptosis and necrosis induced by triggering tumour necrosis factor receptor-1 (TNFR1), reducing the expression of nuclear factor kappa B (NF-kB), and suppression of BRAF/MEK. This efficacy of M. cochinchinensis seed extracts on melanoma cells provides a platform for future clinical trials as potent adjunctive therapy for metastatic melanoma.

Paeonol ameliorates diabetic erectile dysfunction by inhibiting HMGB1/RAGE/NF-kB pathway.

BACKGROUND: The management of diabetes mellitus-induced erectile dysfunction (DMED) is progressively becoming tricky due to the surge in the number of patients and the poor efficiency of phosphodiesterase type 5 inhibitors in DMED. Paeonol (Pae), as a traditional Chinese medicine, has been more and more widely used in the treatment of diabetic complications. However, whether Pae could be a potential therapeutic drug of DMED needs to be further evaluated. OBJECTIVES: To investigate the pharmacological effect and possible mechanism of Pae in the treatment of DMED. METHODS: Intraperitoneal streptozotocin injection and an apomorphine test were used to construct the model of DMED. Seventeen DMED rats were divided into two groups: DMED group (n = 8) and DMED+Pae group (Pae; 100 mg/kg/d; oral administration; n = 9). In addition, there were still 10 normal age-matched male rats as control group. Four weeks later, the cavernous nerve electric stimulation was carried out to measure the erectile response. Moreover, the corpus cavernosum smooth muscle cells (CCSMCs) were primarily isolated and exposed to high glucose (HG) stimulation, Pae treatment and glycyrrhizin (GL; the selective inhibitor of HMGB1). After an incubation for 1 week, the CCSMCs were harvested for detection. RESULTS: The impairment of erectile function was observed in DMED rats compared with control samples, accompanied by the upregulation of HMGB1/RAGE/NF-κB Pathway. The lower nitric oxide and cGMP level and the higher level of inflammation, fibrosis, and apoptosis were also observed in DMED rats. It showed contrast that Pae treatment could improve the erectile function, as well as histologic alteration and related molecular changes. In addition, Pae could downregulate the HMGB1/RAGE/NF-κB pathway to regulate the apoptosis and inflammation levels of CCSMCs in high-glucose conditions, which is similar to the results of GL treatment. CONCLUSION: Pae alleviated ED in DMED rats, likely by inhibiting HMGB1/RAGE/NF-κB Pathway, inflammatory, apoptosis, and fibrotic activity, and moderating endothelial dysfunction. Our study provide evidence for a potential new therapy for DMED.

Effect of leaves and seeds of Achyranthes aspera as feed supplements on the immunological and stress parameters and related gene expressions of Asian catfish (Clarias batrachus).

The immunostimularory properties of Achyranthes aspera leaves and seeds supplemented feeds were evaluated in Asian catfish, Clarias batrachus (0.352±0.008 g). The experimental feeds contained 0.25% leaves (EFL1), 0.5% leaves (EFL2), 0.5% seeds (EFS) and 0% leaves or seeds (control feed; CF). In CF, leaves and seeds were absent. Fish were immunized with chicken-RBC after 60 days of feeding. The blood and tissue samples were collected on 7th, 14th and 21st days after immunization for various assays. The average weight of magur was significantly higher in EFS compared to the other treatments throughout the study period and EFL2 followed this group. Serum lysozyme level of fish was significantly higher in EFS on 7th and 14th days and in EFS and EFL2 on 21st day after immunization compared to the other treatments. Myeloperoxidase and nitric oxide synthase levels were always significantly higher in EFS diet fed fish compared to other treatments. The highest hemagglutination titer level was found in EFS throughout the study period. Thiobarbituric acid reactive substances (TBARS) and carbonyl protein levels were significantly lower in liver and kidney of enriched diets fed magur compared to CF treatment. TBARS and carbonyl protein levels were minimum in EFS diets fed fish. In EFS and EFL2 treatments, the expressions of TNF-α, iNOS and NF-kB were significantly higher compared to the CF group. A. aspera seeds and leaves showed significant immunostimulatory properties in Asian catfish fry.

Rosa davurica inhibits skin photoaging via regulating MAPK/AP-1, NF-κB, and Nrf2/HO-1 signaling in UVB-irradiated HaCaTs.

Rosa davurica is widely used to treat various kinds of diseases because of its high antioxidant, antiviral and anti-inflammatory activities. This use of plant-based materials as medicine is called phytomedicine and has been widely practiced since time immemorial. However, the pharmacological mechanism of R. davurica in skin photoaging is not yet fully understood. Therefore, this study was carried out to evaluate the recovery effects of R. davurica leaf extracts (RDE) in UVB-irradiated human skin keratinocytes (HaCaTs) and investigate whether RDE is a potential therapeutic agent against skin photoaging. The expression of aging-related markers including mitogen-activated protein kinases/activator protein 1 (MAPK/AP-1), nuclear factor-κB (NF-κB), and nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) was evaluated using Western blot analysis. The reactive oxygen species (ROS) was also used by FACS in HaCaTs. Findings indicated that RDE is efficient in scavenging free radicals and dose-dependently reducing ROS generation. Furthermore, RDE notably decreased UVB-induced matrix metalloproteinase-1 (MMP-1) expression through inhibition of MAPK/AP-1 and NF-κB signaling pathways as well as induced blocking of extracellular matrix (ECM) degradation in UVB-irradiated HaCaTs. In addition, RDE improved Nrf2/HO-1 signaling that increases oxidative defense capacity and enhances transforming growth factor-beta (TGF-ß) signaling activation to promote procollagen type I synthesis, relieving UVB-induced skin cell damage. In conclusion, the protective effects of RDE on skin cellular components suggest that it has a high biological potential for skin protection from UVB-induced skin photoaging and is a good candidate for drug and cosmetic application.

The interplay of epilepsy with impaired mitophagy and autophagy linked dementia (MAD): A review of therapeutic approaches.

The duration and, age of dementia have been linked to a higher risk of seizures. The exact mechanism that drives epileptogenesis in impaired mitophagy and autophagy linked dementia (MAD) is fully defined after reviewing the Scopus, Publon, and Pubmed databases. The epileptogenesis in patients with Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD) is due to involvement of amyloid plaques (Aß), phosphorylated tau (pTau), Parkin, NF-kB and NLRP3 inflammasome. Microglia, the prime protective and inflammatory cells in the brain exert crosstalk between mitophagy and inflammation. Several researchers believed that the inflammatory brain cells microglia could be a therapeutic target for the treatment of a MAD associated epilepsy. There are conventional antiepileptic drugs such as gabapentin, lamotrigine, phenytoin sodium, carbamazepine, oxcarbazepine, felbamate, lamotrigine, valproate sodium, and topiramate are prescribed by a psychiatrist to suppress seizure frequency. Also, the conventional drugs generate serious adverse effects and synergises dementia characteristics. The adverse effect of carbamazepine is neurotoxic and also, damages haemopoietic system and respiratory tract. The phenytoin treatment causes cerebellar defect and anemia. Dementia and epilepsy have a complicated relationship, thus targeting mitophagy for cure of epileptic dementia makes sense. Complementary and alternative medicine (CAM) is one of the rising strategies by many patients of the world, not only to suppress seizure frequency but also to mitigate dementia characteristics of patients. Therefore our present review focus on the interplay between epilepsy and MAD and their treatment with CAM approaches.

Huangqi Guizhi Wuwu Decoction can prevent and treat oxaliplatin-induced neuropathic pain by TNFα/IL-1ß/IL-6/MAPK/NF-kB pathway.

OBJECTIVE: This study explored the effects and mechanisms of Huangqi Guizhi Wuwu Decoction on chemotherapy-induced neuropathic pain (CINP). METHODS: Bodyweight and related behavioral testing of the rat model were utilized to investigate the effects of Huangqi Guizhi Wuwu Decoction on CINP. ELISA was used to measure the levels of TNF-α, IL-1ß, and IL-6, in the serum of chronic CINP rats. Immunohistochemistry and Western blot analysis were performed to detect the expression of MAPK pathway related-proteins namely ERK1/2, p38, and JNK, and the expression of downstream essential proteins such as c-Fos, CREB, and NF-κB. RESULTS: Body weight and related behavioral testing of the rat model suggests that Huangqi Guizhi Wuwu Decoction can improve the slow weight gain of oxaliplatin-induced chronic CINP model rats and effectively prevent and treat oxaliplatin-induced regular CIPN rat model of hyperalgesia. It can also oppress the mechanical pain threshold, cold pain threshold, and heat pain threshold decreased. Furthermore, by ELISA, immunohistochemistry, and western blot analysis, we found that Huangqi Guizhi Wuwu Decoction can down-regulate the levels of TNF-α, IL-1ß, and IL-6 in the serum of chronic CINP rats induced by oxaliplatin. It also suppresses the expression of MAPK pathway related-proteins ERK1/2, p38, and JNK. This results in a decrease in the expression of downstream essential proteins, c-Fos, CREB, and Nf-κB. CONCLUSIONS: In conclusion, we found that Huangqi Guizhi Wuwu Decoction can combat nerve cell injury, reduce pain sensitization, and prevent and repair the damage of nerve cells in the oxaliplatin CINP model rats via TNFα/IL-1ß/IL-6/MAPK/NF-kB pathway.