Proteasome and Its Inhibitors

The Proteasome is the major degradation pathway where the misfolded proteins during protein synthesis and other proteins are proteolyzed. It is present in all eukaryotic cells, archaea, and some bacteria. It is a multicatalytic protease, composed of multiple catalytic and regulatory proteins. It possesses three or four different peptidase activities, including trypsin-like, chymotrypsin-like, and peptidylglutamyl-peptide hydrolyzing activities. Most of proteins are ubiquitinated prior to the proteasome degradation. It is estimated that about 20% of 26S proteasomes are engaged in protein degradation in the absence of proteotoxic stress [1">.
Proteasome inhibitors have found applications as therapeutic drugs against diseases like cancer, and wide application in laboratory research. Bortezomib, also called PS-341, Velcade, and MG-341, is an FDA-approved drug for multiple myeloma and mantle cell lymphoma. It is also used in laboratory experiments to inhibit proteasome activity [2">. Several other proteasome inhibitors are proposed to be useful drugs or are undergoing clinical trials and testing, including disulfiram, epigallocatechin-3-gallate, Salinosporamide A, carfilzomib, ONX 0912, CEP-18770, and MLN9708. Silva MC et al. pre-treated neuronal cells with carfilzomib to inhibit proteasome to understand the effect of tau degrader QC-01–175 [3">. GNF6702 inhibits the kinetoplastid proteasome (while possessing no activity against mammalian proteasome) and has been proposed to represent a new class of drugs for Chagas disease, leishmaniasis, and sleeping sickness [4">.
Labome surveys literature for antibodies, instruments, and other reagents. Among the formal publications that contain the explicit references to proteasome inhibitors, MG132 is the predominant choice cited among the articles. Table 1 lists the number of publications for major proteasome inhibitors. Major features of these three proteasome inhibitors are listed in Table 2.

MG132 protects against renal dysfunction by regulating Akt

Diabetic nephropathy (DN), the leading cause of end-stage renal disease (ESRD). To date, mounting evidence has shown that inflammation may contribute to the pathogenesis of DN. Recent reports have shown that proteasome inhibitors display cytoprotection by reducing the phosphorylation of Akt, a serine/threonine kinase, plays a critical role in cellular survival and metabolism and can crosstalk with inflammation. Therefore, we hypothesized that MG132, specific proteasome inhibitor, could provide renoprotection by suppressing Akt-mediated inflammation in DN. In vivo, male Sprague-Dawley rats were divided into normal control group (NC), diabetic nephropathy group (DN), DN model plus MG132 treatment group (MG132), and DN model plus deguelin treatment group (Deguelin)(deguelin, a specific inhibitor of Akt). In vitro, a human glomerular mesangial cell lines (HMCs) was exposed to 5.5 mmol/L glucose (CON), 30 mmol/L glucose (HG), 30 mmol/L glucose with 0.5 umol/L MG132 (MG132) and 30 mmol/L glucose with 5 umol/L deguelin (Deguelin). Compared with NC, DN showed a significant increase in the urinary protein excretion rate and inflammatory cytokines, as well as p-Akt. Compared with CON, HMCs co-cultured with HG was notably proliferated, which is in accord with α-smooth muscle actin (α-SMA) expression. These alterations were inhibited by administration of MG132 or deguelin. In conclusion, MG132 significantly inhibits the development of DN by regulating Akt phosphorylation-mediated inflammatory activation.

MG-132

133407-82-6 (carbobenzoxy-Leu-Leu-leucinal) as a peptide aldehyde effectively blocks the proteolytic activity of proteasome complex.9 Proteasome inhibitors including MG132 have been shown to induce apoptotic cell death through formation of ROS. ROS formation and GSH depletion due to proteasome inhibitors may cause mitochondrial dysfunction and subsequent cytochrome c release, which leads to cell viability loss1, 2.

MG132 dose dependently inhibited the growth of A549 cells with an IC50 of approximately 20 µM. MG132 also reduced the growth of human cervical HeLa cancer cells with an IC50 of approximately 5 µM. Treatment with 0.5 µM MG132 significantly decreased the growth of HeLa cells and induced cell death as well. Cell growth inhibition by MG132 depends on incubation doses of that and cell types3.

MG132 significantly induced a G1 phase arrest of the cell cycle. It inhibits the growth of HT-29 colon cancer cells via inducing G2/M cell cycle arrest4, causes MG-63 osteosarcoma cell arrest at G2/M phase5, prolongs the duration of G0/G1 arrest in MnCl2-treated A549 cells21 and induces a G1 arrest in gastric carcinoma cells6. Deregulation of the ubiquitin-proteasomal system by MG132 can result in different cell cycle phase arrests depending on various cancer cell lines.

Proteasome inhibitors including MG132 have been shown to induce apoptotic cell death through formation of ROS1, 2, 7. MG132 inhibited the growth of human A549 cells via inducing the cell cycle arrest as well as triggering apoptosis, which was in part correlated with the changes of ROS and GSH levels.

References:
1. Ling YH, Liebes L, Zou Y and Perez-Soler R. Reactive oxygen species generation and mitochondrial dysfunction in the apoptotic response to Bortezomib, a novel proteasome inhibitor, in human H460 non-small cell lung cancer cells, 2003; 278: 33714–33723.
2. Qiu JH, Asai A, Chi S, et al. Proteasome inhibitors induce cytochrome c-caspase-3-like protease-mediated apoptosis in cultured cortical neurons. J Neurosci 2000; 20: 259–265.
3. YH. Han, WH. Park, MG132 as a proteasome inhibitor induces cell growth inhibition and cell death in A549 lung cancer cells via influencing reactive oxygen species and GSH level, Human and Experimental Toxicology, 29(7) 607–614.
4. Wu WK, Wu YC, Yu L, et al. Induction of autophagy by proteasome inhibitor is associated with proliferative arrest in colon cancer cells. Biochem Biophys Res Commun 2008; 374: 258–263.
5. Yan XB, Yang DS, Gao X, et al. Caspase-8 dependent osteosarcoma cell apoptosis induced by proteasome inhibitor MG132. Cell Biol Int 2007; 31: 1136–1143.
6. ZhangW, Tong Q, Li S, Wang X andWang Q.MG-132 inhibits telomerase activity, induces apoptosis and G(1) arrest associated with upregulated p27kip1 expression and downregulated survivin expression in gastric carcinoma cells. Cancer Invest 2008; 26:1032–1036.
7. Wu HM, Chi KH, Lin WW. Proteasome inhibitors stimulate activator protein-1 pathway via reactive oxygen species production. FEBS Lett 2002; 526: 101–105.

(S)-MG132

The ubiquitin-proteasome pathway plays an integral role in the selective degradation of intracellular proteins. While important for clearing damaged or misfolded proteins, this proteolytic pathway also regulates the availability of key proteins involved in the control of inflammatory processes, cell cycle regulation, and gene expression.1,2 (S)-MG132 is a potent, reversible and cell permeable proteasome inhibitor that inhibits cell growth in B16 and IPC227F cells with IC50 values of 42 and 77 nM, respectively.3 133407-82-6 at 10 µM inhibits NF-κB activation, sensitizing a variety of carcinoma cell lines to apoptosis.4

Product Description References
1. Lee, D.H., and Goldberg, A.L. Proteasome inhibitors: Valuable new tools for cell biologists Trends in Cell Biology 8, 397-403 (1998).

2. Elliott, P.J., Zollner, T.M., and Boehncke, W.H. Proteasome inhibition: A new anti-inflammatory strategy Journal of Molecular Medicine 81, 235-245 (2003).

3. Vivier, M., Rapp, M., Papon, J., et al. Synthesis, radiosynthesis, and biological evaluation of new proteasome inhibitors in a tumor targeting approach Journal of Medicinal Chemistry 51(4), 1043-1047 (2008).

4. Arlt, A., Vorndamm, J., Breitenbroich, M., et al. Inhibition of NF- k B sensitizes human pancreatic carcinoma cells to apoptosis induced by etoposide (VP16) or doxorubicin Oncogene 20, 859-868 (2001).

Grapiprant (Synonyms: CJ-023423; RQ-00000007; AAT-007)

Grapiprant is a selective EP4 receptor antagonist whose physiological ligand is prostaglandin E2 (PGE2). Target: prostaglandin receptor in vitro: Grapiprant is a novel pharmacologically active ingredient, acts as a selective EP4 receptor antagonist whose physiological ligand is prostaglandin E2 (PGE2). [1"> in vivo: Grapiprant is currently under development for use in humans and dogs for the control of pain and inflammation associated with osteoarthritis. [1"> Results suggested the safety of long-term oral administration of grapiprant to dogs. Efficacy of grapiprant in the treatment of dogs with osteoarthritis needs to be evaluated in other studies. [2">

CJ-023,423 is also effective in models of acute and chronic inflammatory pain. CJ-023,423 significantly reduces mechanical hyperalgesia in the carrageenan model. Furthermore, CJ-023,423 significantly reverses complete Freund's adjuvant-induced chronic inflammatory pain response. Taken together, the present data indicate that CJ-023,423, a highly potent and selective antagonist of both human and rat EP(4) receptors, produces antihyperalgesic effects in animal models of inflammatory pain. Thus, specific blockade of the EP(4) receptor signaling may represent a novel therapeutic approach for the treatment of inflammatory pain.

Grapiprant | EP4 Receptor antagonist

Grapiprant (415903-37-6) is a potent (Ki = 13 nM for human and 20 nM for rat) and selective prostaglandin EP4 receptor antagonist.1 It produces antihyperalgesic effects in animal models of pain, and has significant anti-inflammatory effects in a rat model of adjuvant-induced arthritis.2 EP4 receptors have been shown to be involved in PGE2 stimulation of Th1 differentiation and Th17 expansion revealing a potential role for PGE2 receptors in immunosuppression.3,4 Grapiprant/Pembrolizumab combination is in clinical trials for advanced or metastatic NSCLC adenocarcinoma.5

References/Citations

1) Nakao et al. (2007), CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties; J. Pharmacol. Exp. Ther. 332 686
2) Okumura et al. (2008), Effects of the selective EP4 antagonist, CJ-023,423 on chronic inflammation and bone destruction in rat adjuvant-induced arthritis; J. Pharm. Pharmacol. 60 7235
3) Chen et al. (2010), A novel antagonist of the prostaglandin E2 EP4 receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models; Br. J. Pharmacol. 160 292
4) Wang and DuBois (2016), Wang and DuBois (2016), The Role of Prostaglandin E2 in Tumor-Associated Immunosuppression; Trends Mol. Med. 22 1
5) NCT03696212 and NCT03658772

Engineers at NASA's Jet Propulsion Laboratory (JPL) in Pasadena, California, have installed the main robotic arm on the Mars 2020 rover, according to a recent JPL release.

The main arm includes five electrical motors and five joints, known as the shoulder azimuth joint, shoulder elevation joint, elbow joint, wrist joint and turret joint. Measuring 2.1 meters long, the arm will allow the rover to work as a human geologist by holding and using science tools with its turret, according to JPL, according to agencies. China Industrial Robotic Arm

You have to give a hand to our rover arm installation team, said Ryan van Schilifgaarde, a support engineer at JPL for Mars 2020 assembly. They made an extremely intricate operation look easy. We're looking forward to more of the same when the arm will receive its turret in the next few weeks.

The rover's turret will include high-definition cameras, science instruments, and a percussive drill and coring mechanism. Those tools will be used to analyze and collect samples of Martian rock and soil, which will be cached on the surface for return to Earth by a future mission, said JPL.

Mars 2020 is scheduled to launch from Cape Canaveral Air Force Station in Florida in July 2020, and land at Jezero Crater on Mars on Feb. 18, 2021.
https://www.crprobotic.com/industrialroboticnews/295.html

Pandora jewellery store employee shames man over cheap engagement ring

Engagements are usually one of the most memorable moments of your life, Cheap Jewelry Sites and for some, choosing the perfect ring is a very big part of it.So the last thing you'd expect is for others to make comments on the quality of your carefully chosen ring because no matter what the price tag was, it's about what it symbolises right?

So one woman was understandably upset when an employee mocked the ring her future- husband was buying her and labelled it as too "cheap".

Ariel Desiree McRae and her husband-to-be were at a branch of Pandora jewellers in Nashville, Tennessee, when the employee made the rude comment.The Pandora staff member said: "Y'all can you believe that some men get these as engagement rings? How pathetic."

An infuriated McRae shared her situation on Facebook, explaining how her husband saved up $130 ($191NZD) to buy the special ring, despite the couple having little-to-no money.My husband doesn't have a lot, neither of us do. We scrape and scrape to pay bills and put food in our bellies, but after almost 2 years of dating we decided that we couldn't wait anymore, so we didn't.

"I wasn't even thinking about rings, I just wanted to marry my best friend, but he wouldn't have it. He scraped up just enough money to buy me two matching rings from Pandora. Sterling silver and CZ to be exact. That's what sits on my ring finger, and I am so in love with them.

"While we were purchasing my rings however, another lady that was working there came over to help the lady selling them to us. She said, 'Y'all can you believe that some men get these as engagement rings? When she said that I watched my now husband's face fall. He already felt bad because he couldn't afford the pear-shaped set that so obviously had my heart and covered my Pinterest page. He already felt like a failure, asking me again and again 'Are you sure you'll be happy with these? Are you sure this is okay?' He was so upset at the idea of not making me happy enough and of me not wanting to marry him because my rings didn't cost enough money or weren't flashy enough.

Coated steel cable from Carl Stahl TECHNOCABLES: an overview of the benefits to you

For example, in the case of cable systems that run over pulleys, we recommend using coated cables in order to achieve a high bending cycle and a long service life. With higher bending cycles a longer service life could be achieved.zinc coated steel wire strand
Carl Stahl Technocables uses polyamide as the standard coating material. Polyamide is an optimum cable coating, distinguished by its high wear resistance and high bending cycle capability. A further advantage of the coated cables: The coating protects the rope from dirt.
We recommend PA12 if the cable runs over a pulley or if flexibility is the main priority. This is our standard coating material.
Furthermore, the coating keeps the manufacturing lubricant within the rope. This film of oil functions as a lubricant between the individual wires and strands, thereby reducing wear on the cable.
Are high temperatures or good sliding properties required of your steel wire rope? Then we use special materials for coating of the steel wire rope. For example, we recommend FEP/PTFE for temperatures of between -190°C and + 205° C.
We can also offer PA6. PA6 is stiffer than PA12 and is therefore not suitable for pulleys. However, PA6 has better sliding properties and is therefore highly suitable as a guide cable for example.
Depending on the application, the appropriate coating material is used. Don’t you know which wire rope coating is the right for your rope application? - We're glad to help you finding the right material.

Carbon Steel Wire

Carbon steel is steel in which the main interstitial alloying constituent is carbon in the range of 0.12–2.0%. The American Iron and Steel Institute (AISI) definition says: Steel is considered to be carbon steel when no minimum content is specified or required for chromium, cobalt, molybdenum, nickel, niobium, titanium, tungsten, vanadium or zirconium, or any other element to be added to obtain a desired alloying effect; when the specified minimum for copper does not exceed 0.40 percent; or when the maximum content specified for any of the following elements does not exceed the percentages noted: manganese 1.65, silicon 0.60, copper 0.60. The term "carbon steel" may also be used in reference to steel which is not stainless steel; in this use carbon steel may include alloy steels. As the carbon percentage content rises, steel has the ability to become harder and stronger through heat treating; however, it becomes less ductile. Regardless of the heat treatment, a higher carbon content reduces weldability. In carbon steels, the higher carbon content lowers the melting point.carbon steel flat wire
Spring Works Utah specializes in the custom manufacture of wire springs, flat springs, and wire products using Brite Basic CA260 Carbon Steel Wire material. Our extensive inventory and design experience makes us a resource for customer requests as well as a preferred supplier to spring manufacturers worldwide. We know choosing the right material can be challenging and many times the most important aspect of your design. We will assist you in picking the best material for your specific application, all at the right price. Allow us to be your custom manufacturer utilizing Brite Basic CA260 material.